RS59031B1 - Personalizovana imunoterapija protiv nekoliko tumora nervnih ćelija i mozga - Google Patents

Personalizovana imunoterapija protiv nekoliko tumora nervnih ćelija i mozga

Info

Publication number
RS59031B1
RS59031B1 RS20190775A RSP20190775A RS59031B1 RS 59031 B1 RS59031 B1 RS 59031B1 RS 20190775 A RS20190775 A RS 20190775A RS P20190775 A RSP20190775 A RS P20190775A RS 59031 B1 RS59031 B1 RS 59031B1
Authority
RS
Serbia
Prior art keywords
cell
cells
peptide
cancer
tumor
Prior art date
Application number
RS20190775A
Other languages
English (en)
Inventor
Toni Weinschenk
Jens Fritsche
Steffen Walter
Norbert Hilf
Oliver Schoor
Harpreet Singh
Sabrina Kuttruff-Coqui
Colette Song
Original Assignee
Immatics Biotechnologies Gmbh
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Immatics Biotechnologies Gmbh filed Critical Immatics Biotechnologies Gmbh
Publication of RS59031B1 publication Critical patent/RS59031B1/sr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/19—Dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/20—Cellular immunotherapy characterised by the effect or the function of the cells
    • A61K40/24—Antigen-presenting cells [APC]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
    • A61K40/32—T-cell receptors [TCR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70517—CD8
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70539—MHC-molecules, e.g. HLA-molecules
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • 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
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2833—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against MHC-molecules, e.g. HLA-molecules
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against enzymes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • C12N5/0638—Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0012—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7)
    • C12N9/0026—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7) acting on CH-NH groups of donors (1.5)
    • C12N9/0032—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7) acting on CH-NH groups of donors (1.5) with oxygen as acceptor (1.5.3)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0071—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14)
    • C12N9/0083—Miscellaneous (1.14.99)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/1025—Acyltransferases (2.3)
    • C12N9/1029—Acyltransferases (2.3) transferring groups other than amino-acyl groups (2.3.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1205—Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1229—Phosphotransferases with a phosphate group as acceptor (2.7.4)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/13—Transferases (2.) transferring sulfur containing groups (2.8)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22—Ribonucleases [RNase]; Deoxyribonucleases [DNase]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/93—Ligases (6)
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y105/00—Oxidoreductases acting on the CH-NH group of donors (1.5)
    • C12Y105/03—Oxidoreductases acting on the CH-NH group of donors (1.5) with oxygen as acceptor (1.5.3)
    • C12Y105/03016—Spermine oxidase (1.5.3.16)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
    • C12Y207/04—Phosphotransferases with a phosphate group as acceptor (2.7.4)
    • C12Y207/04008—Guanylate kinase (2.7.4.8)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/03—Phosphoric monoester hydrolases (3.1.3)
    • C12Y301/03048—Protein-tyrosine-phosphatase (3.1.3.48)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y603/00—Ligases forming carbon-nitrogen bonds (6.3)
    • C12Y603/02—Acid—amino-acid ligases (peptide synthases)(6.3.2)
    • C12Y603/02019—Ubiquitin-protein ligase (6.3.2.19), i.e. ubiquitin-conjugating enzyme
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5158—Antigen-pulsed cells, e.g. T-cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • A61K2039/55527—Interleukins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • A61K2039/55527—Interleukins
    • A61K2039/55533—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/80—Vaccine for a specifically defined cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/47—Brain; Nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2510/00—Genetically modified cells
    • 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
    • C12Q2600/136—Screening for pharmacological compounds
    • 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
    • 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
    • C12Q2600/16—Primer sets for multiplex assays

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Wood Science & Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Biomedical Technology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Microbiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Mycology (AREA)
  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Virology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Hospice & Palliative Care (AREA)
  • Physics & Mathematics (AREA)

Description

Predmetni pronalazak odnosi se na peptid, nukleinske kiseline i ćelije za upotrebu u imunoterapijskim metodama. Predmetni pronalazak se konkretno odnosi na imunoterapiju raka. Pored toga, predmetni pronalazak odnosi se na peptidni epitop tumor-asocirane citotoksične T ćelije (CTL), samostalno ili u kombinaciji sa drugim tumor-asociranim peptidima koji predstavljaju aktivne farmaceutske sastojke smeša za vakcinu koji stimulišu antitumorske imunske odgovore. Predmetni pronalazak odnosi se na specifičnu peptidnu sekvencu dobijenu iz HLA molekula klase I humanih tumorskih ćelija koja može da se koristi u smešama za vakcinu za izazivanje antitumorskih imunskih odgovora, kao i na metod za obezbeđivanje optimalnih vakcina osobama kojima su potrebne.
Osnovne informacije o pronalasku
Gliomi su moždani tumori koji potiču od glijalnih ćelija u nervnom sistemu. Glijalne ćelije, koje se obično nazivaju neuroglija ili jednostavno glija, su ne-neuronske ćelije koje obezbeđuju potporu i ishranu, održavaju homeostazu, obrazuju mijelin i učestvuju u prenošenju signala u nervnom sistemu. Dve najvažnije podgrupe glioma su astrocitomi i oligodendrogliomi, koji su dobili naziv u skladu sa vrstom normalnih glijalnih ćelija iz kojih vode poreklo (astrociti, odnosno oligodendrociti). Pripadajući podgrupi astrocitoma, glioblastoma multiforme (koji se u daljem tekstu naziva glioblastom) najčešći je maligni tumor mozga kod odraslih i čini približno 40% svih malignih tumora mozga i približno 50% glioma. On vrši agresivnu invaziju centralnog nervnog sistema i rangiran je najvećim stepenom malignosti (gradus IV) među svim gliomima. Iako postoji konstantan napredak u njihovom lečenju zbog napredaka u neuroimidžingu, mikrohirurgiji, raznovrsnim opcijama lečenja, kao što su temozolomid ili zračenje, glioblastomi ostaju neizlečivi. Stopa smrtnosti ovog tumora mozga je veoma visoka: prosečni očekivani životni vek iznosi 9 do 12 meseci nakon prvog postavljanja dijagnoze. Stopa petogodišnjeg preživljavanja u toku perioda opservacije između 1986. i 1990. godine iznosila je 8,0%. Do danas, stopa petogodišnjeg preživljavanja nakon agresivne terapije koja obuhvata opsežnu resekciju tumora je i dalje manja od 10%. U skladu sa navedenim, postoji snažna medicinska potreba za alternativnim i efikasnim terapijskim metodom.
Tumorske ćelije glioblastoma su najnediferenciranije ćelije među tumorima mozga, tako da tumorske ćelije imaju visok potencijal za migraciju i proliferaciju i visoko su invazivne, što za posledicu ima veoma lošu prognozu. Glioblastomi dovode do smrtnog ishoda zbog brzog, agresivnog i infiltrativnog rasta u mozgu. Infiltrativni obrazac rasta je odgovoran za neresektabilnu prirodu ovih tumora. Glioblastomi su takođe relativno rezistentni na zračenje i hemioterapiju, te su zato stope postterapijske rekurencije visoke. Pored toga, imunski odgovor na neoplastične ćelije je prilično neefikasan u kompletnoj eradikaciji svih neoplastičnih ćelija nakon resekcije i zračne terapije.
Glioblastom se klasifikuje kao primarni glioblastom (de novo) i sekundarni glioblastom, u zavisnosti od razlika u genskom mehanizmu tokom maligne transformacije nediferenciranih astrocita ili glijalnih prekursorskih ćelija. Sekundarni glioblastom se javlja kod mlađe populacije starosti do 45 godina. U toku 4 do 5 godina, u proseku, sekundarni glioblastom se razvija od astrocitoma niskog stepena do nediferenciranog astrocitoma. Suprotno tome, primarni glioblastom se predominantno javlja u starijoj populaciji sa prosečnom starošću od 55 godina. Uopšteno, primarni glioblastom se javlja kao fulminantni glioblastom koji karakteriše progresija tumora unutar 3 meseca od stanja bez kliničkih ili patoloških abnormalnosti (Pathology and Genetics of the Nervous Systems. 29-39 (IARC Press, Lyon, France, 2000)).
Glioblastom migrira duž mijelinizovanih nerava i širi se u čitavom centralnom nervnom sistemu. U većini slučajeva, hirurško lečenje dovodi samo do ograničenog održivog terapijskog efekta. Maligne ćelije glioma izbegavaju detekciju od strane imunskog sistema domaćina tako što proizvode imunosupresivne supstance koje narušavaju proliferaciju T ćelija i proizvodnju imunostimulišućeg citokina IL-2.
Intrakranijalne neoplazme mogu nastati od bilo koje strukture ili vrste ćelija prisutne u CNS-u, uključujući mozak, moždanice, hipofizu, lobanju i čak i rezidualno embrionsko tkivo. Ukupna godišnja incidenca primarnih tumora mozga u Sjedinjenim Američkim Državama iznosi 14 slučajeva na 100.000. Najčešći primarni tumori mozga su meningeomi, koji čine 27% svih primarnih tumora mozga, i glioblastomi, koji čine 23% svih primarnih tumora mozga (pri čemu glioblastomi čine 40% malignih tumora mozga kod odraslih). Mnogi od ovih tumora su agresivni i visokog su gradusa. Primarni tumori mozga su najčešći solidni tumori kod dece i drugi su najčešći uzrok smrti usled raka nakon leukemije kod dece.
Potraga za efikasnom terapijom za glioblastome kod pacijenata se i danas sprovodi. Imunoterapija ili lečenje putem regrutovanja imunskog sistema, za borbu protiv ovih neoplastičnih ćelija je ispitivana.
Postoji kliničko ispitivanje koje je u toku sa IMA950, multipeptidnom vakcinom, koje u Velikoj Britaniji sprovodi Immatics biotechnologies (Tübingen, Nemačka). Peptidi u vakcini su isključivo HLA-A*02 peptidi.
WO 2011/051278 A1, WO 2011/051276 A1, WO 2012/031122 A2 i Chi-Cheng Huang et al.: „Concurrent Gene Signatures for Han Chinese Breast Cancers“, PLoS ONE, svezak 8, br. 10, 3. oktobar 2013. strana e76421) iznose mikročipove za proteine i gensku ekspresiju koji su korišćeni za dobijanje genskih potpisa za npr. karcinome dojke, tj. dijagnozu. Patenti WO 2011/051278 A1 i WO 2011/051276 A1 iznose afinitetne ligande u obliku antitela. U patentu WO 2012/031122 A2 izneta je reaktivnost autoantitela, mehanizam koji se razlikuje od MHC sistema.
I dalje postoji potreba za novom efikasnom i bezbednom opcijom lečenja za glioblastom i meduloblastom i druge tumore koji pokazuju prekomernu ekspresiju proteina predmetnog pronalaska, koja bi poboljšala stanje pacijenata sa drugim HLA alelima ili kombinacijama alela bez primene hemioterapijskih agenasa ili drugih agenasa koji mogu imati ozbiljna neželjena dejstva.
Kratak pregled pronalaska
U prvom aspektu predmetnog pronalaska, predmetni pronalazak odnosi se na peptid koji sadrži ID BR. SEKV 28, ili njegovu farmaceutski prihvatljivu so.
U sledećim tabelama prikazani su peptidi u skladu sa predmetnim pronalaskom, njihovi odgovarajući ID BR. SEKV i prospektivni izvorni proteini za ove peptide. Svi peptidi u tabelama 1a, 1b i 1c vezuju se za alel HLA-A*02, a peptidi u tabelama 1d i 1e se vezuju za HLA-DR alele.
Peptidi klase II u tabelama 1d i 1e su naročito korisni u lečenju malignih tumora koji prekomerno eksprimiraju i/ili prekomerno prezentuju polipeptide BCAN, BIRC5 i/ili PTPRZ1.
Tabela 1a: Peptidi predmetno pronalaska
41 DPP3-001 FLYNEALYSL DPP3/BBS1
S* = opciono fosforilisani serin
Tabela 1b: Predstavleni dodatni e tidi
Tabela 1c: Dodatni peptidi koi su prekomerno eksprimirani u lioblastomu
Tabela 1d: Predstavleni e tidi MHC klase II
Tabela 1e: Dodatni peptidi MHC klase II
SEQ ID NO: Kôd peptida Sekvenca Izvorni protein(i)
U tabelama 2a i b prikazani su predstavljeni dodatni peptidi, njihovi odgovarajući ID BR. SEKV, kao i izvorni proteini iz kojih ovi peptidi mogu nastati. Svi peptidi u tabelama 2 vezuju se za HLA A*24 alele.
Tabela 2a: Predstavl eni dodatni peptidi
Peptid u skladu sa ID BR. SEKV 101 može se dobiti iz bilo kog od sledećih proteina: PCDHGA12, PCDHGC3, PCDHGC5, PCDHGC4, PCDHGB7, PCDHGB6, PCDHGB5, PCDHGB3, PCDHGB2, PCDHGB1, PCDHGA11, PCDHGA10, PCDHGA9, PCDHGA7,
PCDHGA6, PCDHGA5, PCDHGA4, PCDHGA3, PCDHGA2, PCDHGA, PCDHGB4, ili PCDHGA8. Peptid u skladu sa ID BR. SEKV 109 je pomeren okvir čitanja EVPSKQCVS; hr 19, 2+ okvir čitanja: 57954686-57954712. W<+4>: Kinurenin ((S)-2-amino-4-(2-aminofenil)-4-oksobuterna kiselina). Peptid u skladu sa ID BR. SEKV: 99 je deo prvog introna TXN2 (koji podržava podudarni EST, BG169743.1).
Tabela 2b: Dodatni e tidi ko i su rekomerno eks rimirani u lioblastomu
Tabela 2c: Dodatne indikacije (npr. maligni tumori koji bi se tretirali) na osnovu ovde predstavljenih peptida koji su prekomerno eksprimirani i/ili prekomerno prezentovani u navedenim indikaci ama
Tako se drugi poželjni aspekt predmetnog pronalaska odnosi na upotrebu peptida u skladu sa predmetnim pronalaskom za poželjno kombinovanu – poželjnu imunoterapiju malignih bolesti u skladu sa tabelom 2c kako je iznad navedeno, u analogiji sa ovde opisanim primenama za, npr. glioblastom.
Peptidi u skladu sa predmetnim pronalaskom imaju sposobnost da se vezuju za molekul humanog glavnog kompleksa gena tkivne podudarnosti (MHC) klase I.
Predmetni pronalazak se dalje odnosi na peptid u skladu sa predmetnim pronalaskom, naznačeno time što navedeni peptid sadrži nepeptidne veze.
Predmetni pronalazak se dalje odnosi na nukleinsku kiselinu koja kodira peptid u skladu sa predmetnim pronalaskom.
Predmetni pronalazak se dalje odnosi na nukleinsku kiselinu u skladu sa predmetnim pronalaskom koja je DNK, cDNK, RNK ili njihova kombinacija.
Predmetni pronalazak se dalje odnosi na vektor ekspresije koji eksprimira nukleinsku kiselinu u skladu sa predmetnim pronalaskom.
Predmetni pronalazak se dalje odnosi na peptid u skladu sa predmetnim pronalaskom, nukleinsku kiselinu u skladu sa predmetnim pronalaskom ili vektor ekspresije u skladu sa predmetnim pronalaskom za upotrebu u lečenju bolesti.
Predmetni pronalazak se dalje odnosi na antitelo koje specifično prepoznaje peptid u skladu sa predmetnim pronalaskom.
Predmetni pronalazak se dalje odnosi na T-ćelijski receptor koji je reaktivan sa HLA ligandom koji sadrži aminokiselinsku sekvencu ID BR. SEKV 28.
Predmetni pronalazak se dalje odnosi na ćeliju domaćina koja sadrži nukleinsku kiselinu u skladu sa predmetnim pronalaskom ili vektor ekspresije kako je ranije opisan.
Predmetni pronalazak se dalje odnosi na ćeliju domaćina u skladu sa predmetnim pronalaskom koja je antigen-prezentujuća ćelija. Predmetni pronalazak se dalje odnosi na ćeliju domaćina u skladu sa predmetnim pronalaskom, naznačeno time što je antigenprezentujuća ćelija dendritična ćelija.
Predmetni pronalazak se dalje odnosi na metod proizvodnje peptida u skladu sa predmetnim pronalaskom, pri čemu se metod sastoji od kultivisanja ćelije domaćina u skladu sa predmetnim pronalaskom i izolovanja peptida iz ćelije domaćina ili njenog medijuma za kultivaciju.
Predmetni pronalazak se dalje odnosi na in vitro metod za proizvodnju aktiviranih citotoksičnih T limfocita (CTL), pri čemu se metod sastoji od dovođenja u kontakt in vitro CTL sa humanim MHC molekulima klase I sa ubačenim antigenom eksprimiranim na površini prikladne antigenprezentujuće ćelije u toku vremenskog perioda koji je dovoljan da se navedeni CTL aktiviraju na antigen-specifičan način, naznačeno time što je navedeni antigen bilo koji peptid u skladu sa predmetnim pronalaskom.
Predmetni pronalazak se dalje odnosi na metod u skladu sa predmetnim pronalaskom, naznačeno time što se antigen postavlja na MHC molekule klase I eksprimirane na površini prikladne antigen-prezentujuće ćelije tako što se dovoljna količina antigena dovodi u kontakt sa antigenprezentujućom ćelijom.
Predmetni pronalazak se dalje odnosi na aktivirane citotoksične T limfocite (CTL), proizvedene pomoću metoda u skladu sa predmetnim pronalaskom, koji selektivno prepoznaju ćeliju koja aberantno eksprimira polipeptid koji sadrži aminokiselinsku sekvencu u skladu sa predmetnim pronalaskom.
Predstavljen je metod ubijanja ciljnih ćelija kod pacijenta čije ciljne ćelije aberantno eksprimiraju polipeptid koji sadrži bilo koju aminokiselinsku sekvencu u skladu sa predmetnim pronalaskom, pri čemu metod obuhvata davanje pacijentu efikasnog broja citotoksičnih T limfocita (CTL) u skladu sa predmetnim pronalaskom.
Predmetni pronalazak se dalje odnosi na peptid, aktivirani citotoksični T limfocit, antitelo, Tćelijski receptor, nukleinsku kiselinu ili vektor ekspresije, ili ćeliju za upotrebu u lečenju bolesti, naznačeno time što je navedena bolest maligna bolest, poželjno u obliku farmaceutske smeše, npr. vakcine.
Pored toga, predmetni pronalazak predstavlja metod za dobijanje i proizvodnju vakcina za skup pacijenata sa specifičnim skupom alela i/ili koje su specifične za pacijenta.
Predmetni pronalazak se dalje odnosi na ćeliju domaćina koja sadrži nukleinsku kiselinu u skladu sa predmetnim pronalaskom ili vektor ekspresije kako je ranije opisan. Predmetni pronalazak se dalje odnosi na ćeliju domaćina u skladu sa predmetnim pronalaskom koja je antigenprezentujuća ćelija. Predmetni pronalazak se dalje odnosi na ćeliju domaćina u skladu sa predmetnim pronalaskom, naznačeno time što je antigen-prezentujuća ćelija dendritična ćelija.
Predmetni pronalazak se dalje odnosi na metod proizvodnje peptida u skladu sa predmetnim pronalaskom, pri čemu se metod sastoji od kultivisanja ćelije domaćina u skladu sa predmetnim pronalaskom i izolovanja peptida iz ćelije domaćina ili njenog medijuma za kultivaciju.
Predmetni pronalazak se dalje odnosi na in vitro metod za proizvodnju aktiviranih citotoksičnih T limfocita (CTL), pri čemu se metod sastoji od dovođenja u kontakt in vitro CTL sa humanim MHC molekulima klase I sa ubačenim antigenom eksprimiranim na površini prikladne antigenprezentujuće ćelije u toku vremenskog perioda koji je dovoljan da se navedeni CTL aktiviraju na antigen-specifičan način, naznačeno time što je navedeni antigen bilo koji peptid u skladu sa predmetnim pronalaskom.
Predmetni pronalazak se dalje odnosi na metod u skladu sa predmetnim pronalaskom, naznačeno time što se antigen postavlja na MHC molekule klase I eksprimirane na površini prikladne antigen-prezentujuće ćelije tako što se dovoljna količina antigena dovodi u kontakt sa antigenprezentujućom ćelijom. Predmetni pronalazak se dalje odnosi na metod u skladu sa predmetnim pronalaskom, naznačeno time što navedena antigenprezentujuća ćelija sadrži vektor ekspresije koji eksprimira navedeni peptid koji sadrži sekvencu ID BR. SEKV 28.
Predmetni pronalazak se dalje odnosi na aktivirane citotoksične T limfocite (CTL) kako su ovde opisani, proizvedene pomoću metoda u skladu sa predmetnim pronalaskom, koji selektivno prepoznaju ćeliju koja aberantno eksprimira polipeptid koji sadrži aminokiselinsku sekvencu u skladu sa predmetnim pronalaskom.
Dalje, predmetni pronalazak predstavlja metod za proizvodnju personalizovane antitumorske vakcine koja sadrži najmanje jedan peptid u skladu sa predmetnim pronalaskom, nukleinsku kiselinu u skladu sa predmetnim pronalaskom, vektor ekspresije u skladu sa predmetnim pronalaskom, ćeliju domaćina ili ćeliju u skladu sa predmetnim pronalaskom, ili aktivirani citotoksični T limfocit u skladu sa predmetnim pronalaskom, koji su dizajnirani i formulisani za upotrebu kod pojedinačnog pacijenta,
naznačeno time što se navedeni dizajn sastoji od upotrebe baze podataka („magacina“) unapred odabranih i/ili unapred skriniranih tumor-asociranih peptida koji su specifični za pacijenta i/ili grupu pacijenata i/ili maligni tumor.
Peptidi predmetnog pronalaska mogu da se koriste za stvaranje, proizvodnju i razvoj specifičnih antitela protiv kompleksa MHC/peptid predmetnog pronalaska (tj. sadrže sekvencu ID BR. SEKV 28). Ova antitela se mogu koristiti za terapiju, tako što će ciljno dovoditi toksine ili radioaktivne supstance u obolelo tkivo, npr. tumor. Druga primena ovih antitela može biti ciljno dovođenje radionuklida u obolelo tkivo u svrhe imidžinga kao što je PET.
Stoga je dalji aspekt pronalaska da se obezbedi metod za proizvodnju rekombinantnog antitela koje se specifično vezuje za humani glavni kompleks gena tkivne podudarnosti (MHC) klase I koji je u kompleksu sa HLA-restrikovanim antigenom (tj. koji sadrži sekvencu ID BR. SEKV 28), pri čemu se metod sastoji od: imunizacije genetičkim inžinjeringom napravljenog nehumanog sisara koji sadrži ćelije koje eksprimiraju navedeni humani glavni kompleks gena tkivne podudarnosti (MHC) klase I sa solubilnim oblikom MHC molekula klase I koji je u kompleksu sa navedenim HLA-restrikovanim antigenom; izolacije molekula mRNK iz ćelija navedenog sisara koji nije čovek koje proizvode antitela; proizvodnje biblioteke prikaza faga koja prikazuje molekule proteina kodiranih navedenim molekulima mRNK; i izolacije najmanje jednog faga iz navedene biblioteke prikaza faga, pri čemu taj navedeni najmanje jedan fag prikazuje navedeno antitelo koje se specifično vezuje za navedeni humani glavni kompleks gena tkivne podudarnosti (MHC) klase I koji je u kompleksu sa navedenim HLA-restrikovanim antigenom.
Dalji je aspekt pronalaska da se obezbedi antitelo koje se specifično vezuje za humani glavni kompleks gena tkivne podudarnosti (MHC) klase I koji je u kompleksu sa HLA-restrikovanim antigenom, naznačeno time što je antitelo poželjno poliklonalno antitelo, monoklonalno antitelo, bispecifično antitelo i/ili himerno antitelo.
Još jedan aspekt predmetnog pronalaska se zatim odnosi na metod za proizvodnju antitela koje se specifično vezuje za humani glavni kompleks gena tkivne podudarnosti (MHC) klase I koji je u kompleksu sa HLA-restrikovanim antigenom (tj. koji sadrži sekvencu ID BR. SEKV 28), pri čemu se metod sastoji od: imunizacije genetičkim inžinjeringom napravljenog nehumanog sisara koji sadrži ćelije koje eksprimiraju navedeni humani glavni kompleks gena tkivne podudarnosti (MHC) klase I sa solubilnim oblikom MHC molekula klase I koji je u kompleksu sa navedenim HLA-restrikovanim antigenom; izolacije molekula mRNK iz ćelija navedenog sisara koji nije čovek koje proizvode antitela; proizvodnje biblioteke prikaza faga koja prikazuje molekule proteina kodiranih navedenim molekulima mRNK; i izolacije najmanje jednog faga iz navedene biblioteke prikaza faga, pri čemu taj navedeni najmanje jedan fag prikazuje navedeno antitelo koje je u stanju da se specifično veže za navedeni humani glavni kompleks gena tkivne podudarnosti (MHC) klase I koji je u kompleksu sa navedenim HLA-restrikovanim antigenom. Odgovarajući metodi za proizvodnju takvih antitela i jednolančanih glavnih kompleksa gena tkivne podudarnosti klase I, kao i drugi alati.
Dalji je aspekt pronalaska da se obezbedi metod za proizvodnju rastvorljivog T-ćelijskog receptora koji prepoznaje predstavljeni specifični kompleks peptid-MHC. Takvi rastvorljivi Tćelijski receptori mogu da se naprave od specifičnih T-ćelijskih klonova, a njihov afinitet može da se poveća pomoću mutageneze koja cilja komplementarne determinišuće regione.
Stimulacija imunskog odgovora zavisi od prisustva antigena koje imunski sistem domaćina prepoznaje kao strane. Otkriće postojanja tumor-asociranih antigena otvorilo je mogućnost primene imunskog sistema domaćina za intervenciju u rastu tumora. Trenutno se istražuju različiti mehanizmi za iskorišćavanje kako humoralnog tako i ćelijskog dela imunskog sistema za imunoterapiju raka.
Specifični elementi ćelijskog imunskog odgovora su u stanju da specifično prepoznaju i unište ćelije tumora. Izolacija citotoksičnih T ćelija (CTL) iz ćelijskih populacija koje infiltriraju tumor ili iz periferne krvi navodi na to da takve ćelije imaju značajnu ulogu u prirodnim imunskim odbranama protiv raka. U ovom odgovoru naročito važnu ulogu imaju CD8-pozitivne T ćelije, koje prepoznaju molekule klase I glavnog kompleksa gena tkivne podudarnosti (MHC) koji nose peptide od obično 8 do 10 aminokiselinskih ostataka dobijene iz proteina ili defektnih proizvoda ribozoma (DRIP-ovi) koji se nalaze u citosolu. MHC molekuli ljudi se takođe nazivaju humani leukocitni antigeni (HLA).
Postoje dve klase MHC molekula: MHC molekuli klase I koji se nalaze na većini ćelija koje sadrže jedro. MHC molekuli su sastavljeni od alfa teškog lanca i beta-2 mikroglobulina (MHC klasa I receptori) odnosno alfa i beta lanca (MHC klasa II receptori). Njihova trodimenzionalna konformacija rezultuje stvaranjem udubljenja za vezivanje, koje se koristi za nekovalentnu interakciju sa peptidima. MHC klase I prezentuju peptide koji nastaju kao posledica proteolitičkog cepanja predominantno endogenih proteina, DRIP-ova i većih peptida.
MHC molekuli klase II predominantno se nalaze na profesionalnim antigen-prezentujućim ćelijama (APĆ), i primarno prezentuju peptide egzogenih ili transmembranskih proteina koje APĆ preuzimaju u toku procesa endocitoze, i nakon toga obrađuju. Komplekse peptida i MHC molekula klase I prepoznaju CD8-pozitivni citotoksični T limfociti koji nose odgovarajući TCR (T-ćelijski receptor), dok komplekse peptida i MHC molekula klase II prepoznaju CD4-pozitivne pomoćničke T ćelije koje nose odgovarajući TCR. Dobro je poznato da su TCR, peptid i MHC pritom prisutni u stehiometrijskom odnosu od 1:1:1.
CD4-pozitivne pomoćničke T ćelije imaju važnu ulogu u indukovanju i održavanju efikasnih odgovora od strane CD8-pozitivnih citotoksičnih T ćelija (Wang and Livingstone, 2003; Sun and Bevan, 2003; Shedlock and Shen, 2003). Identifikacija CD4-pozitivnih T-ćelijskih epitopa dobijenih iz tumor-asociranih antigena (TAA) je od velikog značaja za razvoj farmaceutskih proizvoda za izazivanje antitumorskih imunskih odgovora (Kobayashi et al., 2002; Qin et al., 2003; Gnjatic et al., 2003). Na mestu tumora, T pomoćničke ćelije, podržavaju citokinski milje koji je povoljan za CTL (Qin and Blankenstein, 2000; Mortara et al., 2006) i privlače efektorske ćelije, npr. CTL, NK ćelije, makrofage, (Marzo et al., 2000; Hwang et al., 2007).
U odsustvu zapaljenja, ekspresija MHC molekula klase II je uglavnom ograničena na ćelije imunskog sistema, naročito profesionalne antigen-prezentujuće ćelije (APĆ), npr. monocite, ćelije izvedene iz monocita, makrofage, dendritične ćelije. Kod pacijenata koji boluju od raka, neočekivano je otkriveno da ćelije tumora eksprimiraju MHC molekule klase II (Dengjel et al., 2006).
Na životinjskim modelima na sisarima, npr. miševi, dokazano je da su čak i u odsustvu CTL efektorskih ćelija (tj. CD8-pozitivnih T limfocita), CD4-pozitivne T ćelije dovoljne za inhibiranje manifestacija tumora putem inhibicije angiogeneze pomoću sekrecije interferona-gama (IFNγ).
Dodatno, pokazano je da CD4-pozitivne T ćelije koje prepoznaju peptide iz tumorasociranih antigena prezentovanih od strane HLA molekula klase II mogu da se suprotstave progresiji tumora pomoću indukcije odgovora antitelima (At) (Kennedy et al., 2003).
Za razliku od tumor-asociranih peptida koji se vezuju za HLA molekule klase I, do danas je opisan samo mali broj liganda klase II tumor-asociranih antigena (TAA).
Budući da je konstitutivna ekspresija HLA molekula klase II obično ograničena na ćelije imunskog sistema, mogućnost izolovanja peptida klase II direktno iz primarnih tumora nije se smatrala mogućom. Međutim, Dengjel i saradnici nedavno su uspešno identifikovali određeni broj epitopa MHC klase II direktno iz tumora (WO 2007/028574, EP 1760 088 B1; (Dengjel et al., 2006).
Antigeni koje prepoznaju tumor-specifični citotoksični T limfociti, to jest, njihovi epitopi, mogu biti molekuli dobijeni iz svih klasa proteina, kao što su enzimi, receptori, faktori transkripcije, itd. koji se eksprimiraju i, u poređenju sa neizmenjenim ćelijama istog porekla, ushodno regulišu u ćelijama datog tumora.
Budući da obe vrste odgovora, CD8 i CD4-zavisan, zajednički i sinergistički doprinose antitumorskom efektu, identifikacija i karakterizacija tumor-asociranih antigena prepoznatih pomoću ili CD8+ CTL (ligand: MHC molekul klase I peptidni epitop) ili pomoću CD4pozitivnih T pomoćničkih ćelija (ligand: MHC molekul klase II peptidni epitop) je važna u razvoju tumorskih vakcina.
Takođe je predstavljen i veoma koristan peptid MHC klase II (vidite ID BR. SEKV 71). Ovaj peptid je koristan protiv glioblastoma i drugih malignih tumora koji prekomerno eksprimiraju i/ili prekomerno prezentuju BCAN.
Da bi peptid pokrenuo (izazvao) ćelijski imunski odgovor, on mora da se veže za MHC molekul. Ovaj proces zavisi od alela MHC molekula i specifičnih polimorfizama aminokiselinske sekvence peptida. Peptidi koji vezuju MHC klasa I su obično dužine 8-12 aminokiselinskih ostataka i obično sadrže dva konzervirana ostatka („sidra“) u svojoj sekvenci koji
interaguju sa odgovarajućim udubljenjem za vezivanje MHC molekula. Na ovaj način, svaki MHC alel ima „vezujući motiv“ koji određuje koji peptidi mogu specifično da se vežu za udubljenje za vezivanje.
U MHC klasa I-zavisnoj imunskoj reakciji, peptidi ne samo da moraju da budu sposobni da se vežu za određene MHC molekule klase I koje eksprimiraju tumorske ćelije, već njih takođe moraju da prepoznaju T ćelije koje nose specifične T-ćelijske receptore (TCR).
Antigeni koje prepoznaju tumor-specifični citotoksični T limfociti, to jest, njihovi epitopi, mogu biti molekuli dobijeni iz svih klasa proteina, kao što su enzimi, receptori, faktori transkripcije, itd. koji se eksprimiraju i, u poređenju sa neizmenjenim ćelijama istog porekla, ushodno regulišu u ćelijama datog tumora.
Trenutno važeća klasifikacija tumor-asociranih antigena sadrži sledeće velike grupe: a) Karcinom-testis antigeni: Prvi TAA koji su ikad identifikovani koje mogu da prepoznaju T ćelije pripadaju ovoj klasi, koja je originalno nazvana karcinom-testis (CT) antigeni zbog ekspresije njenih članova u histološki različitim humanim tumorima i, među normalnim tkivima, samo u spermatocitima/spermatogonijama testisa i, povremeno, u placenti. Budući da ćelije testisa ne eksprimiraju HLA molekule klase I i II, ove antigene ne mogu da prepoznaju T ćelije u normalnim tkivima te se stoga mogu smatrati imunološki tumor-specifičnim. Dobro poznati primeri za CT antigene su pripadnici MAGE familije ili NY-ESO-1.
b) Antigeni diferencijacije: Ove TAA dele tumori i normalno tkivo iz kojeg je tumor nastao; većina njih nalazi se u melanomima i normalnim melanocitima. Mnogi od ovih proteina povezanih sa melanocitnom linijom uključeni su u biosintezu melanina te stoga nisu tumorspecifični, ali bez obzira na to naširoko se koriste za imunoterapiju raka. Primeri uključuju, ali nisu i ograničeni na, tirozinazu i Melan-A/MART-1 za melanom ili PSA za karcinom prostate.
c) Prekomerno eksprimirani TAA: Geni koji kodiraju naširoko eksprimirane TAA detektovani su u histološki različitim tipovima tumora kao i u mnogim normalnim tkivima, generalno sa nižim nivoima ekspresije. Moguće je da su mnogi od epitopa koje normalna tkiva obrađuju i potencijalno prezentuju ispod nivoa praga za prepoznavanje od strane T ćelija, dok njihova prekomerna ekspresija u ćelijama tumora može da pokrene antitumorski odgovor probijanjem prethodno uspostavljene tolerancije. Istaknuti primeri za ovu klasu TAA su Her-2/neu, survivin, telomeraza ili WT1.
d) Tumor-specifični antigeni: Ovi jedinstveni TAA nastaju iz mutacija normalnih gena (kao što je β-katenin, CDK4, itd). Neke od ovih molekularnih promena su u vezi sa neoplastičnom transformacijom i/ili progresijom. Tumor-specifični antigeni su generalno u stanju da indukuju jake imunske odgovore a da pritom ne nose rizik od autoimunskih reakcija protiv normalnih tkiva. S druge strane, ovi TAA su u većini slučajeva relevantni samo za određeni tumor na kojem su identifikovani i obično ih ne deli mnogo individualnih tumora.
e) TAA koji nastaju iz abnormalnih posttranslacionih modifikacija: Takvi TAA mogu nastati iz proteina koji su niti specifični niti prekomerno eksprimirani u tumorima, ali bez obzira na to postaju tumor-asocirani pomoću posttranslacionih procesa koji su primarno aktivni u tumorima. Primeri za ovu klasu nastaju iz izmenjenih obrazaca glikozilacije koji dovode do novih epitopa u tumorima kao za MUC1 ili događaja poput spajanja proteina u toku degradacije, koji mogu i ne moraju biti tumor-specifični.
f) Onkovirusni proteini: Ovi TAA su virusni proteini koji mogu imati kritičnu ulogu u procesu onkogeneze i, zbog toga što su stranog (a ne humanog) porekla, oni mogu pokrenuti T-ćelijski odgovor. Primeri takvih proteina su proteini humanog papiloma virusa tip 16, E6 i E7, koji se eksprimiraju u karcinomu grlića materice.
Da bi proteini mogli da budu prepoznati od strane citotoksičnih T limfocita kao tumorspecifični ili tumor-asocirani antigeni, i da bi mogli da se koriste u terapiji, moraju da budu ispunjeni određeni preduslovi. Antigen bi trebalo da bude uglavnom eksprimiran od strane ćelija tumora a ne uopšte ili samo u uporedivo malim količinama od strane normalnih zdravih tkiva ili u drugom otelotvorenju peptid bi trebalo da bude prekomerno eksprimiran od strane ćelija tumora u poređenju sa normalnim zdravim tkivima. Nadalje je poželjno da dati antigen ne bude samo prisutan u određenoj vrsti tumora, već takođe i u visokim koncentracijama (tj. broj kopija datog peptida po ćeliji). Tumor-specifični i tumorasocirani antigeni se često dobijaju od proteina koji su direktno uključeni u transformaciju normalne ćelije u tumorsku ćeliju zbog funkcije npr. u kontroli ćelijskog ciklusa ili supresiji apoptoze. Pored toga, nishodni ciljevi proteina koji su direktno odgovorni za transformaciju mogu biti ushodno regulisani i tako mogu indirektno biti tumor-asocirani. Takvi indirektni tumor-asocirani antigeni mogu takođe biti ciljevi vakcinalnog pristupa. U oba slučaja, esencijalno je da epitopi budu prisutni u aminokiselinskoj sekvenci antigena, budući da takav peptid („imunogeni peptid“) koji je dobijen iz tumor-asociranog antigena treba da dovede do in vitro ili in vivo T-ćelijskog odgovora.
U osnovi, svaki peptid koji je u stanju da veže MHC molekul može funkcionisati kao T-ćelijski epitop. Preduslov za indukciju in vitro ili in vivo T-ćelijskog odgovora je prisustvo T ćelije sa odgovarajućim TCR i odsustvo imunološke tolerancije za ovaj konkretni epitop.
Zato su TAA početna tačka za razvoj tumorske vakcine. Metodi za identifikaciju i karakterizaciju TAA zasnovani su na upotrebi CTL koji mogu biti izolovani iz pacijenata ili zdravih ispitanika, ili se oni zasnivaju na stvaranju diferencijalnih profila transkripcije ili diferencijalnih obrazaca ekspresije peptida između tumora i normalnih tkiva.
Ipak, identifikacija gena koji su prekomerno eksprimirani u tumorskim tkivima ili humanim tumorskim ćelijskim linijama, ili selektivno eksprimirani u takvim tkivima ili ćelijskim linijama, ne obezbeđuje precizne informacije o upotrebi antigena koji se transkribuju iz ovih gena u imunskoj terapiji. Ovo je iz razloga što je samo pojedinačna potpopulacija epitopa ovih antigena prikladna za takvu primenu budući da mora da bude prisutna T ćelija sa odgovarajućim TCR i da imunološka tolerancija za ovaj naročit epitop bude odsutna ili minimalna. U veoma poželjnom otelotvorenju pronalaska je zato važno da se odaberu samo oni prekomerno ili selektivno prezentovani peptidi protiv kojih se može naći funkcionalna i/ili proliferišuća T ćelija. Takva funkcionalna T ćelija je definisana kao T ćelija koja nakon stimulacije sa specifičnim antigenom može klonalno da se proširi i koja je sposobna da izvrši efektorske funkcije („efektorska T ćelija“).
U slučaju TCR i antitela u skladu sa pronalaskom, imunogenost osnovnih peptida je sekundarna. Za TCR i antitela u skladu sa pronalaskom prezentacija je određujući faktor.
T pomoćničke ćelije imaju važnu ulogu u orkestriranju efektorske funkcije CTL u antitumorskoj imunosti. T-pomoćnički ćelijski epitopi koji izazivaju T-pomoćnički ćelijski odgovor TH1tipa podržavaju efektorske funkcije CD8-pozitivnih T ćelija ubica, koje obuhvataju citotoksične funkcije usmerene protiv tumorskih ćelija koje prikazuju komplekse tumor-asocirani peptid/MHC na površini ćelije. Na ovaj način tumor-asocirani peptidni epitopi T pomoćničke ćelije, samostalno ili u kombinaciji sa drugim tumorasociranim peptidima, mogu da služe kao aktivni farmaceutski sastojci smeša za vakcinu koje stimulišu antitumorske imunske odgovore.
Primene protiv dodatnih malignih tumora predstavljene su u sledećem opisu osnovnih polipeptida peptida u skladu sa pronalaskom.
Kolagen, tip XX, alfa 1 (COL20A1)
COL20A1 je gen za kolagen. Gen COL20A1 mapiran je na hromozomu 20q13.33 (Deloukas et al., 2001). Funkcija ovog gena je i dalje nepoznata. Nedavno je jedna studija identifikovala podskupove združenih gena koji su povezani sa rekurencijom karcinoma dojke, metastazama ili mortalitetom u analizama preživljavanja. Ustanovljen je genski potpis koji čini 16 gena, uključujući COL20A1, za preživljavanje bez prisustva bolesti kod pacijenata Han Kineza sa karcinomom dojke (Huang et al., 2013a).
Poželjan je peptid u skladu sa pronalaskom, aktivirani citotoksični T limfocit u skladu sa pronalaskom, antitelo u skladu sa pronalaskom, T-ćelijski receptor u skladu sa pronalaskom, nukleinska kiselina ili vektor ekspresije u skladu sa pronalaskom, ili ćelija u skladu sa pronalaskom za upotrebu u lečenju raka, naznačeno time što je navedeni maligni tumor izabran iz grupe koju čine: astrocitom, pilocitni astrocitom, disembrioplastični neuroepitelijalni tumor, oligodendrogliomi, ependimom, glioblastom multiforme, mešoviti gliomi, oligoastrocitomi, meduloblastom, retinoblastom, neuroblastom, germinom, teratom, gangliogliomi, gangliocitom, centralni gangliocitom, primitivni neuroektodermalni tumori (PNET, npr. meduloblastom, meduloepiteliom, neuroblastom, retinoblastom, ependimoblastom), tumori parenhima epifize (npr. pineocitom, pineoblastom), tumori ependimalnih ćelija, tumori horoidnog pleksusa, neuroepitelijalni tumori nejasnog porekla (npr. gliomatoza mozga, astroblastom), glioblastom, tumor prostate, karcinom dojke, karcinom jednjaka, kolorektalni karcinom, svetloćelijski karcinom bubrežnih ćelija, karcinom pluća, CNS-a, jajnika, melanom, karcinom pankreasa, skvamocelularni karcinom, leukemija, meduloblastom, karcinom kolona, rektuma, želuca, bubrega, pluća, pankreasa, prostate i kože.
Drugi aspekt predmetnog pronalaska odnosi se na komplet, koji se sastoji od: (a) posude koja sadrži farmaceutsku smešu koja sadrži peptid u skladu sa predmetnim pronalaskom, nukleinsku kiselinu ili vektor ekspresije u skladu sa predmetnim pronalaskom, ćeliju u skladu sa predmetnim pronalaskom ili aktivirani citotoksični T limfocit u skladu sa predmetnim pronalaskom, u rastvoru ili liofiliziranom obliku; (b) opciono, druge posude koja sadrži rastvarač ili rastvor za rekonstituciju za liofiliziranu formulaciju; (c) opciono, uputstva za upotrebu rastvora i/ili rekonstituciju i/ili upotrebu liofilizirane formulacije.
Predstavljen je metod za proizvodnju rekombinantnog antitela koje se specifično vezuje za humani glavni kompleks gena tkivne podudarnosti (MHC) klase I ili II koji je u kompleksu sa HLA-restrikovanim antigenom, pri čemu se metod sastoji od: imunizacije genetičkim inžinjeringom napravljenog nehumanog sisara koji sadrži ćelije koje eksprimiraju navedeni humani glavni kompleks gena tkivne podudarnosti (MHC) klase I ili II sa solubilnim oblikom MHC molekula klase I ili II koji je u kompleksu sa navedenim HLA-restrikovanim antigenom; izolacije molekula mRNK iz ćelija navedenog sisara koji nije čovek koje proizvode antitela; proizvodnje biblioteke prikaza faga koja prikazuje molekule proteina kodiranih navedenim molekulima mRNK; i izolacije najmanje jednog faga iz navedene biblioteke prikaza faga, pri čemu taj navedeni najmanje jedan fag prikazuje navedeno antitelo koje je u stanju da se specifično veže za navedeni humani glavni kompleks gena tkivne podudarnosti (MHC) klase I ili II koji je u kompleksu sa navedenim HLA-restrikovanim antigenom.
Još jedan aspekt predmetnog pronalaska odnosi se na antitelo koje se specifično vezuje za peptid u skladu sa predmetnim pronalaskom, poželjno koje se specifično vezuje za humani glavni kompleks gena tkivne podudarnosti (MHC) klase I koji je u kompleksu sa HLA-restrikovanim antigenom i/ili peptidom u skladu sa predmetnim pronalaskom, naznačeno time što je antitelo poželjno poliklonalno antitelo, monoklonalno antitelo i/ili himerno antitelo.
Termin „peptid“ je korišćen u ovom tekstu da označi seriju aminokiselinskih ostataka, povezanih jedan sa drugim tipično pomoću peptidnih veza između alfa-amino i karbonilnih grupa susednih aminokiselina. Peptidi su poželjno dužine 9 aminokiselina, ali mogu biti i kraći sa dužinom od 8 aminokiselina, ili duži sa dužinom od 10, 11, 12, 13 ili 14 a u slučaju peptida MHC klase II oni mogu biti dužine od 15, 16, 17, 18, 19, 20, 21, 22 ili 23 aminokiselina.
Pored toga, termin „peptid“ će obuhvatati soli serija aminokiselinskih ostataka, povezanih jedan sa drugim tipično pomoću peptidnih veza između alfa-amino i karbonilnih grupa susednih aminokiselina. Poželjno, soli su farmaceutski prihvatljive soli.
Termin „peptid“ će takođe obuhvatati „oligopeptid“. Termin „oligopeptid“ je korišćen u ovom tekstu da označi seriju aminokiselinskih ostataka, povezanih jedan sa drugim tipično pomoću peptidnih veza između alfa-amino i karbonilnih grupa susednih aminokiselina. Oligopeptidi su tipično dužine manje od oko 30 aminokiselinskih ostataka, a duži od oko 15 aminokiselina.
Termin „polipeptid“ označava seriju aminokiselinskih ostataka, povezanih jedan sa drugim tipično pomoću peptidnih veza između alfa-amino i karbonilnih grupa susednih aminokiselina. Suprotno terminima peptid ili oligopeptid, termin polipeptid je namenjen da označi molekule koji sadrže više od oko 30 aminokiselinskih ostataka.
Peptid, oligopeptid, protein ili polinukleotidni kod za takav molekul je „imunogen“ (pa je zato kako je predstavljeno „imunogen“), ako je sposoban da indukuje imunski odgovor. U slučaju predmetnog pronalaska, imunogenost je specifičnije definisana kao sposobnost indukovanja Tćelijskog odgovora. Tako bi „imunogen“ bio molekul koji je u stanju da indukuje imunski odgovor, a u slučaju predmetnog pronalaska, molekul koji je u stanju da indukuje T-ćelijski odgovor.
T-ćelijski „epitop“ klase I zahteva kratak peptid koji je vezan za MHC receptor klase I, obrazujući trojni kompleks (alfa lanac MHC klase I, beta-2-mikroglobulin i peptid), koji može da prepozna T ćelija koja nosi podudarni T-ćelijski receptor koji se vezuje za kompleks MHC/peptid sa odgovarajućim afinitetom. Peptidi koji se vezuju za MHC molekule klase I su tipično dužine od 8 do 14 aminokiselina, a najčešće su dugački 9 aminokiselina.
Kod ljudi postoje tri različita genska lokusa koji kodiraju MHC molekule klase I (MHC molekuli ljudi se takođe nazivaju humani leukocitni antigeni (HLA)): HLA-A, HLA-B i HLA-C. HLAA*01, HLA-A*02 i HLA-B*07 su primeri različitih alela MHC klase I koji mogu biti eksprimirani od ovih lokusa.
Za terapijske i dijagnostičke svrhe, veoma je poželjan peptid koji se vezuje sa odgovarajućim afinitetom za nekoliko različitih receptora HLA klase II. Peptid koji se vezuje za nekoliko različitih HLA molekula klase II naziva se slobodan vezivač.
Na način kako je korišćeno u ovom dokumentu, upućivanje na DNK sekvencu obuhvata i jednolančanu i dvolančanu DNK. Tako, specifična sekvenca, sem ako kontekst ne ukazuje drugačije, odnosi se na jednolančanu DNK takve sekvence, dupleks takve sekvence sa njenim komplementarnim delom (dvolančana DNK) i komplementarni deo takve sekvence. Termin „kodirajući region“ odnosi se na onaj deo gena koji ili prirodno ili normalno kodira proizvod ekspresije datog gena u njegovoj prirodnoj genomskoj sredini, tj. region koji in vivo kodira proizvod prirodne ekspresije tog gena.
Kodirajući region može biti iz nemutiranog („normalnog“), mutiranog ili izmenjenog gena, ili čak iz DNK sekvence, ili gena, koji su u potpunosti sintetizovani u laboratoriji pomoću metoda koji su dobro poznati stručnjacima iz oblasti sinteze DNK.
Termin „nukleotidna sekvenca“ odnosi se na heteropolimer deoksiribonukleotida.
Nukleotidna sekvenca koja kodira određeni peptid, oligopeptid ili polipeptid može biti prirodno postojeća ili mogu biti sintetički napravljene. Uopšteno, DNK segmenti koji kodiraju peptide, polipeptide i proteine ovog pronalaska sastavljaju se iz cDNK fragmenata i kratkih oligonukleotidnih povezivača, ili iz serije oligonukleotida, kako bi se obezbedio sintetički gen koji je u stanju da bude eksprimiran u rekombinantnoj transkripcionoj jedinici koja sadrži regulatorne elemente dobijene iz mikrobnog ili virusnog operona.
Na način kako je korišćen u ovom dokumentu termin „nukleotidni kod za peptid“ odnosi se na nukleotidnu sekvencu koja kodira peptid uključujući veštačke (napravljene od strane ljudi) start i stop kodone kompatibilne za biološki sistem u kojem će se sekvenca eksprimirati.
Termin „proizvod ekspresije“ označava polipeptid ili protein koji je prirodni proizvod translacije gena i bilo koje sekvence nukleinskih kiselina koja kodira ekvivalente koji nastaju iz degeneracije genetskog koda i tako kodiraju istu aminokiselinu(e).
Termin „fragment“, kada se odnosi na kodirajuću sekvencu, označava deo DNK koji sadrži manje od kompletnog kodirajućeg regiona, čiji proizvod ekspresije esencijalno zadržava istu biološku funkciju ili aktivnost kao i proizvod ekspresije kompletnog kodirajućeg regiona.
Termin „DNK segment“ odnosi se na DNK polimer, u obliku zasebnog fragmenta ili kao komponenta većeg DNK konstrukta, koji je dobijen iz DNK koja je izolovana najmanje jednom u suštinski čistom obliku, tj. ne sadrži kontaminirajuće endogene materijale i u količini ili koncentraciji koja omogućava identifikaciju, manipulaciju i ponovno dobijanje segmenta i njegovih komponentnih nukleotidnih sekvenci pomoću standardnih biohemijskih metoda, na primer upotrebom vektora za kloniranje. Takvi segmenti se obezbeđuju u obliku otvorenog okvira čitanja koji nije prekinut unutrašnjim netranslatornim sekvencama, ili intronima, koji su tipično prisutni u eukariotskim genima. Sekvence netranslatorne DNK mogu biti prisutne nishodno od otvorenog okvira čitanja, gde iste ne ometaju manipulaciju ili ekspresiju kodirajućih regiona.
Termin „prajmer“ označava kratku sekvencu nukleinskih kiselina koja može biti uparena sa jednim lancem DNK i obezbeđuje slobodan 3'OH kraj na kojem DNK polimeraza započinje sintezu deoksiribonukleotidnog lanca.
Termin „promoter“ označava region DNK koji je uključen u vezivanje RNK polimeraze kako bi se inicirala transkripcija.
Termin „izolovan“ označava da je materijal uklonjen iz njegove originalne sredine (npr. prirodne sredine ako se on prirodno javlja). Na primer, prirodno postojeći polinukleotid ili polipeptid prisutan u živoj životinji nije izolovan, ali isti polinukleotid ili polipeptid, izdvojen iz nekog ili svih koegzistirajućih materijala u prirodnom sistemu, jeste izolovan. Takvi polinukleotidi mogu biti deo vektora i/ili takvi polinukleotidi ili polipeptidi mogu biti deo smeše, a da i dalje budu izolovani u takvom vektoru ili smeši koji nije deo njegove prirodne sredine.
Polinukleotidi, i rekombinantni ili imunogeni polipeptidi, predstavljeni u skladu sa predmetnim pronalaskom mogu takođe biti u „prečišćenom“ obliku. Termin „prečišćen“ ne zahteva apsolutnu čistoću; on je pre namenjen kao relativna definicija, i može obuhvatati preparate koji su visoko prečišćeni ili preparate koji su samo delimično prečišćeni, jer se ti termini podrazumevaju od strane stručnjaka u relevantnoj oblasti. Na primer, pojedinačni klonovi izolovani iz biblioteke cDNK su dogovorno prečišćeni do elektroforetske homogenosti. Prečišćavanje početnog materijala ili prirodnog materijala do najmanje jednog reda veličine, poželjno dva ili tri reda, i još poželjnije četiri ili pet redova veličine se izričito razmatra. Pored toga, polipeptid patentnog zahteva koji ima čistoću od poželjno 99,999%, ili najmanje 99,99% ili 99,9%; i čak poželjno 99% po težini ili veću izričito se razmatra. Polipeptidi mogu biti u vodenom rastvoru i tada se čistoća definiše čistoćom jedinjenja ne uzimajući u obzir vodu i determinante korišćene za rastvor.
Nukleinske kiseline i proizvodi ekspresije polipeptida predstavljeni u skladu sa predmetnim pronalaskom, kao i vektori ekspresije koji sadrže takve nukleinske kiseline i/ili takve polipeptide, mogu biti u „obogaćenom obliku“. Na način kako je korišćen u ovom dokumentu, termin „obogaćen“ znači da je koncentracija materijala najmanje oko 2, 5, 10, 100 ili 1000 puta veća od njegove prirodne koncentracije (na primer), pri čemu prednost ima 0,01% po težini, poželjno najmanje oko 0,1% po težini. Obogaćeni preparati od oko 0,5%, 1%, 5%, 10% i 20% po težini takođe se razmatraju. Sekvence, konstrukti, vektori, klonovi i drugi materijali koji sačinjavaju predmetni pronalazak mogu pogodno biti u obogaćenom ili izolovanom obliku.
Termin „aktivni fragment“ označava fragment koji izaziva imunski odgovor (tj. ima imunogenu aktivnost) kada se primeni, samostalno ili opciono sa prikladnim adjuvansom, na životinji, kao što je sisar, na primer, zec ili miš, i takođe uključujući ljude, pri čemu takav imunski odgovor po obliku stimuliše T-ćelijski odgovor unutar životinje primaoca, kao što je čovek. Alternativno, „aktivni fragment“ može takođe da se koristi za indukciju T-ćelijskog odgovora in vitro.
Na način kako su korišćeni ovde, termini „deo“, „segment“ i „fragment“, kada se koriste u vezi sa polipeptidima, odnose se na kontinuiranu sekvencu ostataka, kao što su aminokiselinski ostaci, čija sekvenca obrazuje podskup veće sekvence. Na primer, ako je polipeptid bio podvrgnut tretmanu sa bilo kojom od uobičajenih endopeptidaza, kao što su tripsin ili himotripsin, oligopeptidi nastali kao posledica takvog tretmana bi predstavljali delove, segmente ili fragmente početnog polipeptida. Kada se koriste u vezi sa polinukleotidima, ovi termini se odnose na proizvode koji se dobijaju tretiranjem navedenih polinukleotida sa bilo kojom od endonukleaza.
U skladu sa predmetnim pronalaskom, termin „procenat identičnosti“ ili „procentualno identičan“, kada se odnosi na sekvencu, znači da je sekvenca upoređena sa traženom ili opisanom sekvencom nakon poravnanja sekvence koja se upoređuje („upoređena sekvenca“) sa opisanom ili traženom sekvencom („referentna sekvenca“). Procenat identičnosti se zatim utvrđuje prema sledećoj formuli:
Procenat identičnosti = 100 [I -(C/R)]
gde je C broj razlika između referentne sekvence i upoređene sekvence u okviru dužine poravnanja između referentne sekvence i upoređene sekvence, naznačeno time što (i) svaka baza ili aminokiselina u referentnoj sekvenci koja nema odgovarajuću poravnatu bazu ili aminokiselinu u upoređenoj sekvenci, i (ii) svaka praznina u referentnoj sekvenci, i
(iii) svaka poravnata baza ili aminokiselina u referentnoj sekvenci koja se razlikuje od poravnate baze ili aminokiseline u upoređenoj sekvenci, predstavlja razliku; a R je broj baza ili aminokiselina u referentnoj sekvenci u okviru dužine poravnanja sa upoređenom sekvencom, pri čemu se svaka praznina u referentnoj sekvenci takođe broji kao baza ili aminokiselina.
Ako između upoređene sekvence i referentne sekvence postoji poravnanje za koje je procenat identičnosti izračunat pomoću gore navedene formule skoro jednak ili veći od određenog minimalnog procenta identičnosti, onda upoređena sekvenca ima određeni minimalni procenat identičnosti sa referentom sekvencom iako mogu postojati poravnanja u kojima je ovde naveden i ranije izračunat procenat identičnosti manji od određenog procenta identičnosti.
Originalni peptidi koji su ovde predstavljeni mogu biti modifikovani supstitucijom jednog ili više ostataka na različitim, poželjno selektivnim, položajima unutar peptidnog lanca, ako nije navedeno drugačije. Poželjno, ove supstitucije se nalaze na kraju aminokiselinskog lanca. Takve supstitucije mogu biti konzervativne prirode, na primer, kada se jedna aminokiselina zamenjuje aminokiselinom slične strukture i sličnih karakteristika, kao kada se hidrofobna aminokiselina zamenjuje drugom hidrofobnom aminokiselinom. Još konzervativnija bi bila zamena aminokiselina iste ili slične veličine i hemijske prirode, kao kada se leucin zamenjuje izoleucinom. U studijama varijacija sekvenci u familijama prirodno javljajućih homolognih proteina, određene supstitucije aminokiselina se češće tolerišu od drugih, i one često pokazuju korelaciju sa sličnostima u veličini, naelektrisanju, polaritetu i hidrofobnosti između originalne aminokiseline i njene zamene, i kao takve predstavljaju osnovu za definisanje „konzervativnih supstitucija“.
Konzervativne supstitucije su ovde definisane kao zamena u okviru jedne od sledećih pet grupa: Grupa 1 – mali alifatični, nepolarni ili malo polarni ostaci (Ala, Ser, Thr, Pro, Gly); Grupa 2 – polarni, negativno naelektrisani ostaci i njihovi amidi (Asp, Asn, Glu, Gln); Grupa 3 – polarni, pozitivno naelektrisani ostaci (His, Arg, Lys); Grupa 4 – veliki, alifatični, nepolarni ostaci (Met, Leu, Ile, Val, Cys); i Grupa 5 – veliki aromatični ostaci (Phe, Tyr, Trp).
Manje konzervativne supstitucije bi mogle da uključuju zamenu jedne aminokiseline drugom koja ima slične karakteristike ali je malo drugačije veličine, kao što je zamena alaninskog ostatka izoleucinskim ostatkom. Veoma nekonzervativne zamene bi mogle da uključuju supstituisanje kisele aminokiseline polarnom, ili čak i aminokiselinom baznog karaktera. Takve „radikalne“ supstitucije ne mogu, ipak, da se odbace kao potencijalno neefikasne jer hemijski efekti nisu potpuno predvidivi a radikalne supstitucije bi mogle da dovedu do srećnih slučajnih otkrića koji inače ne bi mogli da se predvide iz jednostavnih hemijskih principa.
Naravno, takve supstitucije mogu uključivati strukture koje nisu uobičajene L-aminokiseline. Tako, D-aminokiseline bi mogle da supstituišu L-aminokiseline koje se uobičajeno nalaze u antigenim peptidima pronalaska a da i dalje budu obuhvaćene onim što je ovde objavljeno. Pored toga, aminokiseline koje poseduju nestandardne R grupe (tj. R grupe koje se ne nalaze u uobičajenih 20 aminokiselina prirodnih proteina) takođe se mogu koristiti u svrhe supstituisanja da bi se proizveli imunogeni i imunogeni polipeptidi u skladu sa predmetnim pronalaskom.
Ako se utvrdi da supstitucije na više od jednog položaja rezultuju peptidom sa značajnom jednakom ili većom antigenom aktivnošću kako je definisano u nastavku, onda će kombinacije tih supstitucija biti testirane kako bi se utvrdilo da li kombinovane supstitucije rezultuju aditivnim ili sinergističkim efektima na antigenost peptida. Najviše, u okviru peptida neće biti istovremeno supstituisano više od četiri položaja.
Peptidi pronalaska mogu biti produženi za najviše četiri aminokiseline, što znači da mogu da se dodaju 1, 2, 3 ili 4 aminokiseline na bilo koji kraj u bilo kojoj kombinaciji između 4:0 i 0:4.
Kombinaci e elon aci a u skladu sa pronalaskom mo u se videti iz sledeće tabele 3:
Aminokiseline za elongaciju mogu biti peptidi originalne sekvence proteina ili bilo koja druga aminokiselina. Elongacija može da se koristi za poboljšavanje stabilnosti ili rastvorljivosti peptida.
Termin „T-ćelijski odgovor“ označava specifičnu proliferaciju i aktivaciju efektorskih funkcija indukovanih peptidom in vitro ili in vivo. Za MHC klasa I restrikovane CTL, efektorske funkcije mogu biti liza ciljnih ćelija pulsiranih peptidom, pulsiranih prekursorom peptida ili ciljnih ćelija koje prirodno prezentuju peptid, sekrecija citokina, poželjno interferon-gama, TNF-alfa ili IL-2, indukovana peptidom, sekrecija efektorskih molekula, poželjno granzima ili perforina, indukovana peptidom, ili degranulacija.
Poželjno, kada se CTL specifični za peptid sa ID BR. SEKV 1 do ID BR. SEKV 49, ID BR. SEKV 71 i ID BR. SEKV 74 do 129 testiraju na (upoređuju sa) supstituisane peptide, koncentracija peptida pri kojoj supstituisani peptidi dostižu polovinu maksimalnog povećanja lize u odnosu na pozadinu nije veća od oko 1 mmol/l, poželjno nije veća od oko 1 µmol/l, poželjnije nije veća od oko 1 nmol/l, a još poželjnije nije veća od oko 100 pmol/l, i najpoželjnije nije veća od oko 10 pmol/l. Takođe je poželjno da supstituisani peptid bude prepoznat od strane CTL dobijenih od više od jedne osobe, najmanje dve, a još poželjnije tri osobe.
Tako, ovde predstavljeni epitopi mogu biti identični prirodno javljajućim tumorasociranim ili tumor-specifičnim epitopima ili mogu obuhvatati epitope koji se razlikuju za ne više od 4 ostataka od referentnog peptida, dokle god imaju značajno identičnu antigenu aktivnost. Značajno identična antigena aktivnost podrazumeva stimulaciju T ćelija u uporedivim učestalostima ili brojevima sa uporedivim aviditetom, efektorskim ili memorijskim fenotipom, sličnim obrascem odgovora.
Stimulacija imunskog odgovora zavisi od prisustva antigena koje imunski sistem domaćina prepoznaje kao strane. Otkriće postojanja tumor-asociranih antigena sada je otvorilo mogućnost primene imunskog sistema domaćina za intervenciju u rastu tumora. Trenutno se istražuju različiti mehanizmi za iskorišćavanje kako humoralnog tako i ćelijskog dela imunskog sistema za imunoterapiju raka.
Specifični elementi ćelijskog imunskog odgovora su u stanju da specifično prepoznaju i unište ćelije tumora. Izolacija citotoksičnih T ćelija (CTL) iz ćelijskih populacija koje infiltriraju tumor ili iz periferne krvi navodi na to da takve ćelije imaju značajnu ulogu u prirodnim imunskim odbranama protiv raka. U ovom odgovoru naročito važnu ulogu imaju CD8-pozitivne T ćelije, koje prepoznaju molekule klase I glavnog kompleksa gena tkivne podudarnosti (MHC) koji nose peptide od obično 8 do 12 ostataka dobijene iz proteina ili defektnih proizvoda ribozoma (DRIPovi) koji se nalaze u citosolu. MHC molekuli ljudi se takođe nazivaju humani leukocitni antigeni (HLA).
MHC molekuli klase I se mogu naći na većini ćelija koje sadrže jedro koje prezentuju peptide koji nastaju kao posledica proteolitičkog cepanja uglavnom endogenih proteina, proteina citosola ili jedra, DRIP-ova i većih peptida. Međutim na MHC molekulima klase I se često nalaze i peptidi dobijeni iz endozoma ili egzogenih izvora. Ovaj neklasičan način prezentacije klase I se u literaturi naziva unakrsna prezentacija.
Budući da obe vrste odgovora, CD8 i CD4-zavisan, zajednički i sinergistički doprinose antitumorskom efektu, identifikacija i karakterizacija tumor-asociranih antigena prepoznatih pomoću ili CD8-pozitivnih CTL (MHC molekul klase I) ili pomoću CD4-pozitivnih CTL (MHC molekul klase II) važna je u razvoju tumorskih vakcina. Zato je cilj predmetnog pronalaska, da obezbedi smeše peptida koje sadrže peptide koji se vezuju za MHC komplekse bilo koje od ove dve klase.
Imajući u vidu ozbiljna neželjena dejstva i troškove u vezi sa lečenjem raka preko su potrebni bolji metodi prognoze i dijagnostikovanja. Zato, postoji potreba da se identifikuju drugi faktori koji predstavljaju biomarkere za rak uopšte i konkretno za glioblastom. Pored toga, postoji potreba da se identifikuju faktori koji mogu da se koriste u lečenju raka uopšte i konkretno glioblastoma.
Predmetni pronalazak obezbeđuje peptid koji je koristan u lečenju raka / tumora, poželjno malignih tumora mozga, još poželjnije glioblastoma koji prekomerno ili isključivo prezentuju peptide pronalaska. Za ovaj peptid je pokazano masenom spektrometrijom da ga prirodno prezentuju HLA molekuli na uzorcima primarnog humanog glioblastoma (pogledajte primer 1 i sliku 1).
Dokazano je da su izvorni gen/protein (koji se takođe naziva „protein kompletne dužine“ ili „osnovni protein“) iz kojih su dobijeni peptidi visoko prekomerno eksprimirani u glioblastomu u poređenju sa normalnim tkivima (pogledajte primer 2 i sliku 2 za glioblastom), što pokazuje visok stepen tumorske asocijacije izvornih gena. Štaviše, sami peptidi su jako prekomerno prezentovani na tumorskom tkivu ali ne na normalnim tkivima (pogledajte primer 1 i sliku 3).
HLA-vezani peptidi mogu da budu prepoznati od strane imunskog sistema, specifično T limfocita/T ćelija. T ćelije mogu da unište ćelije koje prezentuju prepoznati kompleks HLA/peptid, npr. ćelije glioblastoma koje prezentuju dobijene peptide.
Za ovde predstavljene peptide je dokazano da su sposobni da stimulišu T-ćelijske odgovore i/ili da su prekomerno prezentovani i da mogu da se koriste za proizvodnju antitela i/ili sTCR u skladu sa predmetnim pronalaskom (pogledajte primere 3 i 1 i slike 4 i 3). Tako su peptidi korisni za generisanje imunskog odgovora kod pacijenta pomoću kojeg mogu da se unište tumorske ćelije. Imunski odgovor kod pacijenta može da se indukuje direktnim davanjem opisanih peptida ili prikladnih prekursorskih supstanci (npr. produženi peptidi, proteini, ili nukleinske kiseline koje kodiraju ove peptide) pacijentu, idealno u kombinaciji sa agensom koji pojačava imunogenost (tj. adjuvansom). Može se očekivati da imunski odgovor koji potiče od takve terapeutske vakcinacije bude visoko specifičan protiv tumorskih ćelija zato što ovde predstavljeni ciljni peptidi nisu prezentovani na normalnim tkivima u uporedivom broju kopija, čime se sprečava rizik od neželjenih autoimunskih reakcija protiv normalnih ćelija kod pacijenta.
Farmaceutske smeše sadrže peptide ili u slobodnom obliku ili u obliku farmaceutski prihvatljive soli. Na način kako je korišćen u ovom tekstu, termin „farmaceutski prihvatljiva so“ se odnosi na derivat opisanih peptida, naznačeno time što je peptid modifikovan pravljenjem kiselih ili baznih soli agensa. Na primer, kisele soli se dobijaju od slobodne baze (tipično naznačeno time što neutralni oblik leka ima neutralnu –NH2 grupu) što uključuje reakciju sa pogodnom kiselinom. Pogodne kiseline za dobijanje kiselih soli uključuju i organske kiseline, npr. sirćetna kiselina, propionska kiselina, glikolna kiselina, piruvična kiselina, oksalna kiselina, jabučna kiselina, malonska kiselina, ćilibarna kiselina, maleinska kiselina, fumarna kiselina, vinska kiselina, limunska kiselina, benzoeva kiselina, cimetna kiselina, bademova kiselina, metansulfonska kiselina, etansulfonska kiselina, p-toluensulfonska kiselina, salicilna kiselina i slične, kao i neorganske kiseline, npr. hlorovodonična kiselina, bromovodonična kiselina, sumporna kiselina, azotna kiselina, fosforna kiselina i slične. Obratno, preparati baznih soli iz kiselih delova koji mogu biti prisutni na peptidu dobijaju se upotrebom farmaceutski prihvatljive baze kao što je natrijum hidroksid, kalijum hidroksid, amonijum hidroksid, kalcijum hidroksid, trimetilamin ili slične.
U jednom posebno poželjnom otelotvorenju, farmaceutske smeše sadrže peptide u vidu soli sirćetne kiseline (acetati), tri-fluor acetata ili hlorovodonične kiseline (hloridi).
Peptid predmetnog pronalaska može da se koristi za stvaranje i razvoj specifičnih antitela protiv kompleksa MHC/peptid. Ona se mogu koristiti za terapiju, tako što će ciljno dovoditi toksine ili radioaktivne supstance u obolelo tkivo. Druga primena ovih antitela može biti ciljno dovođenje radionuklida u obolelo tkivo u svrhe imidžinga kao što je PET. Ova primena može pomoći da se detektuju male metastaze ili utvrdi veličina i precizna lokacija obolelih tkiva.
Zato je predstavljen metod za proizvodnju rekombinantnog antitela koje se specifično vezuje za humani glavni kompleks gena tkivne podudarnosti (MHC) klase I koji je u kompleksu sa HLArestrikovanim antigenom, pri čemu se metod sastoji od: imunizacije genetičkim inžinjeringom napravljenog nehumanog sisara koji sadrži ćelije koje eksprimiraju navedeni humani glavni kompleks gena tkivne podudarnosti (MHC) klase I ili II sa solubilnim oblikom MHC molekula klase I koji je u kompleksu sa navedenim HLA-restrikovanim antigenom; izolacije molekula mRNK iz ćelija navedenog sisara koji nije čovek koje proizvode antitela; proizvodnje biblioteke prikaza faga koja prikazuje molekule proteina kodiranih navedenim molekulima mRNK; i izolacije najmanje jednog faga iz navedene biblioteke prikaza faga, pri čemu taj navedeni najmanje jedan fag prikazuje navedeno antitelo koje se specifično vezuje za navedeni humani glavni kompleks gena tkivne podudarnosti (MHC) klase I koji je u kompleksu sa navedenim HLA-restrikovanim antigenom.
Dalji je aspekt pronalaska da se obezbedi antitelo koje se specifično vezuje za humani glavni kompleks gena tkivne podudarnosti (MHC) klase I koji je u kompleksu sa HLA-restrikovanim antigenom, naznačeno time što je antitelo poželjno poliklonalno antitelo, monoklonalno antitelo, bispecifično antitelo i/ili himerno antitelo.
Predstavljen je metod za proizvodnju navedenog antitela koje se specifično vezuje za humani glavni kompleks gena tkivne podudarnosti (MHC) klase I koji je u kompleksu sa HLArestrikovanim antigenom, pri čemu se metod sastoji od: imunizacije genetičkim inžinjeringom napravljenog nehumanog sisara koji sadrži ćelije koje eksprimiraju navedeni humani glavni kompleks gena tkivne podudarnosti (MHC) klase I ili II sa solubilnim oblikom MHC molekula klase I koji je u kompleksu sa navedenim HLA-restrikovanim antigenom; izolacije molekula mRNK iz ćelija navedenog sisara koji nije čovek koje proizvode antitela; proizvodnje biblioteke prikaza faga koja prikazuje molekule proteina kodiranih navedenim molekulima mRNK; i izolacije najmanje jednog faga iz navedene biblioteke prikaza faga, pri čemu taj navedeni najmanje jedan fag prikazuje navedeno antitelo koje je u stanju da se specifično veže za navedeni humani glavni kompleks gena tkivne podudarnosti (MHC) klase I koji je u kompleksu sa navedenim HLA-restrikovanim antigenom. Odgovarajući metodi za proizvodnju takvih antitela i jednolančanih glavnih kompleksa gena tkivne podudarnosti klase I, kao i ostali alati za proizvodnju ovih antitela izneti su u patentima WO 03/068201, WO 2004/084798, WO 01/72768, WO 03/070752, kao i radu Cohen CJ, Denkberg G, Lev A, Epel M, Reiter Y. Recombinant antibodies with MHC-restricted, peptide-specific, T-cell receptor-like specificity: new tools to study antigen presentation and TCR-peptide-MHC interactions. J Mol Recognit. 2003 SepOct;16(5):324-32.; Denkberg G, Lev A, Eisenbach L, Benhar I, Reiter Y. Selective targeting of melanoma and APCs using a recombinant antibody with TCR-like specificity directed toward a melanoma differentiation antigen. J Immunol.2003 Sep 1;171(5):2197-207; te Cohen CJ, Sarig O, Yamano Y, Tomaru U, Jacobson S, Reiter Y. Direct phenotypic analysis of human MHC class I antigen presentation: visualization, quantitation, and in situ detection of human viral epitopes using peptide-specific, MHC-restricted human recombinant antibodies. J Immunol.2003 Apr 15;170(8):4349-61.
Poželjno, antitelo se vezuje za kompleks sa afinitetom vezivanja manjim od 20 nanomol/l, poželjno ispod 10 nanomol/l, što se u kontekstu predmetnog pronalaska smatra „specifičnim“.
Predstavljen je metod za proizvodnju rastvorljivog T-ćelijskog receptora koji prepoznaje specifični kompleks peptid-MHC. Takvi rastvorljivi T-ćelijski receptori mogu da se naprave od specifičnih T-ćelijskih klonova, a njihov afinitet može da se poveća pomoću mutageneze koja
cilja
komplementarne determinišuće regione. U svrhe odabira T-ćelijskog receptora, može se koristiti prikaz faga (US 2010-0113300, Liddy N, Bossi G, Adams KJ, Lissina A, Mahon TM, Hassan NJ, et al. Monoclonal TCR-redirected tumor cell killing. Nat Med 2012 Jun;18(6):980-987). U svrhu stabilizacije T-ćelijskih receptora u toku prikaza faga i u slučaju praktične primene u vidu leka, alfa i beta lanac mogu da se povežu, npr. neprirodnim disulfidnim vezama, bilo kovalnetnim vezama (jednolančani T-ćelijski receptor) ili pomoću domena dimerizacije (vidite rad Boulter JM, et al. Stable, soluble T-cell receptor molecules for crystallization and therapeutics. Protein Eng 2003 Sep;16(9):707-711.; Card KF, Price-Schiavi SA, Liu B, Thomson E, Nieves E, Belmont H, et al. A soluble single-chain T-cell receptor IL-2 fusion protein retains MHC-restricted peptide specificity and IL-2 bioactivity. Cancer Immunol Immunother 2004 Apr;53(4):345-357; i Willcox BE, Gao GF, Wyer JR, O'Callaghan CA, Boulter JM, Jones EY, et al. Production of soluble alphabeta T-cell receptor heterodimers suitable for biophysical analysis of ligand binding. Protein Sci 1999 Nov;8(11):2418-2423). T-ćelijski receptor može biti povezan sa toksinima, lekovima, citokinima (vidite patent US 2013-0115191), domenima koji regrutuju efektorske ćelije kao što je anti-CD3 domen, itd. kako bi se izvršile određene funkcije na ciljnim ćelijama. Pored toga, on može biti eksprimiran u T ćelijama koje se koriste za adoptivni transfer. Dalje informacije se mogu naći u patentima WO 2004/033685A1 i WO 2004/074322A1. Kombinacija sTCR opisana je u WO 2012/056407A1. Dalji metodi za proizvodnju izneti su u WO 2013/057586A1.
Za selekciju prekomerno prezentovanih peptida, izračunava se profil prezentacije koji pokazuje srednju prezentaciju uzorka kao i varijaciju replikata. Profil postavlja jedno uz drugo uzorke tumora od interesovanja sa polaznim vrednostima uzoraka normalnog tkiva. Svaki od ovih profila može zatim biti konsolidovan u rezultat prekomerne prezentacije pomoću izračunavanja pvrednosti modela linearnih mešovitih efekata (J. Pinheiro, D. Bates, S. DebRoy, Sarkar D., R Core team, nlme: Linear and Nonlinear Mixed Effects Models. 2008) uz prilagođavanje za višestruko testiranje pomoću stope lažnog otkrivanja (Y. Benjamini and Y. Hochberg. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society. Series B (Methodological), svezak 57 (br.1): 289-300, 1995).
Kako bi se HLA ligandi identifikovali i relativno kvantifikovali pomoću masene spektrometrije, HLA molekuli iz uzoraka tkiva zamrznutih brzim zamrzavanjem su prečišćeni a HLA-asocirani peptidi su izolovani. Izolovani peptidi su razdvojeni a sekvence su identifikovane pomoću onlajn eksperimenata nano-elektrosprej-jonizacije (nanoESI) tečne hromatografije-masene spektrometrije (LC-MS). Tako dobijene peptidne sekvence su potvrđene poređenjem obrasca fragmentacije prirodnih TUMAP zabeleženog iz uzoraka glioblastoma sa obrascima fragmentacije odgovarajućih sintetičkih referentnih peptida identičnih sekvenci. Budući da su peptidi direktno identifikovani kao ligandi HLA molekula primarnih tumora, ovi rezultati daju direktan dokaz za prirodnu obradu i prezentaciju identifikovanih peptida na tkivu primarnog tumora dobijenog od pacijenata sa glioblastomom.
Vlasnička linija otkrića XPRESIDENT<®>v2.1 (pogledajte na primer Aplikaciju za registraciju patenta u SAD br.: 13/640,989) omogućava identifikaciju i selekciju relevantnih prekomerno prezentovanih peptida kandidata za vakcinu na osnovu direktne relativne kvantifikacije nivoa HLA-restrikovanog peptida na malignim tkivima u poređenju sa nekoliko različitih nemalignih tkiva i organa. Ovo je postignuto razvojem diferencijalne kvantifikacije bez obeležavanja primenom podataka dobijenih pomoću LC-MS koji su obrađeni vlasničkom linijom za analizu podataka, kombinovanjem algoritama za identifikaciju sekvence, grupisanje spektra, brojanje jona, poravnanje vremena zadržavanja, slabljenje naelektrisanog stanja i normalizaciju.
Ustanovljeni su nivoi prezentacije uključujući procene greške za svaki peptid i uzorak. Identifikovani su peptidi koji su isključivo prezentovani na tumorskom tkivu i peptidi koji su prekomerno prezentovani u tumorskim u poređenju sa nemalignim tkivima i organima.
Kompleksi HLA-peptid iz 32 HLA-A*02-restrikovanih i 13 HLA-A*24-restrikovanih uzoraka tumorskog tkiva glioblastoma zamrznutih brzim zamrzavanjem prečišćeni su a HLA-asocirani peptidi su izolovani i analizirani pomoću LC-MS.
Svi TUMAP koji su sadržani u navedenoj aplikaciji ovim pristupom su identifikovani na uzorcima primarnog glioblastoma čime je potvrđena njihova prezentacija na primarnom glioblastomu.
TUMAP identifikovani na multiplom glioblastomu i normalnim tkivima kvantifikovani su pomoću brojanja jona LC-MS podataka bez obeležavanja. Metod pretpostavlja da oblasti LC-MS signala peptida koreliraju sa njegovom obilnošću u uzorku. Svi kvantitativni signali peptida u raznim LC-MS eksperimentima su normalizovani na osnovu centralne tendencije, uprosečene po uzorku i sjedinjeni u stubičasti dijagram, koji se naziva profil prezentacije. Profil prezentacije objedinjuje različite metode analize kao što su pretraživanje baze podataka proteina, grupisanje spektra, slabljenje naelektrisanog stanja (gubitak naelektrisanja) i poravnanje vremena zadržavanja i normalizaciju.
Predmetni pronalazak se dalje odnosi na prethodno opisani peptid, koji ima sposobnost da se veže za molekul klase I humanog glavnog kompleksa gena tkivne podudarnosti (MHC).
Predmetni pronalazak se dalje odnosi na prethodno opisani peptid, naznačen time što peptid sadrži nepeptidne veze.
Predstavljen je fuzioni protein, koji konkretno sadrži N-terminalne aminokiseline HLA-DR antigen-asociranog nepromenljivog lanca (Ii).
Predmetni pronalazak se dalje odnosi na nukleinsku kiselinu koja kodira prethodno opisani peptid.
Predmetni pronalazak se dalje odnosi na prethodno opisanu nukleinsku kiselinu koja je DNK, cDNK, RNK ili njihova kombinacija.
Predmetni pronalazak se dalje odnosi na vektor ekspresije koji eksprimira prethodno opisanu nukleinsku kiselinu.
Predmetni pronalazak se dalje odnosi na peptid kako je ranije opisan, nukleinsku kiselinu kako je ranije opisana ili vektor ekspresije kako je ranije opisan za upotrebu u lečenju bolesti.
Predmetni pronalazak se dalje odnosi na ćeliju domaćina koja sadrži nukleinsku kiselinu kako je ranije opisana ili vektor ekspresije kako je ranije opisan.
Predmetni pronalazak se dalje odnosi na opisanu ćeliju domaćina koja je antigenprezentujuća ćelija.
Predmetni pronalazak se dalje odnosi na opisanu ćeliju domaćina, naznačeno time što je antigenprezentujuća ćelija dendritična ćelija.
Predmetni pronalazak se dalje odnosi na metod proizvodnje peptida kako je ranije opisan, pri čemu se metod sastoji od kultivisanja opisane ćelije domaćina i izolovanja peptida iz ćelije domaćina ili njenog medijuma za kultivaciju.
Predmetni pronalazak se dalje odnosi na in vitro metod za proizvodnju aktiviranih citotoksičnih T limfocita (CTL), pri čemu se metod sastoji od dovođenja u kontakt in vitro CTL sa humanim MHC molekulima klase I sa ubačenim antigenom eksprimiranim na površini prikladne antigenprezentujuće ćelije u toku
vremenskog perioda koji je dovoljan da se navedeni CTL aktiviraju na antigen-specifičan način, naznačeno time što je navedeni antigen peptid kako je ranije opisan.
Predmetni pronalazak se dalje odnosi na metod kako je opisan, naznačeno time što se antigen postavlja na MHC molekule klase I eksprimirane na površini prikladne antigenprezentujuće ćelije tako što se dovoljna količina antigena dovodi u kontakt sa antigenprezentujućom ćelijom.
Predmetni pronalazak se dalje odnosi na metod kako je ranije opisan, naznačeno time što antigenprezentujuća ćelija sadrži vektor ekspresije koji je u stanju da eksprimira navedeni peptid koji sadrži ID BR. SEKV 28.
Predmetni pronalazak se dalje odnosi na aktivirane citotoksične T limfocite (CTL), proizvedene pomoću opisanog metoda, koji selektivno prepoznaju ćeliju koja aberantno eksprimira polipeptid koji sadrži aminokiselinsku sekvencu kako je ranije opisana.
Predstavljen je metod ubijanja ciljnih ćelija kod pacijenta čije ciljne ćelije aberantno eksprimiraju polipeptid koji sadrži bilo koju opisanu aminokiselinsku sekvencu, pri čemu metod obuhvata davanje efikasnog broja citotoksičnih T limfocita (CTL) pacijentu kako je definisano.
Predmetni pronalazak se dalje odnosi na upotrebu bilo kog opisanog peptida, nukleinske kiseline kako je ranije opisana, vektora ekspresije kako je ranije opisan, ćelije kako je ranije opisana ili aktiviranog citotoksičnog T limfocita kako je ranije opisan za upotrebu u lečenju raka.
Predmetni pronalazak se dalje odnosi na upotrebu kako je ranije opisana, naznačeno time što je navedeni rak glioblastom ili drugi tumor mozga.
Termin „antitela“ je u ovom dokumentu korišćen u širokom smislu i uključuje kako poliklonalna tako i monoklonalna antitela. Pored intaktnih molekula imunoglobulina, pod terminom „antitela“ su takođe obuhvaćeni i fragmenti ili polimeri tih molekula imunoglobulina i humanizovane verzije molekula imunoglobulina, ukoliko oni ispoljavaju bilo koje od željenih svojstava (npr. specifično vezivanje markerskog polipeptida glioblastoma, isporučivanje toksina ćeliji glioblastoma koja eksprimira markerski gen za glioblastom u povećanom stepenu, i/ili inhibicija aktivnosti markerskog polipeptida glioblastoma) opisanih u ovom dokumentu.
Antitela pronalaska mogu biti napravljena pomoću dobro poznatih metoda. Osobi stručnoj u predmetnoj oblasti će biti poznato da za stvaranje antitela pronalaska mogu da se koriste ili markerski polipeptidi za glioblastom kompletne dužine ili njihovi fragmenti. Polipeptid koji će se koristiti za stvaranje antitela pronalaska može biti parcijalno ili kompletno prečišćen iz prirodnog izvora, ili može biti proizveden pomoću tehnika rekombinantne DNK.
Na primer, cDNK koja kodira PTPRZ1, BCAN i FABP7, ili bilo koji drugi polipeptid u skladu sa ID BR. SEKV 1 do ID BR. SEKV 49, ID BR. SEKV 71, i ID BR. SEKV 74 do 129 ili njihovu varijantnu sekvencu koja je najmanje 90% homologna sa ID BR. SEKV 1 do ID BR. SEKV 49, ID BR. SEKV 71, i ID BR. SEKV 74 do 129, ili njegov fragment, može biti eksprimirana u prokariotskim ćelijama (npr. bakterije) ili eukariotskim ćelijama (npr. kvasci, insekti ili ćelije sisara), nakon čega rekombinantni protein može da se prečisti i koristi za stvaranje preparata monoklonalnog ili poliklonalnog antitela koje se specifično vezuje za markerski polipeptid glioblastoma koji se koristi za stvaranje antitela.
Osobi stručnoj u predmetnoj oblasti će biti poznato da stvaranje dva ili više različitih skupova monoklonalnih ili poliklonalnih antitela maksimizira verovatnoću dobijanja antitela sa specifičnošću i afinitetom neophodnim za njegovu namenu (npr. ELISA, imunohistohemija, in vivo imidžing, terapija imunotoksinima). Antitela se testiraju za njihovu željenu aktivnost pomoću poznatih metoda, u skladu sa svrhom za koju će se antitela koristiti (npr. ELISA, imunohistohemija, imunoterapija, itd; za dalje smernice o stvaranju i testiranju antitela pogledajte, npr. Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988). Na primer, antitela mogu da se testiraju u ELISA testovima, Western blot testovima, imunohistohemijskim bojenjem uzoraka glioblastoma fiksiranih u formalinu ili zamrznutih isečaka tkiva. Nakon njihove inicijalne in vitro karakterizacije, antitela namenjena za terapeutsku ili in vivo dijagnostičku upotrebu testiraju se u skladu sa poznatim metodama kliničkog testiranja.
Termin „monoklonalno antitelo“ na način na koji je korišćen u ovom dokumentu odnosi se na antitelo dobijeno iz značajno homogene populacije antitela, to jest, pojedinačna antitela koja sačinjavaju populaciju su identična izuzev za moguće prirodno javljajuće mutacije koje mogu biti prisutne u manjim količinama. Monoklonalna antitela opisana u ovom dokumentu specifično obuhvataju „himerna“ antitela u kojima je deo teškog i/ili lakog lanca identičan sa ili homologan sa korespondentnim sekvencama u antitelima dobijenim iz određenih vrsta ili koja pripadaju određenoj klasi ili potklasi antitela, dok je preostali deo lanca (lanaca) identičan sa ili homologan sa korespondentnim sekvencama u antitelima dobijenim iz drugih vrsta ili koja pripadaju drugoj klasi ili potklasi antitela, kao i fragmente takvih antitela, sve dok oni ispoljavaju željenu antagonističku aktivnost (patent registrovan u SAD pod br.4,816,567).
Monoklonalna antitela pronalaska mogu da se pripreme pomoću metoda hibridoma. U metodu hibridoma, miš ili druga odgovarajuća životinja domaćin se obično imunizuje sa sredstvom za imunizaciju kako bi se izazvali limfociti koji proizvode ili su u stanju da proizvode antitela koja
će specifično da se vezuju za sredstvo za imunizaciju. Alternativno, imunizacija limfocita može da se izvrši in vitro.
Monoklonalna antitela mogu takođe da se naprave pomoću metoda rekombinantne DNK, kao što su one koje su opisane u patentu registrovanom u SAD pod br.4,816,567. DNK koja kodira monoklonalna antitela pronalaska može lako da se izoluje i sekvencionira pomoću konvencionalnih procedura (npr. primenom oligonukleotidnih proba koje su sposobne da se specifično vežu za gene koji kodiraju teške i lake lance mišjih antitela).
Za pripremanje monovalentnih antitela takođe su pogodne i in vitro metode. Digestija antitela u cilju proizvodnje njihovih fragmenata, konkretno, Fab fragmenata, može da se izvrši pomoću rutinskih tehnika poznatih u predmetnoj oblasti. Na primer, digestija može da se izvrši pomoću papaina. Primeri papainske digestije opisani su u patentu WO 94/29348 objavljenom 22. decembra 1994. i patentu registrovanom u SAD pod brojem 4,342,566. Papainska digestija antitela tipično proizvodi dva identična fragmenta koja vezuju antigen, koji se nazivaju Fab fragmenti, i svaki sadrži jedno mesto za vezivanje antigena i rezidualni Fe fragment. Tretiranje pepsinom proizvodi fragment koji ima dva mesta za kombinovanje antigena i sposobnost da unakrsno vezuje antigen.
Fragmenti antitela, bilo da su povezani sa drugim sekvencama ili ne, mogu takođe uključivati insercije, delecije, supstitucije, ili druge izabrane modifikacije konkretnih regiona ili specifičnih aminokiselinskih ostataka, pod uslovom da aktivnost fragmenta nije značajno izmenjena ili narušena u poređenju sa nemodifikovanim antitelom ili fragmentom antitela. Ove modifikacije mogu obezbediti neka dodatna svojstva, kao što je uklanjanje/dodavanje aminokiselina sposobnih za disuflidno vezivanje, povećanje njegove biološke dugovečnosti, menjanje njegovih sekretornih karakteristika itd. U svakom slučaju, fragment antitela mora da poseduje bioaktivno svojstvo, kao što je aktivnost vezivanja, regulacija vezivanja na domenu za vezivanje, itd. Funkcionalni ili aktivni regioni antitela mogu biti identifikovani pomoću mutageneze specifičnog regiona proteina, nakon čega sledi ekspresija i testiranje eksprimiranog polipeptida. Takvi metodi su očigledni osobi stručnoj u predmetnoj oblasti i mogu uključivati mutagenezu specifičnu za mesto nukleinske kiseline koja kodira fragment antitela.
Antitela pronalaska mogu dalje da sadrže humanizovana antitela ili humana antitela. Humanizovani oblici ne-humanih (npr. mišjih) antitela su himerni imunoglobulini, imunoglobulinski lanci ili njihovi fragmenti (poput Fv, Fab, Fab' ili druge podsekvence antitela koje vezuju antigen) koji sadrže najmanju sekvencu dobijenu iz ne-humanog imunoglobulina. Humanizovana antitela uključuju humane imunoglobuline (recipijentno antitelo) u kojim su ostaci iz komplementarnog determinišućeg regiona (CDR) recipijenta zamenjeni ostacima iz CDR ne-humanih vrsta (donorsko antitelo) kao što je miš, pacov ili zec koji imaju željenu specifičnost, afinitet i kapacitet. U nekim slučajevima, ostaci okvira Fv (FR) humanog imunoglobulina se zamenjuju odgovarajućim ne-humanim ostacima. Humanizovana antitela mogu takođe da sadrže ostatke koji se ne nalaze niti u recipijentnom antitelu niti u uvezenim sekvencama CDR ili okvira. Uopšteno, humanizovano antitelo će u značajnoj meri da sadrži sve od najmanje jednog, i tipično dva, varijabilna domena, u kojem svi ili značajno svi CDR regioni odgovaraju regionima ne-humanog imunoglobulina i svi ili značajno svi FR regioni su regioni konsenzus sekvence humanog imunoglobulina. Humanizovano antitelo će takođe optimalno sadržati najmanje deo konstantnog regiona imunoglobulina (Fc), tipično iz humanog imunoglobulina.
Metodi humanizacije ne-humanih antitela su dobro poznati u predmetnoj oblasti. Uopšteno, humanizovano antitelo ima jedan ili više aminokiselinskih ostataka uvedenih u njega iz izvora koji nije ljudski. Ovi ne-humani aminokiselinski ostaci se često nazivaju „uvozni“ ostaci, koji se tipično uzimaju iz „uvoznog“ varijabilnog domena. Humanizacija se u suštini može izvršiti supstitucijom glodarskih CDR ili CDR sekvenci za korespondentne sekvence humanog antitela. U skladu sa tim, takva „humanizovana“ antitela su himerna antitela (patent registrovan u SAD pod brojem 4,816,567), naznačena time što je značajno manje od intaktnog humanog varijabilnog domena supstituisano odgovarajućim sekvencama iz ne-humanih vrsta. U praksi, humanizovana antitela su tipično humana antitela u kojima su neki CDR ostaci, a moguće i neki FR ostaci, supstituisani ostacima sa analognih mesta u antitelima glodara.
U ovu svrhu mogu da se upotrebe transgenske životinje (npr. miševi) koji su sposobni da nakon imunizacije proizvedu kompletan repertoar humanih antitela u odsustvu endogene proizvodnje imunoglobulina. Na primer, opisano je da homozigotna delecija gena koji kodira region spajanja teškog lanca antitela kod miševa sa himernom i gametskom mutacijom rezultira kompletnom inhibicijom endogene proizvodnje antitela. Transfer humanog gametskog niza gena za imunoglobuline u takve miševe sa gametskom mutacijom rezultovaće proizvodnjom humanih antitela nakon izazivanja od strane antigena. Humana antitela mogu takođe da se proizvedu u bibliotekama prikaza faga.
Antitela pronalaska se poželjno daju ispitaniku u farmaceutski prihvatljivom nosaču. Tipično, koristi se odgovarajuća količina farmaceutski prihvatljive soli za pravljenje formulacije kako bi se napravila izotona formulacija. Primeri farmaceutski prihvatljivog nosača uključuju fiziološki rastvor, Ringerov rastvor i rastvor dekstroze. pH rastvora je poželjno od oko 5 do oko 8, još poželjnije od oko 7 do oko 7,5. Dalji nosači obuhvataju preparate sa održivim oslobađanjem, kao što su polupropustljive matrice solidnih hidrofobnih polimera koji sadrže antitelo, pri čemu su matrice u obliku oblikovanih proizvoda, npr. filmovi, lipozomi ili mikročestice. Osobama stručnim u predmetnoj oblasti će biti očigledno da određeni nosači mogu biti poželjniji u zavisnosti od, na primer, načina primene i koncentracije antitela koje se primenjuje.
Antitela se mogu dati ispitaniku, pacijentu ili ćeliji pomoću injekcije (npr. intravenska, intraperitonealna, potkožna, intramuskularna) ili pomoću drugih metoda kao što je infuzija, koje osiguravaju isporučivanje u cirkulaciju u efikasnom obliku. Antitela mogu takođe da se primene intratumorskim ili peritumorskim putevima, kako bi ispoljila lokalne kao i sistemske terapijske efekte. Preferira se lokalna ili intravenska injekcija.
Efikasne doze i režimi primene antitela mogu da se utvrde empirijski a takva određivanja spadaju u okvir veštine predmetne oblasti. Osobe stručne u predmetnoj oblasti će razumeti da će doza antitela, koja mora da se primeni, zavisiti od, na primer, ispitanika koji će dobiti antitelo, načina primene, konkretne vrste korišćenog antitela i drugih lekova koji se primenjuju. Tipična dnevna doza antitela koje se koristi samostalno može se kretati od oko 1 µg/kg do 100 mg/kg telesne težine ili više dnevno, u zavisnosti od gorepomenutih faktora. Nakon primene antitela za tretiranje glioblastoma efikasnost terapijskog antitela može da se proceni na različite načine koji su dobro poznati osobi stručnoj u predmetnoj oblasti. Na primer, veličina, broj i/ili distribucija glioblastoma kod ispitanika koji prima terapiju, može da se prati pomoću standardnih tehnika za imidžing tumora. Antitelo koje se primenjuje u terapijske svrhe, koje zaustavlja rast tumora, rezultuje smanjivanjem veličine tumora i/ili sprečava nastanak novih tumora u poređenju sa tokom bolesti koji bi nastao u odsustvu primene antitela, jeste efikasno antitelo za lečenje glioblastoma.
Budući da su ovde predstavljeni markeri glioblastoma PTPRZ1, BCAN, FABP7 visoko eksprimirani u ćelijama glioblastoma a eksprimirani su u ekstremno malim nivoima u normalnim ćelijama, inhibicija ekspresije PTPRZ1, BCAN, FABP7 ili aktivnosti polipeptida može biti integrisana u bilo koju terapijsku strategiju za lečenje ili prevenciju glioblastoma.
U metodama opisanim ranije u tekstu, koje obuhvataju unošenje i preuzimanje egzogene DNK u ćelije ispitanika (tj. transdukciju ili transfekciju gena), nukleinske kiseline predmetnog pronalaska mogu biti u obliku ogoljene DNK ili nukleinske kiseline mogu biti u vektoru za dostavljanje nukleinskih kiselina ćelijama u cilju inhibicije ekspresije proteina tumorskog markera karcinoma želuca. Vektor može biti komercijalno dostupan preparat, kao što je adenovirusni vektor (Quantum Biotechnologies, Inc. (Laval, Quebec, Kanada). Dostavljanje nukleinskih kiselina ili vektora ćelijama može biti putem različitih mehanizama. U jednom primeru, dostavljanje je moguće putem lipozoma, primenom komercijalno dostupnih preparata lipozoma kao što su LIPOFECTIN, LIPOFECTAMINE (GIBCO- 25 BRL, Inc, Gaithersburg, Merilend), SUPERFECT (Qiagen, Inc. Hilden, Nemačka) i TRANSFECTAM (Promega Biotec, Inc, Madison, Viskonsin), kao i drugih lipozoma koji su razvijeni u skladu sa standardnim procedurama u predmetnoj oblasti. Pored toga, nukleinska kiselina ili vektor ovog pronalaska mogu da se dostavljaju in vivo pomoću elektroporacije, tehnologije koja je dostupna od kompanije Genetronics, Inc. (San Diego, Kalifornija) kao i pomoću aparata SONOPORATION (ImaRx Pharmaceutical Corp, Tucson, Arizona).
Predmetni pronalazak tako obezbeđuje peptid koji sadrži ID BR. SEKV 28, ili njegovu farmaceutski prihvatljivu so.
Peptid pronalaska ima sposobnost da se vezuje za molekul humanog glavnog kompleksa gena tkivne podudarnosti (MHC) klase I.
U predmetnom pronalasku, termin „homologno“ odnosi se na stepen identiteta između sekvenci dveju aminokiselinskih sekvenci, tj. peptidnih ili polipeptidnih sekvenci. Gore pomenuta „homologija“ utvrđena je upoređivanjem dve sekvence koje su poravnate pod optimalnim uslovima preko sekvenci koje se upoređuju. Sekvence koje se ovde upoređuju mogu imati adiciju ili deleciju (na primer, praznina i slično) u optimalnom poravnanju dveju sekvenci. Takva homologija sekvence može da se izračuna kreiranjem poravnanja pomoću, na primer, ClustalW algoritma. Opšte dostupni softver za analizu sekvence, specifičnije, Vector NTI, GENETYX ili alatke za analizu koje su dostupne u javnim bazama podataka.
Osoba stručna u predmetnoj oblasti će moći da proceni da li će T ćelije koje su indukovane varijantom specifičnog peptida biti sposobne da unakrsno reaguju sa samim peptidom (Fong et al., 2001); (Zaremba et al., 1997; Colombetti et al., 2006; Appay et al., 2006).
Ovi CTL mogu naknadno da unakrsno reaguju sa ćelijama i ubijaju ćelije koje eksprimiraju polipeptid koji sadrži prirodnu aminokiselinsku sekvencu srodnog peptida kako je definisan u aspektima pronalaska. Kako se može izvesti iz naučne literature (Rammensee et al., 1997) i baza podataka (Rammensee et al., 1999), određene pozicije peptida koji vezuju HLA su tipično sidreni ostaci koji obrazuju jezgrenu sekvencu koja se uklapa u vezujući motiv HLA receptora, koji je definisan polarnim, elektrofizičkim, hidrofobnim i prostornim svojstvima polipeptidnih lanaca koji čine udubljenje za vezivanje.
Naravno, peptid u skladu sa predmetnim pronalaskom će imati sposobnost da se veže za molekul humanog glavnog kompleksa gena tkivne podudarnosti (MHC) klase I. Vezivanje peptida ili varijante za MHC kompleks može da se testira pomoću metoda poznatih u predmetnoj oblasti.
Predstavljen je fuzioni protein koji sadrži, na primer, 80 N-terminalnih aminokiselina HLA-DR antigen-asociranog nepromenljivog lanca (p33, u nastavku koji je dobijen od američkog Nacionalnog centra za biotehnološke informacije (NCBI), GenBank pristupni broj X00497.
Pored toga, peptid može biti dalje modifikovan da bi se poboljšala stabilnost i/ili vezivanje za MHC molekule kako bi se izazvao jači imunski odgovor. Metodi za takvu optimizaciju peptidne sekvence su dobro poznati u predmetnoj oblasti i uključuju, na primer, uvođenje reverznih peptidnih veza ili nepeptidnih veza.
U reverznoj peptidnoj vezi, aminokiselinski ostaci nisu povezani peptidnim (-CO-NH-) vezama već je peptidna veza obrnuta. Takvi retro-inverzni peptidomimetici mogu biti napravljeni pomoću metoda poznatih u predmetnoj oblasti, na primer poput onih opisanih u radu Meziere et al (1997) J. Immunol.159, 3230-3237. Ovaj pristup obuhvata pravljenje pseudopeptida koji sadrže izmene koje uključuju kostur, a ne orijentaciju bočnih lanaca. Meziere i saradnici (1997) pokazuju da su ovi pseudopeptidi korisni za vezivanje MHC i T-pomoćničke ćelijske odgovore. Retro-inverzni peptidi, koji sadrže NH-CO veze umesto CO-NH peptidnih veza, mnogo su otporniji na proteolizu.
Nepeptidna veza je, na primer, -CH2-NH, -CH2S-, -CH2CH2-, -CH=CH-, -COCH2-, -CH(OH)CH2- i -CH2SO-. Patent registrovan u Sjedinjenim Američkim Državama pod brojem 4,897,445 obezbeđuje metod za sintezu nepeptidnih veza (-CH2-NH) u solidnoj fazi u polipeptidnim lancima koji uključuje polipeptide sintetisane pomoću standardnih postupaka i nepeptidnu vezu sintetisanu reakcijom amino-aldehida i aminokiseline u prisustvu NaCNBH3.
Woodward-ov reagens K može da se koristi za modifikaciju specifičnih ostataka glutaminske kiseline. N-(3-(dimetilamino)propil)-N’-etilkarbodiimid može da se koristi za obrazovanje intramolekularnih unakrsnih veza između lizinskog ostatka i ostatka glutaminske kiseline.
Peptid naznačen time što peptid sadrži nepeptidne veze je poželjno otelotvorenje pronalaska. Uopšteno, peptidi (najmanje oni koji sadrže peptidne veze između aminokiselinskih ostataka) mogu da se sintetišu pomoću Fmoc-poliamid režima sinteze peptida u solidnoj fazi kako je izloženo u radu Lu et al. (1981) i referencama u istom. Privremenu zaštitu N-amino grupe obezbeđuje 9-fluorenilmetiloksikarbonil (Fmoc) grupa.
Ponovljeno cepanje ove zaštitne grupe koja je veoma labilna u bazama vrši se pomoću 20% piperidina u N,N-dimetilformamidu. Funkcionalnosti bočnog lanca mogu da se zaštite u obliku njihovih butil etara (u slučaju serina, treonina i tirozina), butil estara (u slučaju glutaminske kiseline i asparaginske kiseline), butiloksikarbonil derivata (u slučaju lizina i histidina), tritil derivata (u slučaju cisteina) i 4-metoksi-2,3,6-trimetilbenzensulfonil derivata (u slučaju arginina). Kada su glutamin ili asparagin C-terminalni ostaci, za zaštitu amido funkcionalnosti bočnog lanca koristi se 4,4'-dimetoksibenzhidril grupa. Potpora solidne faze zasniva se na polidimetil-akrilamid polimeru koji se sastoji od tri monomera dimetilakrilamida (monomer kostura), bisakriloiletilen diamina (unakrsni povezivač) i akriloilsarkozin metil estra (agens za funkcionalizaciju). Peptidsmola odvojivi vezani agens koji se koristi je derivat 4-hidroksimetil-fenoksisirćetne kiseline koji je labilan u kiselinama. Svi derivati aminokiselina se dodaju u obliku njihovih preformiranih simetričnih anhidridnih derivata sa izuzetkom asparagina i glutamina, koji se dodaju pomoću
procedure reverznog spajanja posredovane N, N-dicikloheksilkarbodiimid/1hidroksibenzotriazolom. Sve reakcije spajanja i deprotekcije se prate pomoću ninhidrin, trinitrobenzen sulfonska kiselina ili izotin test procedura. Nakon završetka sinteze, peptidi se odvajaju od potpore od smole sa istovremenim uklanjanjem zaštitnih grupa bočnog lanca tretiranjem sa 95% trifluorosirćetnom kiselinom koja sadrži 50% smešu čistača. Čistači koji se uobičajeno koriste obuhvataju etanditiol, fenol, anizol i vodu, pri čemu tačan izbor zavisi od konstituentnih aminokiselina peptida koji se sintetizuje. Takođe je moguća kombinacija metodologija za solidnu fazu i fazu rastvora za sintezu peptida (pogledajte, na primer, (Bruckdorfer et al., 2004) i reference koje su tamo citirane).
Trifluorosirćetna kiselina se uklanja evaporacijom in vacuo, sa naknadnom trituracijom sa dietil etrom što obezbeđuje sirovi peptid. Svi prisutni čistači se uklanjaju jednostavnim postupkom ekstrakcije koji po liofilizaciji vodene faze obezbeđuje sirovi peptid bez čistača. Reagensi za sintezu peptida su generalno dostupni kod npr. kompanije Calbiochem-Novabiochem (UK) Ltd, Nottingham NG72QJ, UK.
Prečišćavanje može da se vrši pomoću bilo koje tehnike, ili kombinacije tehnika kao što su rekristalizacija, ekskluziona hromatografija, jonoizmenjivačka hromatografija, hidrofobna hromatografija i (obično) reverzno-fazna tečna hromatografija visokih performansi upotrebom npr. acetonitril/voda gradijenta separacije.
Analiza peptida može da se sprovede upotrebom hromatografije na tankom sloju, elektroforeze, konkretno kapilarne elektroforeze, ekstrakcije iz čvrste faze (CSPE), reverzno-fazne tečne hromatografije visokih performansi, analizom aminokiselina nakon kisele hidrolize i pomoću maseno spektrometrijske analize korišćenjem bombardovanja brzim atomima (FAB), kao i MALDI i ESI-Q-TOF maseno spektrometrijske analize.
Dalji aspekt pronalaska obezbeđuje nukleinsku kiselinu (na primer polinukleotid) koja kodira peptid pronalaska. Polinukleotid može biti, na primer, DNK, cDNK, RNK ili njihove kombinacije, bilo jedno- i/ili dvolančana, ili nativni ili stabilizovani oblici polinukleotida, kao što su, na primer, polinukleotidi sa fosforotioatnim kosturom i oni mogu i ne moraju sadržati introne sve dok kodiraju peptid. Naravno, polinukleotid može da kodira isključivo peptide koji sadrže prirodno postojeće aminokiselinske ostatke spojene prirodnim peptidnim vezama. Još jedan aspekt pronalaska obezbeđuje vektor ekspresije koji eksprimira polipeptid u skladu sa pronalaskom.
Razvijeni su raznovrsni metodi za povezivanje polinukleotida, naročito DNK, sa vektorima, na primer, preko komplementarno kohezivnih terminusa. Na primer, komplementarni homopolimerni traktovi mogu da se dodaju na DNK segment koji se umeće u vektorsku DNK. Vektor i DNK segment se zatim spajaju vodoničnom vezom između komplementarnih homopolimernih repova kako bi se obrazovali molekuli rekombinantne DNK.
Sintetički povezivači koji sadrže jedno ili više restrikcionih mesta obezbeđuju alternativni metod za spajanje DNK segmenta sa vektorima. Sintetički povezivači koji sadrže raznovrsna restrikciona endonukleazna mesta komercijalno su dostupni iz velikog broja izvora, uključujući International Biotechnologies Inc., New Haven, CN, SAD.
Poželjan metod modifikovanja DNK koja kodira polipeptid pronalaska koristi lančanu reakciju polimeraze koja je izneta od strane (Saiki et al., 1988)). Ovaj metod može da se koristi za uvođenje DNK u pogodan vektor, na primer, ugradnjom u prikladna restrikciona
mesta, ili se može koristiti za modifikaciju DNK na druge korisne načine koji su poznati u predmetnoj oblasti. Ako se koriste virusni vektori, poželjni su poks- ili adenovirus vektori.
DNK (ili u slučaju retrovirusnih vektora, RNK) može zatim da se eksprimira u prikladnom domaćinu kako bi proizvodio polipeptid koji sadrži peptid pronalaska. Tako, DNK koja kodira peptid pronalaska može da se koristi u skladu sa poznatim tehnikama, odgovarajuće modifikovanih u smislu ovde sadržanih učenja, da se konstruiše vektor ekspresije, koji se zatim koristi da se odgovarajuća ćelija domaćin transformiše za ekspresiju i proizvodnju polipeptida pronalaska. Takve tehnike uključuju one izložene u patentima registrovanim u SAD pod br. 4,440,859, 4,530,901, 4,582,800, 4,677,063, 4,678,751, 4,704,362, 4,710,463, 4,757,006, 4,766,075 i 4,810,648.
DNK (ili u slučaju retrovirusnih vektora, RNK) koja kodira polipeptid koji sačinjava jedinjenje pronalaska može da se spoji sa širokim spektrom drugih DNK sekvenci za uvođenje u odgovarajućeg domaćina. Pridružena DNK će zavisiti od prirode domaćina, načina uvođenja DNK u domaćina, i od toga da li se želi epizomalno održavanje ili integracija.
Uopšteno, DNK se umeće u vektor ekspresije, kao što je plazmid, u pravilnoj orijentaciji i pravom okviru čitanja za ekspresiju. Ako je neophodno, DNK može da se poveže sa odgovarajućim regulatornim kontrolnim nukleotidnim sekvencama za transkripciju i translaciju koje prepoznaje željeni domaćin, iako su takve kontrole generalno dostupne u vektoru ekspresije. Vektor se zatim standardnim tehnikama uvodi u domaćina. Uopšteno, vektor neće transformisati sve domaćine. Zato će biti neophodno da se izaberu transformisane ćelije domaćini. Jedna tehnika selekcije obuhvata inkorporiranje DNK sekvence u vektor ekspresije, sa svim neophodnim kontrolnim elementima, koja kodira osobinu po izboru u transformisanoj ćeliji, kao što je otpornost na antibiotike.
Alternativno, gen za takvu osobinu po izboru može biti na drugom vektoru, koji se koristi za kotransformaciju željene ćelije domaćina.
Ćelije domaćini koje su transformisane pomoću rekombinantne DNK pronalaska se zatim kultiviraju dovoljno dugo i u odgovarajućim uslovima koji su poznati osobama stručnim u predmetnoj oblasti, uzimajući u obzir učenja izneta u ovom dokumentu, kako bi se omogućila ekspresija polipeptida, koji nakon toga može da se prikupi.
Poznati su mnogi sistemi za ekspresiju, uključujući bakterije (na primer E. coli i Bacillus subtilis), kvasnice (na primer Saccharomyces cerevisiae), filamentozne gljivice (na primer Aspergillus spec.), biljne ćelije, životinjske ćelije i ćelije insekata. Poželjno, sistem mogu biti ćelije sisara kao što su CHO ćelije dostupne iz ATCC kolekcije biologije ćelija.
Tipični plazmidni vektor ćelije sisara za konstitutivnu ekspresiju sadrži CMV ili SV40 promoter sa prikladnim poli A repom i markerom rezistencije, kao što je neomicin. Jedan primer je pSVL koji je dostupan kod kompanije Pharmacia, Piscataway, NJ, SAD. Primer inducibilnog sisarskog vektora ekspresije je pMSG, koji je takođe dostupan kod kompanije Pharmacia. Korisni kvasnički plazmidni vektori su pRS403-406 i pRS413-416 koji su generalno dostupni kod kompanije Stratagene Cloning Systems, La Jolla, CA 92037, SAD. Plazmidi pRS403, pRS404, pRS405 i pRS406 su integrišući plazmidi kvasnice (YIps) i inkorporiraju selektivne markere kvasnica HIS3, TRP1, LEU2 i URA3. Plazmidi pRS413-416 su centromerni plazmidi kvasnice (Ycps). Vektori zasnovani na CMV promoteru (na primer od kompanije Sigma-Aldrich) obezbeđuju prolaznu ili stabilnu ekspresiju, citoplazmatsku ekspresiju ili sekreciju, i N-terminalno ili Cterminalno označavanje u različitim kombinacijama FLAG, 3xFLAG, c-myc ili MAT. Ovi fuzioni proteini omogućavaju detekciju, prečišćavanje i analizu rekombinantnog proteina. Dvostruko označene fuzije obezbeđuju fleksibilnost prilikom detekcije.
Snažni regulatorni region, humani citomegalovirus (CMV) promoter dovodi nivoe ekspresije konstitutivnog proteina čak i do 1 mg/l u COS ćelijama. Za manje potentne ćelijske linije, nivoi proteina su tipično ~0,1 mg/l. Prisustvo izvora SV40 replikacije će rezultovati visokim nivoima DNK replikacije u COS ćelijama koje dozvoljavaju replikaciju SV40. CMV vektori, na primer, mogu sadržati izvor pMB1 (derivat pBR322) za replikaciju u bakterijskim ćelijama, gen za blaktamazu za izbor rezistencije na ampicilin u bakterijama, hGH poliA i izvor f1. Vektori koji sadrže preprotripsin (PPT) vodeću sekvencu mogu usmeriti sekreciju FLAG fuzionih proteina u medijum za kultivaciju za prečišćavanje pomoću ANTI-FLAG antitela, smola i pločica. Drugi vektori i sistemi za ekspresiju su dobro poznati u predmetnoj oblasti za upotrebu sa raznim ćelijama domaćinima.
Predmetni pronalazak se takođe odnosi na ćeliju domaćina koja je transformisana sa konstruktom vektora polinukleotida predmetnog pronalaska. Ćelija domaćin može biti prokariotska ili eukariotska. Bakterijske ćelije mogu biti preferirane prokariotske ćelije domaćini u nekim okolnostima i tipično su soj E. coli kao što su, na primer, sojevi E. coli DH5 dostupan kod kompanije Bethesda Research Laboratories Inc., Bethesda, MD, SAD, i RR1 dostupan kod organizacije American Type Culture Collection (ATCC) iz mesta Rockville, MD, SAD (Br. ATCC 31343). Preferirane eukariotske ćelije domaćini obuhvataju kvasnice, ćelije insekata i sisara, poželjno ćelije kičmenjaka kao što su ćelije miševa, pacova, majmuna ili humane fibroblastne ćelijske linije i ćelijske linije kolona. Ćelije domaćini kvasnica uključuju YPH499, YPH500 i YPH501, koje su generalno dostupne kod kompanije Stratagene Cloning Systems, La Jolla, CA 92037, SAD. Preferirane ćelije domaćini sisara uključuju ovarijalne ćelije kineskog hrčka (CHO) dostupne kod organizacije ATCC kao CCL61, NIH embrionske ćelije švajcarskog miša NIH/3T3 dostupne kod organizacije ATCC kao CRL 1658, COS-1 ćelije dobijene iz bubrega majmuna dostupne kod organizacije ATCC kao CRL 1650 i 293 ćelije koje su humane embrionske ćelije bubrega. Preferirane ćelije insekata su Sf9 ćelije koje mogu da se transfektuju sa bakulovirusnim vektorima ekspresije. Kratak pregled izbora pogodnih ćelija domaćina za ekspresiju može se naći u, na primer, udžbeniku autora Paulina Balbás i Argelia Lorence „Methods in Molecular Biology Recombinant Gene Expression, Reviews and Protocols“, deo jedan, drugo izdanje, ISBN 978-1-58829-262-9, i drugoj literaturi poznatoj stručnoj osobi.
Transformacija odgovarajućih ćelija domaćina sa DNK konstruktom predmetnog pronalaska postiže se dobro poznatim metodama koje tipično zavise od vrste korišćenog vektora. U pogledu transformacije prokariotskih ćelija domaćina, pogledajte, na primer, Cohen et al (1972) Proc. Natl. Acad. Sci. USA 69, 2110, i Sambrook et al (1989) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. Transformacija ćelija kvasnica opisana je u radu Sherman et al (1986) Methods In Yeast Genetics, A Laboratory Manual, Cold Spring Harbor, NY. Metod koji je izložio Beggs (1978) Nature 275,104-109 takođe je koristan. U pogledu ćelija kičmenjaka, reagensi koji su korisni za transfekciju takvih ćelija, na primer kalcijum fosfat i DEAE-dekstran ili formulacije lipozoma, dostupni su kod kompanije Stratagene Cloning Systems, ili Life Technologies Inc., Gaithersburg, MD 20877, SAD. Elektroporacija je takođe korisna za transformaciju i/ili transfekciju ćelija i dobro je poznata u predmetnoj oblasti za transformaciju ćelija kvasnica, bakterijskih ćelija, ćelija insekata i ćelija kičmenjaka.
Uspešno transformirane ćelije, tj. ćelije koje sadrže DNK konstrukt predmetnog pronalaska, mogu da se identifikuju pomoću dobro poznatih tehnika kao što je PCR. Alternativno, prisustvo proteina u supernatantu može da se detektuje pomoću antitela.
Podrazumeva se da su određene ćelije domaćini pronalaska korisne za pripremanje peptida pronalaska, na primer, bakterijske, ćelije kvasnica i insekata. Međutim, u određenim terapeutskim metodama mogu biti korisne druge ćelije domaćini. Na primer, antigenprezentujuće ćelije, kao što su dendritične ćelije, mogu korisno da se upotrebe za ekspresiju peptida pronalaska tako da oni mogu da se ubace u odgovarajuće MHC molekule. Tako, prikazani pronalazak obezbeđuje ćeliju domaćina koja se sastoji od nukleinske kiseline ili vektora ekspresije u skladu sa pronalaskom.
U jednom poželjnom otelotvorenju ćelija domaćin je antigen-prezentujuća ćelija, konkretno dendritična ćelija ili antigen-prezentujuća ćelija. APĆ u koje je postavljen rekombinantni fuzioni protein koje sadrže prostatičnu kiselu fosfatazu (PAP) trenutno se ispituju za lečenje karcinoma prostate (Sipuleucel–T) (Small et al., 2006; Rini et al., 2006).
Dalji aspekt pronalaska obezbeđuje metod za proizvodnju peptida, pri čemu metod obuhvata kultivisanje ćelije domaćina i izolaciju peptida iz ćelije domaćina ili njegovog medijuma za kultivaciju.
U drugom otelotvorenju, peptid, nukleinska kiselina ili vektor ekspresije pronalaska koriste se u medicini. Na primer, peptid ili njegova varijanta mogu biti pripremljeni za intravensku (i.v.) injekciju, potkožnu (s.c.) injekciju, intradermalnu (i.d.) injekciju, intraperitonealnu (i.p.) injekciju, intramuskularnu (i.m.) injekciju. Poželjni načini primene injekcije peptida obuhvataju s.c., i.d., i.p., i.m. i i.v. Poželjni načini primene injekcije DNK obuhvataju i.d., i.m., s.c., i.p. i i.v. Mogu se dati doze od npr. između 50 µg i 1,5 mg, poželjno 125 µg do 500 µg, peptida ili DNK i one će zavisiti od datog peptida ili DNK. Doze u ovom opsegu su uspešno korišćene u ranijim ispitivanjima (Brunsvig et al., 2006; Staehler et al., 2007).
Drugi aspekt predmetnog pronalaska uključuje in vitro metod za proizvodnju aktiviranih T ćelija, pri čemu se metod sastoji od dovođenja u kontakt in vitro T ćelija sa humanim MHC molekulima sa ubačenim antigenom eksprimiranim na površini prikladne antigenprezentujuće ćelije u toku vremenskog perioda koji je dovoljan da se navedena T ćelija aktivira na antigen-specifičan način, naznačeno time što je antigen peptid u skladu sa pronalaskom. Poželjno, sa antigenprezentujućom ćelijom se koristi dovoljna količina antigena.
Poželjno, ćelija sisara ne poseduje ili ima smanjen nivo ili funkciju TAP peptidnog transportera. Pogodne ćelije kojima nedostaje TAP peptidni transporter obuhvataju T2, RMA-S i ćelije vinske mušice. TAP je transporter koji je u vezi sa obradom antigena.
Ćelijska linija T2 koja je deficijentna za ubacivanje humanih peptida dostupna je kod organizacije American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, SAD pod kataloškim brojem CRL 1992; ćelijska linija vinske mušice Schneider 2 dostupna je kod organizacije ATCC pod kataloškim brojem CRL 19863; mišja RMA-S ćelijska linija opisana je u radu Karre et al 1985.
Poželjno, ćelija domaćin pre transfekcije značajno ne eksprimira MHC molekule klase I. Takođe je poželjno da stimulatorna ćelija eksprimira molekul koji je važan za obezbeđivanje kostimulatornog signala za T ćelije kao što su bilo koji od B7.1, B7.2, ICAM-1 i LFA 3. Sekvence nukleinskih kiselina brojnih MHC molekula klase I i kostimulatornih molekula javno su dostupne iz GenBank i EMBL baza podataka.
U slučaju epitopa MHC klase I koji se koristi kao antigen, T ćelije su CD8-pozitivni CTL.
Ako se antigen-prezentujuća ćelija transficira da eksprimira takav epitop, ćelija se poželjno sastoji od vektora ekspresije koji je sposoban da eksprimira peptid koji sadrži ID BR. SEKV 28.
Brojne druge metode mogu da se koriste za generisanje CTL in vitro. Na primer, metode opisane u radovima Peoples et al (1995) i Kawakami et al (1992) koriste autologne tumorinfiltrirajuće limfocite za stvaranje CTL. Plebanski i saradnici (1995) upotrebljavaju autologne limfocite iz periferne krvi (PLB) za pripremanje CTL. Jochmus i saradnici (1997) opisuju proizvodnju autolognih CTL pulsiranjem dendritičnih ćelija sa peptidom ili polipeptidom, ili putem infekcije sa rekombinantnim virusom. Hill i saradnici (1995) i Jerome i saradnici (1993) upotrebljavaju B ćelije u proizvodnji autolognih CTL. Pored toga, makrofagi pulsirani sa peptidom ili polipeptidom, ili inficirani sa rekombinantnim virusom, mogu da se koriste za pripremu autolognih CTL. S. Walter i saradnici 2003. opisuju in vitro prajming T ćelija upotrebom veštačkih antigen-prezentujućih ćelija (aAPĆ), što je takođe prikladan način za generisanje T ćelija protiv peptida izbora. U ovoj studiji, aAPĆ su generisane spajanjem preformiranih kompleksa MHC:peptid za površinu polistirenskih čestica (mikroperle) pomoću biohemije biotin:streptavidin. Ovaj sistem dozvoljava egzaktnu kontrolu gustine MHC na aAPĆ, što omogućava da se selektivno izazovu visoko- ili nisko-aviditetni antigen-specifični T-ćelijski odgovori sa visokom efikasnošću iz uzoraka krvi. Pored ovih kompleksa MHC:peptid, aAPĆ bi trebalo da nose druge proteine sa ko-stimulatornom aktivnošću poput anti-CD28 antitela spojenih za njihovu površinu. Osim toga takvi sistemi zasnovani na aAPĆ često iziskuju dodavanje odgovarajućih solubilnih faktora, npr. citokina kao što je interleukin-12.
Alogene ćelije mogu takođe da se koriste u pripremanju T ćelija a metod je detaljno opisan u patentu WO 97/26328. Na primer, pored ćelija vinske mušice i T2 ćelija, mogu da se koriste druge ćelije za prezentovanje antigena kao što su CHO ćelije, ćelije insekata inficirane bakulovirusom, bakterije, kvasnice, ciljne ćelije inficirane vakcinijom. Pored toga mogu da se koriste i virusi biljaka (pogledajte, na primer, Porta et al (1994)) koji opisuje razvoj mozaičkog virusa crnog pasulja kao sistem sa visokim prinosom za prezentaciju stranih peptida.
Aktivirane T ćelije koje su usmerene protiv peptida pronalaska korisne su u terapiji. Tako, dalji aspekt pronalaska obezbeđuje aktivirane T ćelije koje se mogu dobiti prethodno navedenim metodama pronalaska.
Aktivirane T ćelije, koje su proizvedene pomoću gore navedenog metoda, selektivno će prepoznati ćeliju koja aberantno eksprimira polipeptid koji sadrži aminokiselinsku sekvencu sa ID BR. SEKV 28.
Poželjno, T ćelija prepoznaje ćeliju pomoću interakcije kroz njen TCR sa kompleksom HLA/peptid (na primer, vezivanje). T ćelije su korisne u metodu ubijanja ciljnih ćelija kod pacijenta čije ciljne ćelije aberantno eksprimiraju polipeptid koji sadrži aminokiselinsku sekvencu pronalaska, naznačeno time što se pacijentu daje efikasan broj aktiviranih T ćelija. T ćelije koje se daju pacijentu mogu biti dobijene od pacijenta i aktivirane na način opisan ranije (tj. one su autologne T ćelije). Alternativno, T ćelije nisu od dotičnog pacijenta već od druge osobe. Naravno da je poželjno da osoba bude zdrava osoba. Pod „zdravom osobom“ pronalazači podrazumevaju da osoba bude uopšteno dobrog zdravlja, poželjno da ima kompetentan imunski sistem i, još poželjnije, da ne boluje ni od jedne bolesti za koju se mogu izvršiti testovi i koja se može detektovati.
In vivo, ciljne ćelije za CD8-pozitivne T ćelije u skladu sa predmetnim pronalaskom mogu biti ćelije tumora (koje ponekad eksprimiraju MHC klase II) i/ili ćelije strome koje okružuju tumor (tumorske ćelije) (koje ponekad takođe eksprimiraju MHC klase II; (Dengjel et al., 2006)).
T ćelije predmetnog pronalaska mogu da se koriste kao aktivni sastojci terapeutske smeše. Stoga, predstavljen je metod ubijanja ciljnih ćelija kod pacijenta čije ciljne ćelije aberantno eksprimiraju polipeptid koji sadrži aminokiselinsku sekvencu pronalaska, pri čemu metod obuhvata davanje efikasnog broja T ćelija pacijentu kao što je definisano ranije.
Pod pojmom „aberantno eksprimiran“ pronalazači takođe podrazumevaju da je polipeptid prekomerno eksprimiran u poređenju sa normalnim nivoima ekspresije ili da je gen neaktivan u tkivu iz kojeg je tumor nastao ali da je eksprimiran u tumoru. Pod pojmom „prekomerno eksprimiran“ pronalazači podrazumevaju da je polipeptid prisutan u nivou koji je najmanje 1,2 puta veći od nivoa prisutnog u normalnom tkivu; poželjno je najmanje 2 puta veći, a još poželjnije najmanje 5 puta ili 10 puta veći od nivoa prisutnog u normalnom tkivu.
T ćelije mogu da se dobiju pomoću metoda poznatih u predmetnoj oblasti, npr. ranije opisanih.
Protokoli za ovaj takozvani adoptivni transfer T ćelija dobro su poznati u predmetnoj oblasti. Pregledi se mogu naći u radovima (Gattinoni et al., 2006) i (Morgan et al., 2006).
Svaki molekul pronalaska, tj. peptid, nukleinska kiselina, antitelo, vektor ekspresije, ćelija, aktivirani CTL, T-ćelijski receptor ili nukleinska kiselina koja ga kodira koristan je za lečenje poremećaja, koji karakterišu ćelije koje izbegavaju imunski odgovor. Zato svaki molekul predmetnog pronalaska može da se koristi kao lek ili u proizvodnji leka. Molekul može da se koristi samostalno ili u kombinaciji sa drugim molekulom(ima) pronalaska ili poznatim molekulom(ima).
Poželjno, lek predmetnog pronalaska je vakcina. Ona se može dati direktno pacijentu, primeniti u zahvaćeni organ ili sistemski i.d., i.m., s.c., i.p. i i.v., ili primeniti ex vivo u ćelije dobijene od pacijenta ili humane ćelijske linije koje se nakon toga daju pacijentu, ili koristiti in vitro za odabir subpopulacije imunskih ćelija dobijenih od pacijenta, koje se zatim ponovo daju pacijentu. Ako se nukleinska kiselina primenjuje u ćelije in vitro, može biti od koristi da ćelije budu transficirane tako da ko-eksprimiraju imunostimulišuće citokine, kao što je interleukin-2. Peptid može biti značajno prečišćen, ili kombinovan sa imunostimulišućim adjuvansom (pogledajte u nastavku), ili da se koristi u kombinaciji sa imunostimulatornim citokinima, ili da se primenjuje sa pogodnim dostavnim sistemom, kao na primer lipozomima. Od ovde predstavljenih peptida se očekuje da stimulišu CD4 ili CD8 T ćelije. Ipak, stimulacija CD8 CTL je efikasnija u prisustvu pomoći koju pružaju CD4 T-pomoćničke ćelije. Tako, za epitope MHC klase I koji stimulišu CD8 CTL, fuzioni partner ili delovi hibridnog molekula prikladno obezbeđuju epitope koji stimulišu CD4-pozitivne T ćelije. CD4- i CD8-stimulišući epitopi su dobro poznati u predmetnoj oblasti i uključuju one identifikovane u predmetnom pronalasku.
U jednom aspektu, vakcina sadrži najmanje jedan peptid koji sadrži aminokiselinsku sekvencu iznetu u ID BR. SEKV 28 i najmanje jedan dodatni peptid, poželjno dva do 50, poželjnije dva do 25, još poželjnije dva do 20 i najpoželjnije dva, tri, četiri, pet, šest, sedam, osam, devet, deset, jedanaest, dvanaest, trinaest, četrnaest, petnaest, šesnaest, sedamnaest ili osamnaest peptida. Peptid(i) može biti dobijen od jednog ili više specifičnih TAA i može se vezivati za MHC molekule klase I.
Polinukleotid može biti značajno prečišćen ili sadržan u pogodnom vektoru ili sistemu za dostavljanje. Nukleinska kiselina može biti DNK, cDNK, PNK, RNK ili njihova kombinacija. Metodi za dizajniranje i uvođenje takve nukleinske kiseline su dobro poznati u predmetnoj oblasti. Kratak pregled je dat od strane npr. (Pascolo et al., 2005). Polinukleotidne vakcine se lako pripremaju, ali način delovanja ovih vektora u indukovanju imunskog odgovora nije u potpunosti jasan. Prikladni vektori i sistemi za dostavljanje uključuju virusnu DNK i/ili RNK, kao što su sistemi zasnovani na adenovirusu, virusu vakcinije, retrovirusima, herpes virusu, adenoasociranom virusu ili hibridima koji sadrže elemente više od jednog virusa. Nevirusni sistemi za dostavljanje uključuju katjonske lipide i katjonske polimere i dobro su poznati u oblasti dostavljanja DNK. Fizičko dostavljanje, kao što je preko „genskog pištolja“, može takođe da se koristi. Peptid ili peptidi koje kodira nukleinska kiselina mogu biti fuzioni protein, na primer sa epitopom koji stimuliše T ćelije za dati suprotni CDR kako je navedeno ranije.
Medikament pronalaska može takođe da sadrži jedan ili više adjuvansa. Adjuvansi su supstance koje nespecifično pojačavaju ili potenciraju imunski odgovor (npr. imunske odgovore posredovane CTL i pomoćničkim T (TH) ćelijama na antigen, i na taj način se smatraju korisnim u leku predmetnog pronalaska. Pogodni adjuvansi uključuju, ali nisu i ograničeni na, 1018 ISS, soli aluminijuma, AMPLIVAX<®>, AS15, BCG, CP-870,893, CpG7909, CyaA, dSLIM, flagelin ili TLR5 ligande dobijene od flagelina, FLT3 ligand, GM-CSF, IC30, IC31, imikvimod (ALDARA<®>), rezikvimod, ImuFact IMP321, interleukine poput IL-2, IL-13, IL-21, interferonalfa ili -beta, ili njihove pegilovane derivate, IS Patch, ISS, ISCOMATRIX, ISCOMs, JuvImmune<®>, LipoVac, MALP2, MF59, monofosforil lipid A, Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, emulzije voda u ulju i ulje u vodi, OK-432, OM-174, OM-197-MP-EC, ONTAK, OspA, PepTel® vektorski sistem, poli(laktid ko-glikolid) [PLG]-zasnovane i mikročestice dekstrana, talaktoferin, SRL172, virozome i druge virusu slične partikule, YF-17D, VEGF klopku, R848, beta-glukan, Pam3Cys, QS21 stimulon kompanije Aquila, koji je dobijen od saponina, mikobakterijske ekstrakte i sintetičke mimetike bakterijskog ćelijskog zida i druge zaštićene adjuvanse kao što su Ribi-jev Detox, Quil, ili Superfos. Preferirani su adjuvansi kao što je Freund-ov ili GM-CSF. Nekoliko imunoloških adjuvanasa
(npr. MF59) specifičnih za dendritične ćelije i njihova priprema opisani su ranije (Allison and Krummel, 1995; Allison and Krummel, 1995). Takođe, mogu se koristiti citokini. Nekoliko citokina je direktno dovedeno u vezu sa uticajem na migraciju dendritičnih ćelija u limfna tkiva (npr. TNF-), ubrzavanjem sazrevanja dendritičnih ćelija u efikasne antigenprezentujuće ćelije za T limfocite (npr. GM-CSF, IL-1 i IL-4) (patent registrovan u SAD pod br.5,849,589) i delovanjem kao imunoadjuvansi (npr. IL-12, IL-15, IL-23, IL-7, IFN-alfa, IFN-beta) [Gabrilovich 1996].
Takođe, objavljeno je da CpG imunostimulatorni oligonukleotidi poboljšavaju efekte adjuvanasa u sastavu vakcine. Bez ograničavanja postojećom teorijom, CpG oligonukleotidi deluju aktiviranjem urođenog (neadaptivnog) imunskog sistema preko Toll-like receptora (TLR), uglavnom TLR9. Aktivacija TLR9 pokrenuta CpG-om pojačava antigen-specifične humoralne i ćelijske odgovore na širok spektar antigena, uključujući peptidne ili proteinske antigene, žive ili mrtve viruse, vakcine dendritičnim ćelijama, autologne ćelijske vakcine i polisaharidne konjugate kako u profilaktičkim tako i terapijskim vakcinama. Što je važnije, on poboljšava sazrevanje i diferencijaciju dendritičnih ćelija, što dovodi do pojačane aktivacije TH1ćelija i snažnog stvaranja citotoksičnih T limfocita (CTL), čak i u odsustvu pomoći CD4 T ćelija. Predominacija TH1indukovana pomoću TLR9 stimulacije se održava čak i u prisustvu adjuvanasa u vakcini kao što je aluminijum ili nekompletni Freund-ov adjuvans (IFA) koji normalno promovišu predominaciju TH2. CpG oligonukleotidi pokazuju još veću adjuvansnu aktivnost kada se formulišu ili istovremeno primenjuju sa drugim adjuvansima ili u formulacijama kao što su mikročestice, nanočestice, lipidne emulzije ili slične formulacije, koje su naročito neophodne za indukovanje snažnog odgovora kada je antigen relativno slab. Oni takođe ubrzavaju imunski odgovor i omogućavaju da se doze antigena smanje za približno dva reda veličine, sa uporedivim odgovorima antitelima na punu dozu vakcine bez CpG u pojedinim eksperimentima (Krieg, 2006). Patent registrovan u SAD pod br.6,406,705 B1 opisuje kombinovanu upotrebu CpG oligonukleotida, adjuvanasa u obliku nenukleinskih kiselina i antigena za indukovanje antigenspecifičnog imunskog odgovora. Antagonist CpG TLR9 je dSLIM (double Stem Loop Immunomodulator) kompanije Mologen (Berlin, Nemačka) koji je preferirana komponenta farmaceutske smeše predmetnog pronalaska. Takođe, mogu se koristiti i drugi molekuli koji vezuju TLR kao što su RNK koja vezuje TLR 7, TLR 8 i/ili TLR 9.
Drugi primeri korisnih adjuvanasa uključuju, ali nisu i ograničeni na, hemijski modifikovane CpG-jeve (npr. CpR, Idera), analoge dsRNK kao što su Poly(I:C) i njegovi derivati (npr.
AmpliGen®,
Hiltonol®, poli-(ICLC), poli(IC-R), poli(I:C12U), ne-CpG bakterijska DNK ili RNK kao i imunoaktivne male molekule i antitela poput ciklofosfamida, sunitiniba, bevacizumaba, celebreksa, NCX-4016, sildenafila, tadalafila, vardenafila, sorafeniba, temozolomida, temsirolimusa, XL-999, CP-547632, pazopaniba, VEGF klopke, ZD2171, AZD2171, antiCTLA4, druga antitela koja ciljaju ključne strukture imunskog sistema (npr. anti-CD40, antiTGFbeta, anti-TNFalfa receptor) i SC58175, koji mogu delovati terapijski i/ili kao adjuvans. Količine i koncentracije adjuvanasa i aditiva korisnih u kontekstu predmetnog pronalaska, stručnjak iz ove oblasti može lako da utvrdi bez izvođenja suvišnih eksperimenata.
Poželjni adjuvansi su imikvimod, rezikvimod, GM-CSF, ciklofosfamid, sunitinib, bevacizumab, interferon-alfa, CpG oligonukleotidi i derivati, poli-(I:C) i derivati, RNK, sildenafil, i formulacije čestica sa PLG ili virozomima.
U poželjnom otelotvorenju, farmaceutskoj smeši u skladu sa pronalaskom adjuvans je izabran iz grupe koja se sastoji od faktora stimulacije kolonija, kao što je faktor stimulacije granulocitnomakrofagne kolonije (GM-CSF, sargramostim), imikvimoda, rezikvimoda i interferona alfa.
U poželjnom otelotvorenju, farmaceutskoj smeši u skladu sa pronalaskom adjuvans je izabran iz grupe koja se sastoji od faktora stimulacije kolonija, kao što je faktor stimulacije granulocitnomakrofagne kolonije (GM-CSF, sargramostim), imikvimoda i rezikvimoda.
U poželjnom otelotvorenju farmaceutske smeše u skladu sa pronalaskom, adjuvans je imikvimod ili rezikvimod.
Ova smeša se koristi za parenteralnu primenu, kao što je subkutana, intradermalna, intramuskularna ili oralnu primenu. Za navedeno, peptidi i opciono drugi molekuli se rastvaraju ili suspenduju u farmakološki prihvatljivom, poželjno, vodenom nosaču. Pored toga, smeša može sadržati pomoćne materije, poput pufera, vezujućih agenasa, raspršivača, rastvarača, aroma, lubrikanata itd. Peptidi takođe mogu biti primenjeni zajedno sa imunostimulišućim supstancama kao što su citokini. Opsežna lista pomoćnih materija koje se mogu koristiti u navedenom sastavu može, na primer, biti preuzeta iz A. Kibbe, Handbook of Pharmaceutical Excipients, 3. Ed. 2000, American Pharmaceutical Association and pharmaceutical press. Smeša se može koristiti za prevenciju, profilaksu i/ili terapiju adenomatoznih ili malignih oboljenja. Primerne formulacije se mogu naći u patentu EP2113253. Bez obzira na to, u zavisnosti od broja i fizičkohemijskih karakteristika peptida pronalaska, potrebno je dalje istraživanje kako bi se obezbedile formulacije za specifične kombinacije peptida koje su stabilne duže od 12-18 meseci.
Predmetni pronalazak obezbeđuje lek koji je koristan u lečenju malignih tumora, konkretno nemikrocelularnog karcinoma pluća, karcinoma želuca, karcinoma bubrežnih ćelija, karcinoma kolona, adenokarcinoma, karcinoma prostate, benigne neoplazme i malignog melanoma.
Predmetni pronalazak dalje uključuje komplet koji se sastoji od: (a) posude koja sadrži farmaceutsku smešu koja sadrži peptid u skladu sa predmetnim pronalaskom, aktivirani citotoksični T limfocit u skladu sa predmetnim pronalaskom, antitelo u skladu sa predmetnim pronalaskom, T-ćelijski receptor u skladu sa predmetnim pronalaskom, nukleinsku kiselinu ili vektor ekspresije u skladu sa predmetnim pronalaskom, ili ćeliju u skladu sa predmetnim pronalaskom, u rastvoru ili liofiliziranom obliku; (b) druge posude koja sadrži rastvarač ili rastvor za rekonstituciju za liofiliziranu formulaciju; i (c) opciono, uputstva za (i) upotrebu rastvora ili (ii) rekonstituciju i/ili upotrebu liofilizirane formulacije.
Komplet dalje može da se sastoji od jednog ili više od navedenih (iii) pufer, (iv) rastvarač, (v) filter, (vi) igla ili (v) brizgalica ili najmanje jednog ili više peptida izabranih iz grupe koju čine ID
BR. SEKV 1 do ID BR. SEKV 27, i ID BR. SEKV 29 do ID BR. SEKV 131. Posuda je preferirano boca, bočica, brizgalica ili epruveta; i ona može biti višekratna posuda. Farmaceutska smeša je preferirano liofilizirana.
Kompleti predmetnog pronalaska se poželjno sastoje od liofilizirane formulacije predmetnog pronalaska u pogodnoj posudi i uputstava za njenu rekonstituciju i/ili upotrebu. Pogodne posude uključuju, na primer, boce, bočice (npr. bočice sa dve šupljine), brizgalice (kao što su brizgalice sa dve šupljine) i epruvete. Posuda može biti izrađena od različitih materijala kao što su staklo ili plastika. Poželjno, komplet i/ili posuda sadrži/e uputstva o ili u vezi sa posudom koja navode uputstva za rekonstituciju i/ili upotrebu. Na primer, na nalepnici može biti navedeno da liofilizirana formulacija treba da se rekonstituiše do koncentracija peptida kako je opisano ranije. Na nalepnici može dalje da bude naznačeno da je formulacija korisna ili namenjena za potkožnu primenu.
Posuda u kojoj se nalazi formulacija može da bude višekratna bočica, što omogućava ponavljane primene (npr. 2-6 primena) rekonstituisane formulacije. Komplet može dalje da sadrži i drugu posudu u kojoj se nalazi pogodni rastvarač (npr. rastvor natrijum bikarbonata).
Nakon mešanja rastvarača i liofilizirane formulacije, konačna koncentracija peptida u rekonstituisanoj formulaciji je poželjno najmanje 0,15 mg/ml/peptida (=75 µg) a poželjno ne više od 3 mg/ml/peptida (=1500 µg). Komplet može dalje da uključuje druge materijale poželjne sa komercijalne ili korisničke tačke gledišta, uključujući druge pufere, rastvarače, filtere, igle, brizgalice i uputstva za upotrebu uz pakovanje.
Kompleti predmetnog pronalaska mogu da imaju jednu posudu koja sadrži formulaciju farmaceutskih smeša u skladu sa predmetnim pronalaskom sa ili bez drugih komponenti (npr. druga jedinjenja ili farmaceutske smeše ovih drugih jedinjenja) ili mogu da imaju zasebnu posudu za svaku komponentu.
Poželjno, kompleti pronalaska obuhvataju formulaciju pronalaska upakovanu za upotrebu u kombinaciji sa istovremenom primenom drugog jedinjenja (kao što su adjuvansi (npr. GM-CSF), hemioterapijski agens, prirodni proizvod, hormon ili antagonist, antiangiogeni agens ili inhibitor, agens koji indukuje apoptozu ili helirajući agens) ili njegove farmaceutske smeše. Komponente kompleta mogu biti u vidu prethodno napravljenog kompleksa ili svaka komponenta može biti u odvojenoj zasebnoj posudi pre primene kod pacijenta. Komponente kompleta mogu biti obezbeđene u jednom ili više tečnih rastvora, poželjno, vodenom rastvoru, poželjnije sterilnom vodenom rastvoru. Komponente kompleta mogu takođe biti obezbeđene kao čvrste materije, koje se mogu pretvoriti u tečnosti dodavanjem pogodnih rastvarača, koji su preferirano obezbeđeni u drugoj zasebnoj posudi.
Posuda terapeutskog kompleta može biti bočica, epruveta, pljosnata boca, boca, brizgalica ili neka druga posuda za čuvanje čvrstih supstanci ili tečnosti. Obično, kada postoji više od jedne komponente, komplet će sadržati drugu bočicu ili drugu posudu, koja omogućava zasebno doziranje. Komplet takođe može sadržati drugu posudu za farmaceutski prihvatljivu tečnost. Poželjno, terapeutski komplet će sadržati pribor (npr. jednu ili više igala, brizgalice, kapaljke, pipete itd.) koji omogućava primenu agenasa pronalaska koji su komponente prikazanog kompleta.
Prikazana formulacija je jedna koja je pogodna za primenu peptida na bilo koji prihvatljiv način primene kao što je oralni (enteralni), nazalni, očni, supkutani, intradermalni, intramuskularni, intravenski ili transdermalni. Poželjno, primena je s.c., a najpoželjnije i.d. Primena može biti i pomoću infuzione pumpe.
Budući da je peptid pronalaska dobijen iz ID BR. SEKV 28 izolovan iz glioblastoma, lek pronalaska se poželjno koristi za lečenje glioblastoma.
Predmetni pronalazak će sada biti opisan u sledećim primerima koji opisuju njegova poželjna otelotvorenja, ali to neće biti ograničeno na ovde navedeno.
Slika 1: Primerni maseni spektar iz IGF2BP3-001 koji pokazuje njegovu prezentaciju na primarnom uzorku tumora glioblastoma. NanoESI-LCMS je izvršena na peptidnom pulu eluiranom iz uzorka glioblastoma 6010. Maseni hromatogram za m/z 536.3229 ± 0,001 Da, z=2 pokazuje maksimum peptida na vremenu retencije 48,76 min. B) Detektovani maksimum u masenom hromatogramu na 48,76 min otkrio je signal m/z 536.3229 u MS spektru. C) Maseni spektar kolizijom indukovane disocijacije iz izabranog prekursora m/z 536.3229 zabeležen u nanoESI-LCMS eksperimentu na datom vremenu retencije potvrdio je prisustvo IGF2BP3-001 u uzorku tumora glioblastom 6010. D) Obrazac fragmentacije sintetičkog IGF2BP3-001 referentnog peptida zabeležen je i upoređen sa generisanim prirodnim obrascem fragmentacije TUMAP prikazanim u C za verifikaciju sekvence.
Slika 2: Profili ekspresije mRNK izabranih proteina u normalnim tkivima i u 22 uzoraka glioblastoma. a) CSRP2 (ID kompleta probe: 211126_s_at); b) PTPRZ1 (ID kompleta probe: 204469_at).
Slika 3: Profili prezentacije za izabrane peptide HLA klase I. Profil prezentacije izračunat je za svaki peptid koji pokazuje srednju prezentaciju uzorka kao i varijacije replikata. Profil postavlja jedno uz drugo uzorke tumora od interesovanja sa polaznim vrednostima uzoraka normalnog tkiva. a) CSRP2-001 (HLA-A*02); b) PTP-012 (HLA-A*02); c) TMEM255A-001 (HLA-A*24); d) PJA2-001 (HLA-A*24).
Slika 4: Primerni rezultati peptid-specifične in vitro imunogenosti TUMAP klase I za HLA*A02 i HLA*A24. Specifične CD8+ T ćelije obojene su HLA multimerima od kojih je svaki bio povezan sa dva različita fluorohroma. Tačkasti dijagrami pokazuju MHC multimer-dvostruko-pozitivne populacije za stimulišuće peptide (levi paneli) i odnosne stimulacije negativne kontrole (desni paneli).
PRIMERI
PRIMER 1:
Identifikacija i kvantifikacija tumor-asociranih peptida prezentovanih na površini ćelije Uzorci tkiva
Tumorska tkiva pacijenata obezbedili su Univerzitet u Hajdelbergu, Univerzitet u Tubingenu, oba u Nemačkoj, Univerzitet u Ženevi, Švajcarska. Pre operacije su od svih pacijenata pribavljeni pisani informisani pristanci. Tkiva su zamrznuta brzim zamrzavanjem u tečnom azotu neposredno nakon operacije i uskladištena na -80 °C do izolacije TUMAP.
Izolacija HLA peptida iz uzoraka tkiva
Pulovi HLA peptida iz uzoraka tkiva zamrznutih brzim zamrzavanjem dobijeni su imunskom precipitacijom iz čvrstih tkiva u skladu sa blago modifikovanim protokolom (Falk et al., 1991; Seeger et al., 1999) primenom HLA-A*02-specifičnog antitela BB7.2, HLA-A, -B, -Cspecifičnog antitela W6/32, CNBr-aktivirane sefaroze, tretiranja kiselinom i ultrafiltracije.
Metode
Dobijeni skupovi HLA peptida su odvojeni prema njihovoj hidrofobnosti pomoću reverzno-fazne hromatografije (Acquity UPLC sistem, Waters) a eluirani peptidi su analizirani u LTQ-Orbitrap hibridnom masenom spektrometru (ThermoElectron) opremljenom ESI izvorom. Pulovi peptida su direktno postavljeni na analitičku mikrokapilarnu kolonu od fuzirane silike (75 µm i.d. x 250 mm) upakovanu sa 1,7 µm C18 reverzno-faznim materijalom (Waters) uz primenu brzine protoka od 400 nl u minutu. Nakon toga, peptidi su izdvojeni primenom dvostepenog 180-minutnog binarnog gradijenta iz 10% do 33% B pri brzini protoka od 300 nl u minutu. Gradijent su činili rastvarač A (0,1% mravlja kiselina u vodi) i rastvarač B (0,1% mravlja kiselina u acetonitrilu). Staklena kapilara obložena zlatom (PicoTip, New Objective) je korišćena za uvođenje u nanoESI izvor. LTQ-Orbitrap maseni spektrometar je radio u režimu zavisnom od podataka primenom strategije TOP5 (5 najvećih). Ukratko, iniciran je ciklus skeniranja sa kompletnim skeniranjem visoke masene preciznosti u orbitrap (R = 30000), što je bilo praćeno MS/MS skeniranjima takođe u orbitrap (R = 7500) na 5 najzastupljenijih prekursorskih jona sa dinamičkim isključivanjem prethodno odabranih jona. Tandem maseni spektri su interpretirani pomoću SEQUEST i dodatnom ručnom kontrolom. Identifikovana peptidna sekvenca je potvrđena poređenjem generisanog obrasca fragmentacije prirodnog peptida sa obrascem fragmentacije sintetičkog referentnog peptida identične sekvence. Na slici 1 je prikazan primerni spektar koji je dobijen iz tumorskog tkiva za MHC klasa I-asocirani peptid GF2BP3-001 i njegov elucioni profil na UPLC sistemu.
Relativna LC-MS kvantifikacija bez obeležavanja izvršena je pomoću brojanja jona tj. ekstrakcijom i analizom LC-MS karakteristika (Mueller et al., 2007). Metod pretpostavlja da oblast LC-MS signala peptida korelira sa njegovom obilnošću u uzorku. Ekstrahovane karakteristike su dalje obrađene pomoću slabljenja naelektrisanog stanja i poravnanja vremena zadržavanja (Mueller et al., 2007). Na kraju, sve LC-MS karakteristike su referencirane sa rezultatima identifikacije sekvence kako bi se kvantitativni podaci od različitih uzoraka i tkiva kombinovali u profile prezentacije peptida. Kvantitativni podaci su normalizovani na dvostepeni način u skladu sa centralnom tendencijom kako bi se uračunala varijacija u okviru tehničkih i bioloških replikata. Tako svaki identifikovani peptid može biti povezan sa kvantitativnim podacima što omogućava relativnu kvantifikaciju između uzoraka i tkiva. Pored toga, svi kvantitativni podaci dobijeni za peptidne kandidate su ručno pregledani kako bi se osigurala doslednost podataka i potvrdila tačnost automatizovane analize. Za svaki peptid je izračunat profil prezentacije koji pokazuje srednju prezentaciju uzorka kao i varijacije replikata. Profil postavlja jedno uz drugo uzorke glioblastoma sa polaznim vrednostima uzoraka normalnog tkiva.
Profili prezentacije primernih prekomerno prezentovanih peptida prikazani su na slici 3.
PRIMER 2 Profiliranje ekspresije gena koji kodiraju ovde predstavljene peptide Nisu svi peptidi koji su identifikovani kao da su prezentovani na površini tumorskih ćelija od strane MHC molekula pogodni za imunoterapiju, zato što je većina ovih peptida dobijena iz normalnih ćelijskih proteina koje eksprimiraju mnoge vrste ćelija. Samo nekoliko ovih peptida je tumor-asocirano i verovatno je da su sposobni da indukuju T ćelije sa velikom specifičnošću prepoznavanja za tumor iz kojeg su dobijeni. Da bi identifikovali takve peptide i sveli rizik od autoimunosti indukovane vakcinacijom na minimum, pronalazači su se fokusirali na one peptide koji su dobijeni od proteina koji su prekomerno eksprimirani na tumorskim ćelijama u poređenju sa većinom normalnih tkiva.
Idealni peptid će biti izveden iz proteina koji je jedinstven za tumor i nije prisutan u bilo kom drugom tkivu. Da bi se identifikovali peptidi koji su dobijeni iz gena sa profilom ekspresije sličnim idealnom, identifikovani peptidi su dodeljeni proteinima, odnosno genima, iz kojih su dobijeni i generisani su profili ekspresije ovih gena.
RNK izvori i priprema
Hirurški odstranjeni uzorci tkiva obezbeđeni su od strane nekoliko ustanova kako je navedeno u primeru 1 nakon što je od svakog pacijenta pribavljen pisani informisani pristanak. Uzorci tumorskog tkiva su zamrznuti brzim zamrzavanjem u tečnom azotu neposredno nakon operacije i kasnije homogenizovani avanom i tučkom u prisustvu tečnog azota. Ukupna RNK je pripremljena iz ovih uzoraka pomoću TRI reagensa (Ambion, Darmstadt, Nemačka) nakon čega je sledilo čišćenje sa RNeasy (QIAGEN, Hilden, Nemačka); oba metoda su izvedena u skladu sa protokolom proizvođača.
Ukupna RNK iz zdravih humanih tkiva dobijena je komercijalno (Ambion, Huntingdon, UK;
Clontech, Heidelberg, Nemačka; Stratagene, Amsterdam, Holandija; BioChain, Hayward, CA, SAD). RNK od nekoliko pojedinaca (između 2 i 123 osobe) izmešana je tako da je RNK od svakog pojedinca bila težinski podjednaka.
Kvalitet i kvantitet svih uzoraka RNK procenjen je na Agilent 2100 bioanalizatoru (Agilent, Waldbronn, Nemačka) upotrebom RNA 6000 Pico LabChip kompleta (Agilent).
Eksperimenti na mikročipu
Analiza genske ekspresije svih uzoraka RNK iz tumorskih i normalnih tkiva izvršena je pomoću
Affymetrix Human Genome (HG) U133A ili HG-U133 Plus 2.0 oligonukleotidnih mikročipova
(Affymetrix, Santa Clara, CA, SAD). Svi koraci su izvršeni u skladu sa priručnikom za Affymetrix. Ukratko, sintetisana je dvolančana cDNK iz 5–8 µg ukupne RNK, primenom SuperScript RTII (Invitrogen) i oligo-dT-T7 prajmera (MWG Biotech, Ebersberg, Nemačka) kako je opisano u priručniku. In vitro transkripcija je izvršena sa kompletom BioArray High Yield RNA Transcript Labelling Kit (ENZO Diagnostics, Inc., Farmingdale, NY, SAD) za U133A čipove ili sa kompletom GeneChip IVT Labelling Kit (Affymetrix) za U133 Plus 2.0 čipove, nakon čega je sledila fragmentacija, hibridizacija i bojenje cRNK sa streptavidin-fikoeritrin i biotiniliranim anti-streptavidin antitelom (Molecular Probes, Leiden, Holandija). Slike su skenirane skenerom Agilent 2500A GeneArray Scanner (U133A) ili Affymetrix Gene-Chip Scanner 3000 (U133 Plus 2.0), a podaci su analizirani pomoću GCOS softvera (Affymetrix), upotrebom podrazumevanih podešavanja za sve parametre. Za normalizaciju je korišćeno 100 konstitutivnih gena obezbeđenih od strane kompanije Affymetrix. Vrednosti relativne ekspresije izračunate su iz logaritamskih odnosa signala datih od strane softvera a normalni uzorak bubrega je arbitrarno podešen na 1,0.
Primerni profili ekspresije ovde predstavljenih izvornih gena koji su veoma prekomerno eksprimirani ili isključivo eksprimirani u glioblastomu prikazani su na slici 2.
PRIMER 3 In vitro imunogenost za glioblastom MHC klasa I-prezentovane peptide Da bismo dobili informacije u pogledu imunogenosti ovde predstavljenih TUMAP, sproveli smo istraživanja korišćenjem in vitro eseja za pripremu T ćelija zasnovanog na ponovljenim stimulacijama CD8+ T ćelija pomoću veštačkih antigen-prezentujućih ćelija (aAPĆ) napunjenih sa kompleksima peptid/MHC i anti-CD28 antitelom. Na ovaj način mogli smo da pokažemo imunogenost za 69 HLA-A*0201 i 58 HLA-A*24-restrikovana TUMAP koji su do sada predstavljeni dokazujući da su ovi peptidi T-ćelijski epitopi protiv kojih kod ljudi postoje CD8+ prekursorske T ćelije.
In vitro priprema CD8+ T ćelija
Da bismo izvršili in vitro stimulacije pomoću veštačkih antigen-prezentujućih ćelija napunjenih kompleksom peptid-MHC (pMHC) i anti-CD28 antitelom, prvo smo izolovali CD8+ T ćelije iz svežih proizvoda leukafereze HLA-A*02 putem pozitivne selekcije primenom CD8 mikroperli (Miltenyi Biotec, Bergisch-Gladbach, Nemačka) zdravih donora dobijenih iz Zavoda za transfuziju u Tubingenu nakon pribavljanja informisanog pristanka.
Izolovani CD8+ limfociti ili PBMC su inkubirani do primene u T-ćelijskom medijumu (TCM) koji je sadržao RPMI-Glutamax (Invitrogen, Karlsruhe, Nemačka) u koji je dodat 10% humani toplotom inaktiviran AB serum (PAN-Biotech, Aidenbach, Nemačka), 100 U/ml penicilina / 100 µg/ml streptomicina (Cambrex, Cologne, Nemačka), 1 mmol/l natrijum piruvata (CC Pro, Oberdorla, Nemačka), 20 µg/ml gentamicina (Cambrex). U ovom koraku u TCM je takođe dodato 2,5 ng/ml IL-7 (PromoCell, Heidelberg, Nemačka) i 10 U/ml IL-2 (Novartis Pharma, Nürnberg, Nemačka). Stvaranje perli obloženih sa pMHC/anti-CD28, stimulacije T ćelija i očitavanje su izvršeni u visoko definisanom in vitro sistemu primenom četiri različita pMHC molekula po uslovu stimulacije i 8 različitih pMHC molekula po uslovu očitavanja. Svi kompleksi pMHC korišćeni za punjenje aAPĆ i citometrijsko očitavanje dobijeni su iz UVindukovane izmene MHC liganda sa manjim modifikacijama. Da bismo odredili količinu pMHC monomera dobijenog izmenom sproveli smo sendvič ELISA testove zasnovane na streptavidinu prema (Rodenko et al., 2006). Prečišćeno ko-stimulatorno mišje IgG2a anti-humano CD28 At 9.3 (Jung et al., 1987) bilo je hemijski biotinilirano pomoću sulfo-N-hidroksisukcinimidobiotina kako je preporučeno od strane proizvođača (Perbio, Bonn, Nemačka). Korišćene perle bile su polistirenske čestice obložene streptavidinom prečnika 5,6 µm (Bangs Laboratories, Illinois, SAD).
pMHC korišćeni kao kontrole za visoko imunogene i nisko imunogene stimulacije bili su A*0201/MLA-001 (peptid ELAGIGILTV iz modifikovanog Melan-A/MART-1), odnosno A*0201/DDX5-001 (YLLPAIVHI iz DDX5).
800.000 perli / 200 µl je bilo obloženo u pločicama sa 96 mesta u prisustvu 4 x 12,5 ng različitih biotin-pMHC, isprano i naknadno je dodato 600 ng biotin anti-CD28 u zapremini od 200 µl. Stimulacije su bile pokrenute u pločicama sa 96 mesta istovremenim inkubiranjem 1x10<6>CD8+ T ćelija sa 2x10<5>ispranih obloženih perli u 200 µl TCM u koji je dodato 5 ng/ml IL-12 (PromoCell) u toku 3-4 dana na 37°C. Polovina medijuma je zatim zamenjena sa svežim TCM u koji je dodato 80 U/ml IL-2 i inkubacija je nastavljena u toku 3-4 dana na 37°C. Ovaj ciklus stimulacije je izvršen ukupno tri puta, sa 12 pojedinačnih mesta po uslovu. Za očitavanje pMHC multimera primenom 8 različitih pMHC molekula po uslovu, korišćen je pristup dvodimenzionalnog kombinatornog kodiranja kako je ranije opisan (Andersen et al., 2012) sa manjim modifikacijama koje su obuhvatale spajanje sa 5 različitih fluorohroma. Na kraju, analize multimera su izvršene bojenjem ćelija sa bojom Live/dead near IR dye (Invitrogen, Karlsruhe, Nemačka), klonom CD8FITC antitela SK1 (BD, Heidelberg, Nemačka) i fluorescentnim pMHC multimerima. Za analizu je korišćen BD LSRII SORP citometar opremljen odgovarajućim laserima i filterima. Peptidspecifične ćelije izračunate su kao procenat ukupnih CD8+ ćelija. Evaluacija analize multimera izvršena je primenom FlowJo softvera (Tree Star, Oregon, SAD). In vitro priprema specifičnih multimer+ CD8+ limfocita detektovana je upoređivanjem sa stimulacijama irelevantne kontrole. Imunogenost datog antigena detektovana je ako je pronađeno da najmanje jedno procenjivo in vitro stimulisano mesto jednog zdravog donora sadrži specifičnu CD8+ T-ćelijsku liniju nakon in vitro stimulacije (tj. ovo mesto je sadržalo najmanje 1% specifičnih multimer+ među CD8+ T ćelijama a procenat specifičnih multimer+ ćelija je bio najmanje 10x veći od srednje vrednosti stimulacija irelevantne kontrole).
In vitro imunogenost za peptide glioblastoma
Za testirane HLA klasa I peptide, in vitro imunogenost je mogla da se pokaže stvaranjem peptidspecifičnih T-ćelijskih linija. Primerni rezultati protočne citometrije nakon bojenja TUMAPspecifičnog multimera za dva ovde predstavljena peptida prikazani su na slici 4 zajedno sa odgovarajućim negativnim kontrolama. Rezultati za ovde predstavljenih 69 HLA-A*0201 i 58 HLA-A*24 peptida sumirani su u tabelama 5a i b.
Tabela 5a: In vitro imunogenost ovde predstavljenih HLA-A*02 klasa I peptida Primerni rezultati in vitro eksperimenata imunogenosti izvršenih od strane podnosioca za ovde predstavljene peptide.
<20 % = ; 20 % - 49 % = +; 50 % - 70 %= ++; > 70 % = +++
Tabela 5b: In vitro imunogenost HLA-A*24 klasa I peptida pronalaska Primerni rezultati in vitro eksperimenata imunogenosti izvršenih od strane pronalazača za peptide pronalaska.
<20 % = ; 20 % - 49 % = +; 50 % - 70 %= ++; > 70 % = +++
Bibliografija
An CH, et al. (2012). Frameshift mutations of vacuolar protein sorting genes in gastric and colorectal cancers with microsatellite instability. Hum. Pathol.43, 40-47.
Araki W, et al. (2008). A family of membrane proteins associated with presenilin expression and gamma-secretase function. FASEB J 22, 819-827.
Aronica E, et al. (2001). Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumors from patients with intractable epilepsy. Neuropathol. Appl. Neurobiol.27, 223-237.
Aslibekyan S, et al. (2012). Genetic variation in fatty acid elongases is not associated with intermediate cardiovascular phenotypes or myocardial infarction. Eur. J Clin Nutr. 66, 353-359.
Aylsworth A, Jiang SX, Desbois A, Hou ST (2009). Characterization of the role of fulllength CRMP3 and its calpain-cleaved product in inhibiting microtubule polymerization and neurite outgrowth. Exp. Cell Res.315, 2856-2868.
Bargo S, et al. (2010). Transforming acidic coiled-coil protein-3 (Tacc3) acts as a negative regulator of Notch signaling through binding to CDC10/Ankyrin repeats. Biochem. Biophys. Res Commun. 400, 606-612.
Bayraktar S, et al. (2013). USP-11 as a predictive and prognostic factor following neoadjuvant therapy in women with breast cancer. Cancer J 19, 10-17.
Bi J, et al. (2010). Overexpression of clusterin correlates with tumor progression, metastasis in gastric cancer: a study on tissue microarrays. Neoplasma 57, 191-197. Bock AJ, et al. (2012). SCARA3 mRNA is overexpressed in ovarian carcinoma compared with breast carcinoma effusions. Hum. Pathol.43, 669-674.
Brait M, et al. (2012). Correlation between BRAF mutation and promoter methylation of TIMP3, RARbeta2 and RASSF1A in thyroid cancer. Epigenetics. 7, 710-719.
Breeden L, Nasmyth K (1987). Similarity between cell-cycle genes of budding yeast and fission yeast and the Notch gene of Drosophila. Nature 329, 651-654.
Brocke KS, et al. (2010). Glutamate receptors in pediatric tumors of the central nervous system. Cancer Biol. Ther.9, 455-468.
Bruchovsky N, et al. (1996). Control of tumor progression by maintenance of apoptosis. Prostate Suppl 6, 13-21.
Burkhart RA, et al. (2013). Mitoxantrone Targets Human Ubiquitin-Specific Peptidase 11 (USP11) and Is a Potent Inhibitor of Pancreatic Cancer Cell Survival. Mol. Cancer Res.
11, 901911.
Canoll PD, et al. (1993). The expression of a novel receptor-type tyrosine phosphatase suggests a role in morphogenesis and plasticity of the nervous system. Brain Res. Dev. Brain Res. 75, 293298.
Carroll M, Borden KL (2013). The Oncogene eIF4E: Using Biochemical Insights to Target Cancer. J Interferon Cytokine Res.33, 227-238.
Casado ME, et al. (2013). Hormone-sensitive lipase deficiency disturbs the fatty acid composition of mouse testis. Prostaglandins Leukot. Essent. Fatty Acids 88, 227-233. Casati C, et al. (2003). The apoptosis inhibitor protein survivin induces tumor-specific CD8+ and CD4+ T cells in colorectal cancer patients. Cancer Res.63, 4507-4515.
Chaiwatanasirikul KA, Sala A (2011). The tumour-suppressive function of CLU is explained by its localisation and interaction with HSP60. Cell Death. Dis.2, e219.
Chakravarti A, et al. (2002). Quantitatively determined survivin expression levels are of prognostic value in human gliomas. J Clin Oncol 20, 1063-1068.
Chan JY, Ong CW, Salto-Tellez M (2011). Overexpression of neurone glial-related cell adhesion molecule is an independent predictor of poor prognosis in advanced colorectal cancer. Cancer Sci.102, 1855-1861.
Chekenya M, et al. (2002). NG2 proteoglycan promotes angiogenesis-dependent tumor growth in CNS by sequestering angiostatin. FASEB J 16, 586-588.
Chekenya M, et al. (2008). The progenitor cell marker NG2/MPG promotes chemoresistance by activation of integrin-dependent PI3K/Akt signaling. Oncogene 27, 5182-5194.
Chekenya M, Pilkington GJ (2002). NG2 precursor cells in neoplasia: functional, histogenesis and therapeutic implications for malignant brain tumours. J Neurocytol.31, 507-521.
Chekenya M, et al. (1999). The NG2 chondroitin sulfate proteoglycan: role in malignant progression of human brain tumours. Int J Dev. Neurosci. 17, 421-435.
Chen D, et al. (2012). Antisense oligonucleotide against clusterin regulates human hepatocellular carcinoma invasion through transcriptional regulation of matrix metalloproteinase-2 and ecadherin. Int. J Mol. Sci.13, 10594-10607.
Cheung IY, et al. (2008). Exploiting gene expression profiling to identify novel minimal residual disease markers of neuroblastoma. Clin Cancer Res. 14, 7020-7027.
Chung FY, et al. (2010). Differential gene expression profile of MAGE family in taiwanese patients with colorectal cancer. J Surg. Oncol 102, 148-153.
Claro da ST, Polli JE, Swaan PW (2013). The solute carrier family 10 (SLC10): beyond bile acid transport. Mol. Aspects Med.34, 252-269.
Coon SW, et al. (2004). Prognostic implications of loss of heterozygosity at 8p21 and 9p21 in head and neck squamous cell carcinoma. Int. J Cancer 111, 206-212.
Cui J, et al. (1998). Chromosome 7 abnormalities in prostate cancer detected by dual-color fluorescence in situ hybridization. Cancer Genet. Cytogenet.107, 51-60.
Culjkovic-Kraljacic B, et al. (2012). The oncogene eIF4E reprograms the nuclear pore complex to promote mRNA export and oncogenic transformation. Cell Rep.2, 207-215. Cunningham JM, et al. (1996). Allelic imbalance and microsatellite instability in prostatic adenocarcinoma. Cancer Res.56, 4475-4482.
De RA, et al. (2012). A Radial Glia Gene Marker, Fatty Acid Binding Protein 7 (FABP7), Is Involved in Proliferation and Invasion of Glioblastoma Cells. PLoS. ONE.7, e52113.
Demokan S, et al. (2010). KIF1A and EDNRB are differentially methylated in primary HNSCC and salivary rinses. Int. J Cancer 127, 2351-2359.
Deng F, et al. (2006). Stargazin and other transmembrane AMPA receptor regulating proteins interact with synaptic scaffolding protein MAGI-2 in brain. J Neurosci.26, 7875-7884.
Dowler S, et al. (2000). Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities. Biochem. J 351, 19-31.
Edelman AM, et al. (2005). Doublecortin kinase-2, a novel doublecortin-related protein kinase associated with terminal segments of axons and dendrites. J Biol Chem.280, 8531-8543.
Engel M, et al. (1996). Chondroitin sulfate proteoglycans in the developing central nervous system. I. cellular sites of synthesis of neurocan and phosphacan. J Comp Neurol.366, 34-43.
Etcheverry A, et al. (2010). DNA methylation in glioblastoma: impact on gene expression and clinical outcome. BMC. Genomics 11, 701.
Frank M, Kemler R (2002). Protocadherins. Curr. Opin. Cell Biol.14, 557-562.
Futerman AH, Riezman H (2005). The ins and outs of sphingolipid synthesis. Trends Cell Biol. 15, 312-318.
Gallucci M, et al. (2006). Cytogenetic profiles as additional markers to pathological features in clinically localized prostate carcinoma. Cancer Lett.237, 76-82.
Garagnani P, et al. (2012). Methylation of ELOVL2 gene as a new epigenetic marker of age. Aging Cell 11, 1132-1134.
Gary SC, Kelly GM, Hockfield S (1998). BEHAB/brevican: a brain-specific lectican implicated in gliomas and glial cell motility. Curr. Opin. Neurobiol.8, 576-581.
Gary SC, et al. (2000). cDNA cloning, chromosomal localization, and expression analysis of human BEHAB/brevican, a brain specific proteoglycan regulated during cortical development and in glioma. Gene 256, 139-147.
Godbout R, Bisgrove DA, Shkolny D, Day RS, III (1998). Correlation of B-FABP and GFAP expression in malignant glioma. Oncogene 16, 1955-1962.
Gorka B, et al. (2007). NrCAM, a neuronal system cell-adhesion molecule, is induced in papillary thyroid carcinomas. Br. J Cancer 97, 531-538.
Gorlov IP, et al. (2007). Seizure 6-like (SEZ6L) gene and risk for lung cancer. Cancer Res.
67, 8406-8411.
Graf F, et al. (2010). Cyclin-dependent kinase 4/6 (cdk4/6) inhibitors: perspectives in cancer therapy and imaging. Mini. Rev. Med. Chem.10, 527-539.
Grumet M, et al. (1991). Structure of a new nervous system glycoprotein, Nr-CAM, and its relationship to subgroups of neural cell adhesion molecules. J Cell Biol. 113, 1399-1412.
Grunda JM, et al. (2010). Rationally designed pharmacogenomic treatment using concurrent capecitabine and radiotherapy for glioblastoma; gene expression profiles associated with outcome. Clin Cancer Res. 16, 2890-2898.
Grunda JM, et al. (2006). Increased expression of thymidylate synthetase (TS), ubiquitin specific protease 10 (USP10) and survivin is associated with poor survival in glioblastoma multiforme (GBM). J Neurooncol.80, 261-274.
Guerrero-Preston R, et al. (2011). NID2 and HOXA9 promoter hypermethylation as biomarkers for prevention and early detection in oral cavity squamous cell carcinoma tissues and saliva. Cancer Prev. Res. (Phila) 4, 1061-1072.
Gunther HS, et al. (2008). Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria. Oncogene 27, 2897-2909. Guvenc H, et al. (2013). Impairment of Glioma Stem Cell Survival and Growth by a Novel Inhibitor for Survivin-Ran Protein Complex. Clin Cancer Res.
Han HJ, Tokino T, Nakamura Y (1998). CSR, a scavenger receptor-like protein with a protective role against cellular damage causedby UV irradiation and oxidative stress. Hum. Mol. Genet.7, 1039-1046.
Hartomo TB, et al. (2013). Minimal residual disease monitoring in neuroblastoma patients based on the expression of a set of real-time RT-PCR markers in tumorinitiating cells. Oncol Rep.29, 1629-1636.
He J, et al. (2010). Identification of cell surface glycoprotein markers for glioblastomaderived stem-like cells using a lectin microarray and LC-MS/MS approach. J Proteome. Res 9, 25652572.
Hirao K, et al. (1998). A novel multiple PDZ domain-containing molecule interacting with Nmethyl-D-aspartate receptors and neuronal cell adhesion proteins. J Biol. Chem. 273, 2110521110.
Hirayama T, Yagi T (2006). The role and expression of the protocadherin-alpha clusters in the CNS. Curr. Opin. Neurobiol.16, 336-342.
Hirokawa N, Noda Y (2008). Intracellular transport and kinesin superfamily proteins, KIFs: structure, function, and dynamics. Physiol Rev. 88, 1089-1118.
Hjelmqvist L, et al. (2002). ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biol.3, RESEARCH0027.
Hood FE, Royle SJ (2011). Pulling it together: The mitotic function of TACC3. Bioarchitecture. 1, 105-109.
Ideguchi H, et al. (2002). Structural and functional characterization of the USP11 deubiquitinating enzyme, which interacts with the RanGTP-associated protein RanBPM. Biochem. J 367, 87-95.
Ingley E, Hemmings BA (1994). Pleckstrin homology (PH) domains in signal transduction. J Cell Biochem.56, 436-443.
Ishiuchi S (2009). [New roles of glutamate receptors in glias and gliomas]. Brain Nerve 61, 753764.
Ishiuchi S, et al. (2002). Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat. Med 8, 971-978. Ishwad CS, et al. (1995). Molecular and cytogenetic analysis of chromosome 7 in uterine leiomyomas. Genes Chromosomes. Cancer 14, 51-55.
Jamain S, et al. (2003). Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 34, 27-29.
Jiang JC, Kirchman PA, Zagulski M, Hunt J, Jazwinski SM (1998). Homologs of the yeast longevity gene LAG1 in Caenorhabditis elegans and human. Genome Res. 8, 1259-1272. Jin F, et al. (2008). Comparison between cells and cancer stem-like cells isolated from glioblastoma and astrocytoma on expression of anti-apoptotic and multidrug resistanceassociated protein genes. Neuroscience 154, 541-550.
Jung CK, Jung JH, Park GS, Lee A, Kang CS, Lee KY (2006). Expression of transforming acidic coiled-coil containing protein 3 is a novel independent prognostic marker in nonsmall cell lung cancer. Pathol. Int 56, 503-509.
Kajiwara Y, et al. (2003). Expression of survivin in astrocytic tumors: correlation with malignant grade and prognosis. Cancer 97, 1077-1083.
Kallenbach S, et al. (2003). Changes in subcellular distribution of protocadherin gamma proteins accompany maturation of spinal neurons. J Neurosci. Res.72, 549-556.
Kang GH, Lee S, Cho NY, Gandamihardja T, Long TI, Weisenberger DJ, Campan M, Laird PW (2008). DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis. Lab Invest 88, 161-170.
Kaur J, Demokan S, Tripathi SC, Macha MA, Begum S, Califano JA, Ralhan R (2010). Promoter hypermethylation in Indian primary oral squamous cell carcinoma. Int. J Cancer 127, 2367-2373.
Kawahara Y, Ito K, Sun H, Ito M, Kanazawa I, Kwak S (2004). GluR4c, an alternative splicing isoform of GluR4, is abundantly expressed in the adult human brain. Brain Res. Mol. Brain Res. 127, 150-155.
Kim DH, Mohapatra G, Bollen A, Waldman FM, Feuerstein BG (1995). Chromosomal abnormalities in glioblastoma multiforme tumors and glioma cell lines detected by comparative genomic hybridization. Int. J Cancer 60, 812-819.
Kim N, Yoo JC, Han JY, Hwang EM, Kim YS, Jeong EY, Sun CH, Yi GS, Roh GS, Kim HJ, Kang SS, Cho GJ, Park JY, Choi WS (2012). Human nuclear clusterin mediates apoptosis by interacting with Bcl-XL through C-terminal coiled coil domain. J Cell Physiol 227, 1157-1167.
Kimura J, Kudoh T, Miki Y, Yoshida K (2011). Identification of dihydropyrimidinaserelated protein 4 as a novel target of the p53 tumor suppressor in the apoptotic response to DNA damage. Int. J Cancer 128, 1524-1531.
Kohannim O, et al. (2012). Discovery and Replication of Gene Influences on Brain Structure Using LASSO Regression. Front Neurosci.6, 115.
Koide T, et al. N (2012). Common variants in MAGI2 gene are associated with increased risk for cognitive impairment in schizophrenic patients. PLoS. ONE.7, e36836.
Kolehmainen J, et al. (2003). Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am. J Hum. Genet.72, 1359-1369.
Kurimoto F, et al. (2001). Unchanged frequency of loss of heterozygosity and size of the deleted region at 8p21-23 during metastasis of lung cancer. Int. J Mol. Med.8, 89-93.
Laumonnier F, et al. (2004). X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum. Genet.74, 552557.
Lawson-Yuen A, Saldivar JS, Sommer S, Picker J (2008). Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur. J Hum. Genet.16, 614-618. Li H, Liu S, Zhu X, Yang S, Xiang J, Chen H (2010). Clusterin immunoexpression and its clinical significance in patients with non-small cell lung cancer. Lung 188, 423-431.
Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W (2002). Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416, 648-653.
Li X, et al. (2013). MAGI2 enhances the sensitivity of BEL-7404 human hepatocellular carcinoma cells to staurosporine-induced apoptosis by increasing PTEN stability. Int. J Mol. Med.
Liang Y, et al. (2005). Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Proc. Natl. Acad. Sci. U. S. A 102, 5814-5819.
Lin C, Meng S, Zhu T, Wang X (2010). PDCD10/CCM3 acts downstream of {gamma}protocadherins to regulate neuronal survival. J Biol. Chem. 285, 41675-41685. Liu X, Chen N, Wang X, He Y, Chen X, Huang Y, Yin W, Zhou Q (2006). Apoptosis and proliferation markers in diffusely infiltrating astrocytomas: profiling of 17 molecules. J Neuropathol. Exp. Neurol.65, 905-913.
Lobas MA, et al. (2012). Molecular heterogeneity in the choroid plexus epithelium: the 22member gamma-protocadherin family is differentially expressed, apically localized, and implicated in CSF regulation. J Neurochem. 120, 913-927.
Loyo M, et al. (2011). A survey of methylated candidate tumor suppressor genes in nasopharyngeal carcinoma. Int. J Cancer 128, 1393-1403.
Lu KV, et al. (2005). Differential induction of glioblastoma migration and growth by two forms of pleiotrophin. J Biol Chem.280, 26953-26964.
Luksch H, et al. (2011). Silencing of selected glutamate receptor subunits modulates cancer growth. Anticancer Res.31, 3181-3192.
Marchand M, et al. (1999). Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1. Int. J. Cancer 80, 219-230.
Marchand M, et al. (1995). Tumor regression responses in melanoma patients treated with a peptide encoded by gene MAGE-3. Int. J Cancer 63, 883-885.
Marei HE, et al. (2012). Gene expression profile of adult human olfactory bulb and embryonic neural stem cell suggests distinct signaling pathways and epigenetic control. PLoS. ONE.7, e33542.
McManus KJ, Barrett IJ, Nouhi Y, Hieter P (2009). Specific synthetic lethal killing of RAD54Bdeficient human colorectal cancer cells by FEN1 silencing. Proc. Natl. Acad. Sci. U. S. A 106, 3276-3281.
Mellai M, Caldera V, Patrucco A, Annovazzi L, Schiffer D (2008). Survivin expression in glioblastomas correlates with proliferation, but not with apoptosis. Anticancer Res. 28, 109-118.
Meyer-Puttlitz B, Junker E, Margolis RU, Margolis RK (1996). Chondroitin sulfate proteoglycans in the developing central nervous system. II. Immunocytochemical localization of neurocan and phosphacan. J Comp Neurol.366, 44-54.
Midorikawa Y, et al. (2002). Identification of genes associated with dedifferentiation of hepatocellular carcinoma with expression profiling analysis. Jpn. J Cancer Res. 93, 636-643.
Milev P, et al. (1994). Interactions of the chondroitin sulfate proteoglycan phosphacan, the extracellular domain of a receptor-type protein tyrosine phosphatase, with neurons, glia, and neural cell adhesion molecules. J Cell Biol.127, 1703-1715.
Min J, et al. (2007). (Dihydro)ceramide synthase 1 regulated sensitivity to cisplatin is associated with the activation of p38 mitogen-activated protein kinase and is abrogated by sphingosine kinase 1. Mol. Cancer Res.5, 801-812.
Mita R, Coles JE, Glubrecht DD, Sung R, Sun X, Godbout R (2007). B-FABP-expressing radial glial cells: the malignant glioma cell of origin? Neoplasia.9, 734-744.
Morales G, et al. (1993). Induction of axonal growth by heterophilic interactions between the cell surface recognition proteins F11 and Nr-CAM/Bravo. Neuron 11, 1113-1122. Morishita H, Yagi T (2007). Protocadherin family: diversity, structure, and function. Curr. Opin. Cell Biol.19, 584-592.
Mosavi LK, Cammett TJ, Desrosiers DC, Peng ZY (2004). The ankyrin repeat as molecular architecture for protein recognition. Protein Sci.13, 1435-1448.
Mulholland PJ, et al. (2006). Genomic profiling identifies discrete deletions associated with translocations in glioblastoma multiforme. Cell Cycle 5, 783-791.
Muller S, et al. (2003). A role for receptor tyrosine phosphatase zeta in glioma cell migration. Oncogene 22, 6661-6668.
Musacchio A, Gibson T, Rice P, Thompson J, Saraste M (1993). The PH domain: a common piece in the structural patchwork of signalling proteins. Trends Biochem. Sci.18, 343-348.
Nasr Z, Robert F, Porco JA, Jr., Muller WJ, Pelletier J (2013). eIF4F suppression in breast cancer affects maintenance and progression. Oncogene 32, 861-871.
Nestle FO, et al. (1998). Vaccination of melanoma patients with peptide- or tumor lysatepulsed dendritic cells. Nat Med.4, 328-332.
Nishioka M, Kohno T, Takahashi M, Niki T, Yamada T, Sone S, Yokota J (2000). Identification of a 428-kb homozygously deleted region disrupting the SEZ6L gene at 22q12.1 in a lung cancer cell line. Oncogene 19, 6251-6260.
Niu Z, Li X, Hu B, Li R, Wang L, Wu L, Wang X (2012). Small interfering RNA targeted to secretory clusterin blocks tumor growth, motility, and invasion in breast cancer. Acta Biochim. Biophys. Sin. (Shanghai) 44, 991-998.
Ohmae S, et al. (2006). Molecular identification and characterization of a family of kinases with homology to Ca2+/calmodulin-dependent protein kinases I/IV. J Biol. Chem. 281, 20427-20439.
Olsen ML, Sontheimer H (2008). Functional implications for Kir4.1 channels in glial biology: from K+ buffering to cell differentiation. J Neurochem.107, 589-601.
Ostrow KL, et al. (2009). Pharmacologic unmasking of epigenetically silenced genes in breast cancer. Clin Cancer Res.15, 1184-1191.
Ozerdem U (2006). Targeting of pericytes diminishes neovascularization and lymphangiogenesis in prostate cancer. Prostate 66, 294-304.
Panico F, et al. (2013). Prognostic role of clusterin in resected adenocarcinomas of the lung. Lung Cancer 79, 294-299.
Pattani KM, et al. (2010). Endothelin receptor type B gene promoter hypermethylation in salivary rinses is independently associated with risk of oral cavity cancer and premalignancy. Cancer Prev. Res. (Phila) 3, 1093-1103.
Perrin FE, Rathjen FG, Stoeckli ET (2001). Distinct subpopulations of sensory afferents require F11 or axonin-1 for growth to their target layers within the spinal cord of the chick. Neuron 30, 707-723.
Piesche M, Hildebrandt Y, Zettl F, Chapuy B, Schmitz M, Wulf G, Trumper L, Schroers R (2007). Identification of a promiscuous HLA DR-restricted T-cell epitope derived from the inhibitor of apoptosis protein survivin. Hum. Immunol. 68, 572-576.
Pinheiro PS, Perrais D, Coussen F, Barhanin J, Bettler B, Mann JR, Malva JO, Heinemann SF, Mulle C (2007). GluR7 is an essential subunit of presynaptic kainate autoreceptors at hippocampal mossy fiber synapses. Proc. Natl. Acad. Sci. U. S. A 104, 12181-12186. Prakash S, et al. (2005). Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. J Pediatr. Hematol. Oncol 27, 179-187.
Puyol M, et al. (2010). A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18, 63-73. Raji OY, Agbaje OF, Duffy SW, Cassidy A, Field JK (2010). Incorporation of a genetic factor into an epidemiologic model for prediction of individual risk of lung cancer: the Liverpool Lung Project. Cancer Prev. Res. (Phila) 3, 664-669.
Rostomily RC, et al. (2010). Quantitative proteomic analysis of oligodendrogliomas with and without 1p/19q deletion. J Proteome. Res.9, 2610-2618.
Saadoun S, Papadopoulos MC, Krishna S (2003). Water transport becomes uncoupled from K+ siphoning in brain contusion, bacterial meningitis, and brain tumours: immunohistochemical case review. J Clin Pathol.56, 972-975.
Saarikangas J, Hakanen J, Mattila PK, Grumet M, Salminen M, Lappalainen P (2008). ABBA regulates plasma-membrane and actin dynamics to promote radial glia extension. J Cell Sci.121, 1444-1454.
Saddoughi SA, Ogretmen B (2013). Diverse functions of ceramide in cancer cell death and proliferation. Adv. Cancer Res.117, 37-58.
Saito T, et al. (2007). Survivin subcellular localization in high-grade astrocytomas: simultaneous expression in both nucleus and cytoplasm is negative prognostic marker. J Neurooncol. 82, 193198.
Sakurai T, Friedlander DR, Grumet M (1996). Expression of polypeptide variants of receptortype protein tyrosine phosphatase beta: the secreted form, phosphacan, increases dramatically during embryonic development and modulates glial cell behavior in vitro. J Neurosci. Res. 43, 694-706.
Sakurai T, et al. (2001). Overlapping functions of the cell adhesion molecules Nr-CAM and L1 in cerebellar granule cell development. J Cell Biol.154, 1259-1273.
Sakurai T, Lustig M, Nativ M, Hemperly JJ, Schlessinger J, Peles E, Grumet M (1997). Induction of neurite outgrowth through contactin and Nr-CAM by extracellular regions of glial receptor tyrosine phosphatase beta. J Cell Biol.136, 907-918.
Sarai N, et al. (2008). Biochemical analysis of the N-terminal domain of human RAD54B. Nucleic Acids Res.36, 5441-5450.
Sasaki T, Lopes MB, Hankins GR, Helm GA (2002). Expression of survivin, an inhibitor of apoptosis protein, in tumors of the nervous system. Acta Neuropathol.104, 105-109. Schoenfeld AR, Apgar S, Dolios G, Wang R, Aaronson SA (2004). BRCA2 is ubiquitinated in vivo and interacts with USP11, a deubiquitinating enzyme that exhibits prosurvival function in the cellular response to DNA damage. Mol. Cell Biol. 24, 7444-7455.
Sehgal A, et al. (1998). Cell adhesion molecule Nr-CAM is over-expressed in human brain tumors. Int J Cancer 76, 451-458.
Sehgal A, Ricks S, Warrick J, Boynton AL, Murphy GP (1999). Antisense human neuroglia related cell adhesion molecule hNr-CAM, reduces the tumorigenic properties of human glioblastoma cells. Anticancer Res.19, 4947-4953.
Seifert W, Kuhnisch J, Maritzen T, Horn D, Haucke V, Hennies HC (2011). Cohen syndromeassociated protein, COH1, is a novel, giant Golgi matrix protein required for Golgi integrity. J Biol. Chem.286, 37665-37675.
Senkal CE, et al. (2007). Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas. Mol. Cancer Ther. 6, 712-722.
Sentelle RD, et al. (2012). Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat Chem. Biol.8, 831-838.
Separovic D, Breen P, Joseph N, Bielawski J, Pierce JS, VAN BE, Gudz TI (2012). siRNAmediated down-regulation of ceramide synthase 1 leads to apoptotic resistance in human head and neck squamous carcinoma cells after photodynamic therapy. Anticancer Res. 32, 2479-2485.
Shiota M, et al. (2012). Clusterin mediates TGF-beta-induced epithelial-mesenchymal transition and metastasis via Twist1 in prostate cancer cells. Cancer Res.72, 5261-5272. Shoji H, Tsuchida K, Kishi H, Yamakawa N, Matsuzaki T, Liu Z, Nakamura T, Sugino H (2000). Identification and characterization of a PDZ protein that interacts with activin type II receptors. J Biol. Chem. 275, 5485-5492.
Siow DL, Wattenberg BW (2012). Mammalian ORMDL proteins mediate the feedback response in ceramide biosynthesis. J Biol. Chem.287, 40198-40204.
Skaletsky H et al (2003). The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423, 825-837.
Splinter PL, Lazaridis KN, Dawson PA, LaRusso NF (2006). Cloning and expression of SLC10A4, a putative organic anion transport protein. World J Gastroenterol. 12, 6797-6805.
Stepulak A, et al. (2009). Expression of glutamate receptor subunits in human cancers. Histochem. Cell Biol.132, 435-445.
Stoeckli ET, Landmesser LT (1995). Axonin-1, Nr-CAM, and Ng-CAM play different roles in the in vivo guidance of chick commissural neurons. Neuron 14, 1165-1179. Suzuki H, Gabrielson E, Chen W, Anbazhagan R, Van EM, Weijenberg MP, Herman JG, Baylin SB (2002). A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet.31, 141-149.
Svendsen A et al (2011). Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma. Acta Neuropathol.122, 495-510.
Tan G, Sun SQ, Yuan DL (2008). Expression of Kir 4.1 in human astrocytic tumors: correlation with pathologic grade. Biochem. Biophys. Res. Commun. 367, 743-747. Thurner B et al (1999). Vaccination with mage-3A1 peptide-pulsed mature, monocytederived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp. Med 190, 1669-1678.
Tsai JR, et al. (2007). Differential expression profile of MAGE family in non-small-cell lung cancer. Lung Cancer 56, 185-192.
Tsourlakis MC, et al. (2013). High Nr-CAM expression is associated with favorable phenotype and late PSA recurrence in prostate cancer treated by prostatectomy. Prostate Cancer Prostatic. Dis.
Tuy FP, Saillour Y, Kappeler C, Chelly J, Francis F (2008). Alternative transcripts of Dclk1 and Dclk2 and their expression in doublecortin knockout mice. Dev. Neurosci.30, 171-186.
Uematsu M, et al. (2005). Prognostic significance of the immunohistochemical index of survivin in glioma: a comparative study with the MIB-1 index. J Neurooncol.72, 231-238. Ulbricht U, et al. (2003). Expression and function of the receptor protein tyrosine phosphatase zeta and its ligand pleiotrophin in human astrocytomas. J Neuropathol. Exp. Neurol. 62, 12651275.
Ulbricht U, Eckerich C, Fillbrandt R, Westphal M, Lamszus K (2006). RNA interference targeting protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta suppresses glioblastoma growth in vitro and in vivo. J Neurochem. 98, 1497-1506.
Valiente M, et al. (2005). Binding of PTEN to specific PDZ domains contributes to PTEN protein stability and phosphorylation by microtubule-associated serine/threonine kinases. J Biol. Chem. 280, 28936-28943.
van AM, Schepens M, de BD, Janssen B, Merkx G, Geurts van KA (2000). Construction of a 350-kb sequence-ready 11q13 cosmid contig encompassing the markers D11S4933 and D11S546: mapping of 11 genes and 3 tumor-associated translocation breakpoints. Genomics 66, 35-42.
Vissers JH, Nicassio F, van LM, Di Fiore PP, Citterio E (2008). The many faces of ubiquitinated histone H2A: insights from the DUBs. Cell Div.3, 8.
Volkmer H, Leuschner R, Zacharias U, Rathjen FG (1996). Neurofascin induces neurites by heterophilic interactions with axonal NrCAM while NrCAM requires F11 on the axonal surface to extend neurites. J Cell Biol.135, 1059-1069.
Wang J, et al. (2011). Targeting the NG2/CSPG4 proteoglycan retards tumour growth and angiogenesis in preclinical models of GBM and melanoma. PLoS. ONE.6, e23062. Wang X, Su H, Bradley A (2002). Molecular mechanisms governing Pcdh-gamma gene expression: evidence for a multiple promoter and cis-alternative splicing model. Genes Dev. 16, 1890-1905.
Warth A, Mittelbronn M, Wolburg H (2005). Redistribution of the water channel protein aquaporin-4 and the K+ channel protein Kir4.1 differs in low- and high-grade human brain tumors. Acta Neuropathol. (Berl) 109, 418-426.
Weake VM, Workman JL (2008). Histone ubiquitination: triggering gene activity. Mol. Cell 29, 653-663.
Weiskirchen R, Erdel M, Utermann G, Bister K (1997). Cloning, structural analysis, and chromosomal localization of the human CSRP2 gene encoding the LIM domain protein CRP2. Genomics 44, 83-93.
Wellstein A (2012). ALK receptor activation, ligands and therapeutic targeting in glioblastoma and in other cancers. Front Oncol 2, 192.
Wheater MJ, Johnson PW, Blaydes JP (2010). The role of MNK proteins and eIF4E phosphorylation in breast cancer cell proliferation and survival. Cancer Biol. Ther. 10, 728-735.
Wiltshire TD, Lovejoy CA, Wang T, Xia F, O'Connor MJ, Cortez D (2010). Sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition identifies ubiquitin-specific peptidase 11 (USP11) as a regulator of DNA double-strand break repair. J Biol. Chem. 285, 14565-14571.
Wood JD, Yuan J, Margolis RL, Colomer V, Duan K, Kushi J, Kaminsky Z, Kleiderlein JJ, Sharp AH, Ross CA (1998). Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins. Mol. Cell Neurosci. 11, 149-160.
Wu A, et al. (2011). Elevated expression of CDK4 in lung cancer. J Transl. Med.9, 38.
Xiao L, Rao JN, Zou T, Liu L, Marasa BS, Chen J, Turner DJ, Passaniti A, Wang JY (2007). Induced JunD in intestinal epithelial cells represses CDK4 transcription through its proximal promoter region following polyamine depletion. Biochem. J 403, 573-581. Xie D, Zeng YX, Wang HJ, Wen JM, Tao Y, Sham JS, Guan XY (2006). Expression of cytoplasmic and nuclear Survivin in primary and secondary human glioblastoma. Br. J Cancer 94, 108-114.
Xu C, et al. (2013). Polymorphisms in seizure 6-like gene are associated with bipolar disorder I: evidence of gene x gender interaction. J Affect. Disord.145, 95-99.
Yamada A, Irie K, Deguchi-Tawarada M, Ohtsuka T, Takai Y (2003). Nectin-dependent localization of synaptic scaffolding molecule (S-SCAM) at the puncta adherentia junctions formed between the mossy fibre terminals and the dendrites of pyramidal cells in the CA3 area of the mouse hippocampus. Genes Cells 8, 985-994.
Yan J, Feng J, Schroer R, Li W, Skinner C, Schwartz CE, Cook EH, Jr., Sommer SS (2008). Analysis of the neuroligin 4Y gene in patients with autism. Psychiatr. Genet. 18, 204-207.
Yang GF, Li XM, Xie D (2009). Overexpression of clusterin in ovarian cancer is correlated with impaired survival. Int. J Gynecol. Cancer 19, 1342-1346.
Yang H, et al. (2012). In vivo study of breast carcinoma radiosensitization by targeting eIF4E. Biochem. Biophys. Res. Commun. 423, 878-883.
Yasukawa M, et al. (2013). Dpysl4 is involved in tooth germ morphogenesis through growth regulation, polarization and differentiation of dental epithelial cells. Int. J Biol. Sci. 9, 382-390.
Ylisaukko-oja T, et al. (2005). Analysis of four neuroligin genes as candidates for autism. Eur. J Hum. Genet.13, 1285-1292.
Zacharias U, Norenberg U, Rathjen FG (1999). Functional interactions of the immunoglobulin superfamily member F11 are differentially regulated by the extracellular matrix proteins tenascinR and tenascin-C. J Biol. Chem.274, 24357-24365.
Zadravec D, et al. (2011). ELOVL2 controls the level of n-6 28:5 and 30:5 fatty acids in testis, a prerequisite for male fertility and sperm maturation in mice. J Lipid Res.52, 245-255.
Zangen I, et al. (2007). Ependymoma gene expression profiles associated with histological subtype, proliferation, and patient survival. Acta Neuropathol.113, 325-337.
Zekri AR, et al. (2012). Molecular prognostic profile of Egyptian HCC cases infected with hepatitis C virus. Asian Pac. J Cancer Prev.13, 5433-5438.
Zelano J, et al. (2013). The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants. Exp. Neurol. 239, 73-81.
Zhen HN, et al. (2005). Survivin expression and its relation with proliferation, apoptosis, and angiogenesis in brain gliomas. Cancer 104, 2775-2783.
Zheng D, et al. (2010). Abba promotes PDGF-mediated membrane ruffling through activation of the small GTPase Rac1. Biochem. Biophys. Res. Commun.401, 527-532. Zhu ZH, Yu YP, Shi YK, Nelson JB, Luo JH (2009). CSR1 induces cell death through inactivation of CPSF3. Oncogene 28, 41-51.
Aaltonen K, et al. (2009). High cyclin B1 expression is associated with poor survival in breast cancer. Br. J Cancer 100, 1055-1060.
Abd-Elaziz M, Akahira J, Moriya T, Suzuki T, Yaegashi N, Sasano H (2003). Nuclear receptor DAX-1 in human common epithelial ovarian carcinoma: an independent prognostic factor of clinical outcome. Cancer Sci.94, 980-985.
Abe M, Watanabe N, McDonell N, Takato T, Ohira M, Nakagawara A, Ushijima T (2008). Identification of genes targeted by CpG island methylator phenotype in neuroblastomas, and their possible integrative involvement in poor prognosis. Oncology 74, 50-60.
Abraham R, Pagano F, Gomella LG, Baffa R (2007). Chromosomal deletions in bladder cancer:
shutting down pathways. Front Biosci. 12, 826-838.
Abramic M, Simaga S, Osmak M, Cicin-Sain L, Vukelic B, Vlahovicek K, Dolovcak L (2004). Highly reactive cysteine residues are part of the substrate binding site of mammalian dipeptidyl peptidases III. Int. J Biochem. Cell Biol.36, 434-446.
Agarwal R, et al. (2009). Integrative analysis of cyclin protein levels identifies cyclin b1 as a classifier and predictor of outcomes in breast cancer. Clin Cancer Res 15, 3654-3662. Akita K, et al. (2004). Heparan sulphate proteoglycans interact with neurocan and promote neurite outgrowth from cerebellar granule cells. Biochem. J 383, 129-138.
Al-Joudi FS, Iskandar ZA, Imran AK (2007). Survivin expression correlates with unfavourable prognoses in invasive ductal carcinoma of the breast. Med J Malaysia 62, 6-8.
Alarmo EL, Rauta J, Kauraniemi P, Karhu R, Kuukasjarvi T, Kallioniemi A (2006). Bone morphogenetic protein 7 is widely overexpressed in primary breast cancer. Genes Chromosomes. Cancer 45, 411-419.
Allison JP, Krummel MF (1995). The Yin and Yang of T cell costimulation. Science 270, 932933.
Ammar H, Closset JL (2008). Clusterin activates survival through the phosphatidylinositol 3kinase/Akt pathway. J Biol. Chem.283, 12851-12861.
An CH, Kim YR, Kim HS, Kim SS, Yoo NJ, Lee SH (2012). Frameshift mutations of vacuolar protein sorting genes in gastric and colorectal cancers with microsatellite instability. Hum. Pathol.43, 40-47.
Andersen RS, et al. (2012). Parallel detection of antigen-specific T cell responses by combinatorial encoding of MHC multimers. Nat. Protoc.7, 891-902.
Aoki M, et al. (2011). Expression of BMP-7 in human gastric cancer and its clinical significance. Br. J Cancer 104, 714-718.
Appay V, et al. (2006). Decreased specific CD8+ T cell cross-reactivity of antigen recognition following vaccination with Melan-A peptide. Eur. J Immunol. 36, 1805-1814. Appolloni I, Calzolari F, Barilari M, Terrile M, Daga A, Malatesta P (2012). Antagonistic modulation of gliomagenesis by Pax6 and Olig2 in PDGF-induced oligodendroglioma. Int. J Cancer 131, E1078-E1087.
Araki W, Takahashi-Sasaki N, Chui DH, Saito S, Takeda K, Shirotani K, Takahashi K, Murayama KS, Kametani F, Shiraishi H, Komano H, Tabira T (2008). A family of membrane proteins associated with presenilin expression and gamma-secretase function. FASEB J 22, 819-827.
Ariyannur PS, et al. (2010). Methamphetamine-induced neuronal protein NAT8L is the NAA biosynthetic enzyme: implications for specialized acetyl coenzyme A metabolism in the CNS. Brain Res.1335, 1-13.
Aronica E, et al. (2001). Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumours from patients with intractable epilepsy. Neuropathol. Appl. Neurobiol.27, 223-237.
Aslibekyan S, et al. (2012). Genetic variation in fatty acid elongases is not associated with intermediate cardiovascular phenotypes or myocardial infarction. Eur. J Clin Nutr. 66, 353-359.
Augustin I, et al. (2012). The Wnt secretion protein Evi/Gpr177 promotes glioma tumourigenesis. EMBO Mol. Med.4, 38-51.
Axelson H (2004). The Notch signaling cascade in neuroblastoma: role of the basic helixloophelix proteins HASH-1 and HES-1. Cancer Lett.204, 171-178.
Aylsworth A, Jiang SX, Desbois A, Hou ST (2009). Characterization of the role of fulllength CRMP3 and its calpain-cleaved product in inhibiting microtubule polymerization and neurite outgrowth. Exp. Cell Res.315, 2856-2868.
Azari AA et al (2006). Retinal disease expression in Bardet-Biedl syndrome-1 (BBS1) is a spectrum from maculopathy to retina-wide degeneration. Invest Ophthalmol. Vis. Sci.
47, 50045010.
Azuma M, Toyama R, Laver E, Dawid IB (2006). Perturbation of rRNA synthesis in the bap28 mutation leads to apoptosis mediated by p53 in the zebrafish central nervous system. J Biol. Chem.281, 13309-13316.
Ball DW (2004). Achaete-scute homolog-1 and Notch in lung neuroendocrine development and cancer. Cancer Lett.204, 159-169.
Balzeau J, Peterson A, Eyer J (2012). The vimentin-tubulin binding site peptide (Vim-TBS.5881) crosses the plasma membrane and enters the nuclei of human glioma cells. Int. J Pharm.423, 77-83.
Bar-Yehuda S, Stemmer SM, Madi L, Castel D, Ochaion A, Cohen S, Barer F, Zabutti A, PerezLiz G, Del VL, Fishman P (2008). The A3 adenosine receptor agonist CF102 induces apoptosis of hepatocellular carcinoma via de-regulation of the Wnt and NF-kappaB signal transduction pathways. Int. J Oncol 33, 287-295.
Bargo S, Raafat A, McCurdy D, Amirjazil I, Shu Y, Traicoff J, Plant J, Vonderhaar BK, Callahan R (2010). Transforming acidic coiled-coil protein-3 (Tacc3) acts as a negative regulator of Notch signaling through binding to CDC10/Ankyrin repeats. Biochem. Biophys. Res Commun. 400, 606-612.
Barnett M, et al. (2001). Paraneoplastic brain stem encephalitis in a woman with anti-Ma2 antibody. J Neurol. Neurosurg. Psychiatry 70, 222-225.
Bartsch S, et al. (1992). Expression of tenascin in the developing and adult cerebellar cortex. J Neurosci. 12, 736-749.
Bayraktar S, Gutierrez Barrera AM, Liu D, Pusztai L, Litton J, Valero V, Hunt K, Hortobagyi GN, Wu Y, Symmans F, Arun B (2013). USP-11 as a predictive and prognostic factor following neoadjuvant therapy in women with breast cancer. Cancer J 19, 10-17.
Beljan PR, Durdov MG, Capkun V, Ivcevic V, Pavlovic A, Soljic V, Peric M (2012). IMP3 can predict aggressive behaviour of lung adenocarcinoma. Diagn. Pathol.7, 165.
Berthold J, Schenkova K, Ramos S, Miura Y, Furukawa M, Aspenstrom P, Rivero F (2008a). Characterization of RhoBTB-dependent Cul3 ubiquitin ligase complexes--evidence for an autoregulatory mechanism. Exp. Cell Res. 314, 3453-3465.
Berthold J, Schenkova K, Rivero F (2008b). Rho GTPases of the RhoBTB subfamily and tumorigenesis. Acta Pharmacol. Sin.29, 285-295.
Bi J, et al. (2010). Overexpression of clusterin correlates with tumor progression, metastasis in gastric cancer: a study on tissue microarrays. Neoplasma 57, 191-197. Bigarella CL, Borges L, Costa FF, Saad ST (2009). ARHGAP21 modulates FAK activity and impairs glioblastoma cell migration. Biochim. Biophys. Acta 1793, 806-816.
Bigarella et al. (2012). Post-translational modification of the RhoGTPase activating protein 21, ARHGAP21, by SUMO2/3. FEBS Lett.586, 3522-3528.
Bikeye SN, et al. (2010). ASPM-associated stem cell proliferation is involved in malignant progression of gliomas and constitutes an attractive therapeutic target. Cancer Cell Int 10, 1.
Bikeye SN, et al. (2011). Correction: ASPM-associated stem cell proliferation is involved in malignant progression of gliomas and constitutes an attractive therapeutic target. Cancer Cell Int.11, 10.
Bivona TG, et al. (2011). FAS and NF-kappaB signalling modulate dependence of lung cancers on mutant EGFR. Nature 471, 523-526.
Blom T, Roselli A, Tanner M, Nupponen NN (2008). Mutation and copy number analysis of LNX1 and Numbl in nervous system tumors. Cancer Genet. Cytogenet. 186, 103-109. Bocciardi R, et al. (2005). Molecular characterization of a t(2;6) balanced translocation that is associated with a complex phenotype and leads to truncation of the TCBA1 gene. Hum. Mutat. 26, 426-436.
Bock AJ, Nymoen DA, Brenne K, Kaern J, Davidson B (2012). SCARA3 mRNA is overexpressed in ovarian carcinoma compared with breast carcinoma effusions. Hum. Pathol. 43, 669-674.
Bonnefont JP, Djouadi F, Prip-Buus C, Gobin S, Munnich A, Bastin J (2004). Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol. Aspects Med. 25, 495-520.
Borges M, Linnoila RI, van de Velde HJ, Chen H, Nelkin BD, Mabry M, Baylin SB, Ball DW (1997). An achaete-scute homologue essential for neuroendocrine differentiation in the lung. Nature 386, 852-855.
Bourdon MA, Wikstrand CJ, Furthmayr H, Matthews TJ, Bigner DD (1983). Human gliomamesenchymal extracellular matrix antigen defined by monoclonal antibody. Cancer Res. 43, 2796-2805.
Boureux A, Vignal E, Faure S, Fort P (2007). Evolution of the Rho family of ras-like GTPases in eukaryotes. Mol. Biol. Evol.24, 203-216.
Bozinov O, Kohler S, Samans B, Benes L, Miller D, Ritter M, Sure U, Bertalanffy H (2008). Candidate genes for the progression of malignant gliomas identified by microarray analysis. Neurosurg. Rev. 31, 83-89.
Brait M, et al. (2012). Correlation between BRAF mutation and promoter methylation of TIMP3, RARbeta2 and RASSF1A in thyroid cancer. Epigenetics. 7, 710-719.
Breeden L, Nasmyth K (1987). Similarity between cell-cycle genes of budding yeast and fission yeast and the Notch gene of Drosophila. Nature 329, 651-654.
Bret C, et al. (2009). Expression of genes encoding for proteins involved in heparan sulphate and chondroitin sulphate chain synthesis and modification in normal and malignant plasma cells. Br. J Haematol. 145, 350-368.
Brocke KS, et al. (2010). Glutamate receptors in pediatric tumors of the central nervous system. Cancer Biol. Ther.9, 455-468.
Bruchovsky N, Snoek R, Rennie PS, Akakura K, Goldenberg LS, Gleave M (1996). Control of tumor progression by maintenance of apoptosis. Prostate Suppl 6, 13-21.
Bruckdorfer T, Marder O, Albericio F (2004). From production of peptides in milligram amounts for research to multi-tons quantities for drugs of the future. Curr. Pharm. Biotechnol. 5, 29-43.
Bruning-Richardson A, et al. (2011). ASPM and microcephalin expression in epithelial ovarian cancer correlates with tumour grade and survival. Br. J Cancer 104, 1602-1610. Brunskill EW, Witte DP, Shreiner AB, Potter SS (1999). Characterization of npas3, a novel basic helix-loop-helix PAS gene expressed in the developing mouse nervous system. Mech. Dev. 88, 237-241.
Brunsvig PF, et al. (2006). Telomerase peptide vaccination: a phase I/II study in patients with non-small cell lung cancer. Cancer Immunol. Immunother. 55, 1553-1564.
Budreck EC, Scheiffele P (2007). Neuroligin-3 is a neuronal adhesion protein at GABAergic and glutamatergic synapses. Eur. J Neurosci. 26, 1738-1748.
Burch TC, Watson MT, Nyalwidhe JO (2013). Variable metastatic potentials correlate with differential plectin and vimentin expression in syngeneic androgen independent prostate cancer cells. PLoS. ONE.8, e65005.
Burkhart RA, et al. (2013). Mitoxantrone Targets Human Ubiquitin-Specific Peptidase 11 (USP11) and Is a Potent Inhibitor of Pancreatic Cancer Cell Survival. Mol. Cancer Res.
11, 901911.
Burris TP, Nawaz Z, Tsai MJ, O'Malley BW (1995). A nuclear hormone receptorassociated protein that inhibits transactivation by the thyroid hormone and retinoic acid receptors. Proc. Natl. Acad. Sci. U. S. A 92, 9525-9529.
Cabeza-Arvelaiz Y, Sepulveda JL, Lebovitz RM, Thompson TC, Chinault AC (2001). Functional identification of LZTS1 as a candidate prostate tumor suppressor gene on human chromosome 8p22. Oncogene 20, 4169-4179.
Calboli FC, et al. (2010). A genome-wide association study of neuroticism in a populationbased sample. PLoS. ONE.5, e11504.
Camoes MJ, et al. (2012). Potential downstream target genes of aberrant ETS transcription factors are differentially affected in Ewing's sarcoma and prostate carcinoma. PLoS. ONE.
7, e49819.
Canoll PD, Barnea G, Levy JB, Sap J, Ehrlich M, Silvennoinen O, Schlessinger J, Musacchio JM (1993). The expression of a novel receptor-type tyrosine phosphatase suggests a role in morphogenesis and plasticity of the nervous system. Brain Res. Dev. Brain Res. 75, 293-298.
Cantara S, D'Angeli F, Toti P, Lignitto L, Castagna MG, Capuano S, Prabhakar BS, Feliciello A, Pacini F (2012). Expression of the ring ligase PRAJA2 in thyroid cancer. J Clin Endocrinol. Metab 97, 4253-4259.
Caren H, Ejeskar K, Fransson S, Hesson L, Latif F, Sjoberg RM, Krona C, Martinsson T (2005). A cluster of genes located in 1p36 are down-regulated in neuroblastomas with poor prognosis, but not due to CpG island methylation. Mol. Cancer 4, 10.
Cargnello M, Roux PP (2011). Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol. Mol. Biol. Rev.75, 50-83.
Carinci F, et al. (2005). Potential markers of tongue tumor progression selected by cDNA microarray. Int. J Immunopathol. Pharmacol. 18, 513-524.
Carney ME, O'Reilly RC, Sholevar B, Buiakova OI, Lowry LD, Keane WM, Margolis FL, Rothstein JL (1995). Expression of the human Achaete-scute 1 gene in olfactory neuroblastoma (esthesioneuroblastoma). J Neurooncol.26, 35-43.
Carroll M, Borden KL (2013). The Oncogene eIF4E: Using Biochemical Insights to Target Cancer. J Interferon Cytokine Res.33, 227-238.
Casado ME, et al. (2013). Hormone-sensitive lipase deficiency disturbs the fatty acid composition of mouse testis. Prostaglandins Leukot. Essent. Fatty Acids 88, 227-233. Casati C, et al. (2003). The apoptosis inhibitor protein survivin induces tumor-specific CD8+ and CD4+ T cells in colorectal cancer patients. Cancer Res.63, 4507-4515.
Casper M, Grunhage F, Lammert F (2011). Cancer risk in chronic hepatitis B: Do genomewide association studies hit the mark? Hepatology 53, 1390-1392.
Cayan F, Tok E, Aras-Ates N, Ayaz L, Akbay E, Gen R, Karakas S, Dilek S (2010). Insulin receptor substrate-2 gene polymorphism: is it associated with endometrial cancer? Gynecol. Endocrinol. 26, 378-382.
Cervantes MD, Coyne RS, Xi X, Yao MC (2006). The condensin complex is essential for amitotic segregation of bulk chromosomes, but not nucleoli, in the ciliate Tetrahymena thermophila. Mol. Cell Biol.26, 4690-4700.
Cervelli M, Amendola R, Polticelli F, Mariottini P (2012). Spermine oxidase: ten years after. Amino. Acids 42, 441-450.
Cervelli M et al (2010). Spermine oxidase (SMO) activity in breast tumor tissues and biochemical analysis of the anticancer spermine analogues BENSpm and CPENSpm. BMC. Cancer 10, 555.
Chae SW, Sohn JH, Kim DH, Choi YJ, Park YL, Kim K, Cho YH, Pyo JS, Kim JH (2011). Overexpressions of Cyclin B1, cdc2, p16 and p53 in human breast cancer: the clinicopathologic correlations and prognostic implications. Yonsei Med. J 52, 445-453. Chaiwatanasirikul KA, Sala A (2011). The tumour-suppressive function of CLU is explained by its localisation and interaction with HSP60. Cell Death. Dis.2, e219.
Chakravarti A, Noll E, Black PM, Finkelstein DF, Finkelstein DM, Dyson NJ, Loeffler JS (2002). Quantitatively determined survivin expression levels are of prognostic value in human gliomas. J Clin Oncol 20, 1063-1068.
Chan JY, Ong CW, Salto-Tellez M (2011). Overexpression of neurone glial-related cell adhesion molecule is an independent predictor of poor prognosis in advanced colorectal cancer. Cancer Sci.102, 1855-1861.
Chanock SJ, Foster CB, Miller FW, O'Hanlon TP (2004). HLA-A, -B, -Cw, -DQA1 and -DRB1 Alleles in a Caucasian Population from Bethesda, USA. Hum. Immunol. 65, 1211-1223.
Charfi C, Voisin V, Levros LC, Jr., Edouard E, Rassart E (2011). Gene profiling of Graffi murine leukemia virus-induced lymphoid leukemias: identification of leukemia markers and Fmn2 as a potential oncogene. Blood 117, 1899-1910.
Chekenya M, Hjelstuen M, Enger PO, Thorsen F, Jacob AL, Probst B, Haraldseth O, Pilkington G, Butt A, Levine JM, Bjerkvig R (2002). NG2 proteoglycan promotes angiogenesis-dependent tumor growth in CNS by sequestering angiostatin. FASEB J 16, 586-588.
Chekenya M, et al. (2008). The progenitor cell marker NG2/MPG promotes chemoresistance by activation of integrin-dependent PI3K/Akt signaling. Oncogene 27, 5182-5194.
Chekenya M, Pilkington GJ (2002). NG2 precursor cells in neoplasia: functional, histogenesis and therapeutic implications for malignant brain tumours. J Neurocytol.31, 507-521.
Chekenya M, Rooprai HK, Davies D, Levine JM, Butt AM, Pilkington GJ (1999). The NG2 chondroitin sulfate proteoglycan: role in malignant progression of human brain tumours. Int J Dev. Neurosci.17, 421-435.
Chen C, Bartenhagen C, Gombert M, Okpanyi V, Binder V, Rottgers S, Bradtke J, TeiglerSchlegel A, Harbott J, Ginzel S, Thiele R, Fischer U, Dugas M, Hu J, Borkhardt A (2013a). Nextgeneration-sequencing-based risk stratification and identification of new genes involved in structural and sequence variations in near haploid lymphoblastic leukemia. Genes Chromosomes. Cancer 52, 564-579.
Chen D, Wang Y, Zhang K, Jiao X, Yan B, Liang J (2012a). Antisense oligonucleotide against clusterin regulates human hepatocellular carcinoma invasion through transcriptional regulation of matrix metalloproteinase-2 and e-cadherin. Int. J Mol. Sci.
13, 10594-10607.
Chen J, Xu J, Zhao W, Hu G, Cheng H, Kang Y, Xie Y, Lu Y (2005). Characterization of human LNX, a novel ligand of Numb protein X that is downregulated in human gliomas. Int. J Biochem. Cell Biol.37, 2273-2283.
Chen JC, Chen Y, Wu JM, Su YH, Tai KF, Tseng SH (2006). Effects of irradiated tumor vaccine and infusion of granulocyte-macrophage colony-stimulating factor and interleukin-12 on established gliomas in rats. Cancer Immunol. Immunother. 55, 873-883. Chen L, Zhu YY, Zhang XJ, Wang GL, Li XY, He S, Zhang JB, Zhu JW (2009). TSPAN1 protein expression: a significant prognostic indicator for patients with colorectal adenocarcinoma. World J Gastroenterol.15, 2270-2276.
Chen P, Wang SJ, Wang HB, Ren P, Wang XQ, Liu WG, Gu WL, Li DQ, Zhang TG, Zhou CJ (2012b). The distribution of IGF2 and IMP3 in osteosarcoma and its relationship with angiogenesis. J Mol. Histol.43, 63-70.
Chen ST, et al. (2011). Insulin-like growth factor II mRNA-binding protein 3 expression predicts unfavorable prognosis in patients with neuroblastoma. Cancer Sci. 102, 2191-2198.
Chen YW, Chu HC, Ze-Shiang L, Shiah WJ, Chou CP, Klimstra DS, Lewis BC (2013b). p16 Stimulates CDC42-dependent migration of hepatocellular carcinoma cells. PLoS. ONE. 8, e69389.
Cheng YC, Lee CJ, Badge RM, Orme AT, Scotting PJ (2001). Sox8 gene expression identifies immature glial cells in developing cerebellum and cerebellar tumours. Brain Res. Mol. Brain Res.92, 193-200.
Cheung IY, Feng Y, Gerald W, Cheung NK (2008). Exploiting gene expression profiling to identify novel minimal residual disease markers of neuroblastoma. Clin Cancer Res.14, 70207027.
Chih B, Afridi SK, Clark L, Scheiffele P (2004). Disorder-associated mutations lead to functional inactivation of neuroligins. Hum. Mol. Genet.13, 1471-1477.
Chih B, Liu P, Chinn Y, Chalouni C, Komuves LG, Hass PE, Sandoval W, Peterson AS (2012). A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nat Cell Biol.14, 61-72.
Chiquet-Ehrismann R (1993). Tenascin and other adhesion-modulating proteins in cancer. Semin. Cancer Biol.4, 301-310.
Chiquet-Ehrismann R, Chiquet M (2003). Tenascins: regulation and putative functions during pathological stress. J Pathol.200, 488-499.
Chirasani SR, et al. (2010). Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells. Brain 133, 19611972.
Choi CH, Lee JS, Kim SR, Lee YY, Kim CJ, Lee JW, Kim TJ, Lee JH, Kim BG, Bae DS (2011). Direct inhibition of eIF4E reduced cell growth in endometrial adenocarcinoma. J Cancer Res. Clin Oncol 137, 463-469.
Chubykin AA, Atasoy D, Etherton MR, Brose N, Kavalali ET, Gibson JR, Sudhof TC (2007). Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron 54, 919-931.
Chung FY, et al. (2010). Differential gene expression profile of MAGE family in taiwanese patients with colorectal cancer. J Surg. Oncol 102, 148-153.
Cillo C, et al. (2011). The HOX gene network in hepatocellular carcinoma. Int. J Cancer 129, 2577-2587.
Cimino-Mathews A, Subhawong AP, Elwood H, Warzecha HN, Sharma R, Park BH, Taube JM, Illei PB, Argani P (2013). Neural crest transcription factor Sox10 is preferentially expressed in triple-negative and metaplastic breast carcinomas. Hum. Pathol. 44, 959-965.
Clark JL, Dresser K, Hsieh CC, Sabel M, Kleer CG, Khan A, Shaw LM (2011). Membrane localization of insulin receptor substrate-2 (IRS-2) is associated with decreased overall survival in breast cancer. Breast Cancer Res. Treat.130, 759-772.
Claro da ST, Polli JE, Swaan PW (2013). The solute carrier family 10 (SLC10): beyond bile acid transport. Mol. Aspects Med.34, 252-269.
Clements JA, Mercer FC, Paterno GD, Gillespie LL (2012). Differential splicing alters subcellular localization of the alpha but not beta isoform of the MIER1 transcriptional regulator in breast cancer cells. PLoS. ONE.7, e32499.
Colombetti S, Basso V, Mueller DL, Mondino A (2006). Prolonged TCR/CD28 engagement drives IL-2-independent T cell clonal expansion through signaling mediated by the mammalian target of rapamycin. J Immunol. 176, 2730-2738.
Coon SW, Savera AT, Zarbo RJ, Benninger MS, Chase GA, Rybicki BA, Van Dyke DL (2004). Prognostic implications of loss of heterozygosity at 8p21 and 9p21 in head and neck squamous cell carcinoma. Int. J Cancer 111, 206-212.
Cooper WA, Kohonen-Corish MR, McCaughan B, Kennedy C, Sutherland RL, Lee CS (2009).
Expression and prognostic significance of cyclin B1 and cyclin A in non-small cell lung cancer. Histopathology 55, 28-36.
Coppieters F, Casteels I, Meire F, De JS, Hooghe S, van RN, Van EH, Matuleviciene A, Nunes L, Meersschaut V, Walraedt S, Standaert L, Coucke P, Hoeben H, Kroes HY, Vande WJ, de RT, Leroy BP, De BE (2010). Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes. Hum. Mutat.31, E1709-E1766.
Coppola D, Fu L, Nicosia SV, Kounelis S, Jones M (1998). Prognostic significance of p53, bcl-2, vimentin, and S100 protein-positive Langerhans cells in endometrial carcinoma. Hum. Pathol.29, 455-462.
Cruz-Garcia D, Diaz-Ruiz A, Rabanal-Ruiz Y, Peinado JR, Gracia-Navarro F, Castano JP, Montero-Hadjadje M, Tonon MC, Vaudry H, Anouar Y, Vazquez-Martinez R, Malagon MM (2012). The Golgi-associated long coiled-coil protein NECC1 participates in the control of the regulated secretory pathway in PC12 cells. Biochem. J 443, 387-396.
Cruz-Garcia D, Vazquez-Martinez R, Peinado JR, Anouar Y, Tonon MC, Vaudry H, Castano JP, Malagon MM (2007). Identification and characterization of two novel (neuro)endocrine long coiled-coil proteins. FEBS Lett.581, 3149-3156.
Cui J, Deubler DA, Rohr LR, Zhu XL, Maxwell TM, Changus JE, Brothman AR (1998). Chromosome 7 abnormalities in prostate cancer detected by dual-color fluorescence in situ hybridization. Cancer Genet. Cytogenet.107, 51-60.
Culjkovic-Kraljacic B, Baguet A, Volpon L, Amri A, Borden KL (2012). The oncogene eIF4E reprograms the nuclear pore complex to promote mRNA export and oncogenic transformation. Cell Rep.2, 207-215.
Cunningham JM, Shan A, Wick MJ, McDonnell SK, Schaid DJ, Tester DJ, Qian J, Takahashi S, Jenkins RB, Bostwick DG, Thibodeau SN (1996). Allelic imbalance and microsatellite instability in prostatic adenocarcinoma. Cancer Res.56, 4475-4482.
Dallosso AR, Oster B, Greenhough A, Thorsen K, Curry TJ, Owen C, Hancock AL, Szemes M, Paraskeva C, Frank M, Andersen CL, Malik K (2012). Long-range epigenetic silencing of chromosome 5q31 protocadherins is involved in early and late stages of colorectal tumorigenesis through modulation of oncogenic pathways. Oncogene 31, 4409-4419.
de Blaquiere GE, May FE, Westley BR (2009). Increased expression of both insulin receptor substrates 1 and 2 confers increased sensitivity to IGF-1 stimulated cell migration. Endocr. Relat Cancer 16, 635-647.
De BA, Hendrix A, Maynard D, Van BM, Daniels A, Pauwels P, Gespach C, Bracke M, De WO (2013). Differential secretome analysis of cancer-associated fibroblasts and bone marrow-derived precursors to identify microenvironmental regulators of colon cancer progression. Proteomics. 13, 379-388.
De FS, Russo G, Angiolillo A, Pietropaolo C (1993). Human L7a ribosomal protein: sequence, structural organization, and expression of a functional gene. Gene 126, 227-235.
de HT, Hasselt N, Troost D, Caron H, Popovic M, Zadravec-Zaletel L, Grajkowska W, Perek M, Osterheld MC, Ellison D, Baas F, Versteeg R, Kool M (2008). Molecular risk stratification of medulloblastoma patients based on immunohistochemical analysis of MYC, LDHB, and CCNB1 expression. Clin Cancer Res 14, 4154-4160.
De RA, Pellegatta S, Rossi M, Tunici P, Magnoni L, Speranza MC, Malusa F, Miragliotta V, Mori
E, Finocchiaro G, Bakker A (2012). A Radial Glia Gene Marker, Fatty Acid Binding Protein 7 (FABP7), Is Involved in Proliferation and Invasion of Glioblastoma Cells. PLoS. ONE. 7, e52113.
Deloukas P et al (2001). The DNA sequence and comparative analysis of human chromosome 20. Nature 414, 865-871.
Demokan S, Chang X, Chuang A, Mydlarz WK, Kaur J, Huang P, Khan Z, Khan T, Ostrow KL,
Brait M, Hoque MO, Liegeois NJ, Sidransky D, Koch W, Califano JA (2010). KIF1A and EDNRB are differentially methylated in primary HNSCC and salivary rinses. Int. J Cancer 127, 2351-2359.
den Hollander AI, Johnson K, de Kok YJ, Klebes A, Brunner HG, Knust E, Cremers FP (2001). CRB1 has a cytoplasmic domain that is functionally conserved between human and Drosophila. Hum. Mol. Genet.10, 2767-2773.
den Hollander AI, van Driel MA, de Kok YJ, van de Pol DJ, Hoyng CB, Brunner HG, Deutman AF, Cremers FP (1999). Isolation and mapping of novel candidate genes for retinal disorders using suppression subtractive hybridization. Genomics 58, 240-249.
Deng F, Price MG, Davis CF, Mori M, Burgess DL (2006). Stargazin and other transmembrane AMPA receptor regulating proteins interact with synaptic scaffolding protein MAGI-2 in brain. J Neurosci.26, 7875-7884.
Deng R, Wang X, Liu Y, Yan M, Hanada S, Xu Q, Zhang J, Han Z, Chen W, Zhang P (2013). A new gamboge derivative Compound 2 inhibits cancer stem-like cells via suppressing EGFR tyrosine phosphorylation in head and neck squamous cell carcinoma. J Cell Mol. Med.
Deng X, Shibata H, Takeuchi N, Rachi S, Sakai M, Ninomiya H, Iwata N, Ozaki N, Fukumaki Y
(2007). Association study of polymorphisms in the glutamate transporter genes SLC1A1, SLC1A3, and SLC1A6 with schizophrenia. Am. J Med. Genet. B Neuropsychiatr. Genet.
144B, 271-278.
Dengjel J, Nastke MD, Gouttefangeas C, Gitsioudis G, Schoor O, Altenberend F, Muller M,
Kramer B, Missiou A, Sauter M, Hennenlotter J, Wernet D, Stenzl A, Rammensee HG, Klingel K, Stevanovic S (2006). Unexpected Abundance of HLA Class II Presented Peptides in Primary Renal Cell Carcinomas. Clin Cancer Res.12, 4163-4170.
Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004). Processing of primary microRNAs by the Microprocessor complex. Nature 432, 231-235.
Donati D, Di BC, Lucarelli E, Dozza B, Frisoni T, Aldini NN, Giardino R (2008). OP-1 application in bone allograft integration: preliminary results in sheep experimental surgery. Injury 39 Suppl 2, S65-S72.
Dondeti VR, Wubbenhorst B, Lal P, Gordan JD, D'Andrea K, Attiyeh EF, Simon MC, Nathanson KL (2012). Integrative genomic analyses of sporadic clear cell renal cell carcinoma define disease subtypes and potential new therapeutic targets. Cancer Res.72, 112-121.
Dong Y, Sui L, Watanabe Y, Sugimoto K, Tokuda M (2002). Clinical relevance of cyclin B1 overexpression in laryngeal squamous cell carcinoma. Cancer Lett.177, 13-19.
Dong Z, Xu X, Du L, Yang Y, Cheng H, Zhang X, LI Z, Wang L, Li J, Liu H, Qu X, Wang C (2013). Leptin-mediated regulation of MT1-MMP localization is KIF1B dependent and enhances gastric cancer cell invasion. Carcinogenesis 34, 974-983.
Donson AM, Erwin NS, Kleinschmidt-DeMasters BK, Madden JR, Addo-Yobo SO, Foreman NK (2007). Unique molecular characteristics of radiation-induced glioblastoma. J Neuropathol. Exp. Neurol. 66, 740-749.
Dowler S, Currie RA, Campbell DG, Deak M, Kular G, Downes CP, Alessi DR (2000). Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositidebinding specificities. Biochem. J 351, 19-31.
Dubois T, Paleotti O, Mironov AA, Fraisier V, Stradal TE, De Matteis MA, Franco M, Chavrier P (2005). Golgi-localized GAP for Cdc42 functions downstream of ARF1 to control Arp2/3 complex and F-actin dynamics. Nat Cell Biol.7, 353-364.
Ebermann I, Wiesen MH, Zrenner E, Lopez I, Pigeon R, Kohl S, Lowenheim H, Koenekoop RK, Bolz HJ (2009). GPR98 mutations cause Usher syndrome type 2 in males. J Med. Genet.46, 277280.
Eckes B, Dogic D, Colucci-Guyon E, Wang N, Maniotis A, Ingber D, Merckling A, Langa F, Aumailley M, Delouvee A, Koteliansky V, Babinet C, Krieg T (1998). Impaired mechanical stability, migration and contractile capacity in vimentin-deficient fibroblasts. J Cell Sci.111 ( Pt 13), 1897-1907.
Eckes B, Zigrino P, Kessler D, Holtkotter O, Shephard P, Mauch C, Krieg T (2000). Fibroblastmatrix interactions in wound healing and fibrosis. Matrix Biol.19, 325-332. Edelman AM, Kim WY, Higgins D, Goldstein EG, Oberdoerster M, Sigurdson W (2005). Doublecortin kinase-2, a novel doublecortin-related protein kinase associated with terminal segments of axons and dendrites. J Biol Chem. 280, 8531-8543.
Edwards MC, Liegeois N, Horecka J, Depinho RA, Sprague GF, Jr., Tyers M, Elledge SJ (1997). Human CPR (cell cycle progression restoration) genes impart a Far- phenotype on yeast cells. Genetics 147, 1063-1076.
Egland KA, Liu XF, Squires S, Nagata S, Man YG, Bera TK, Onda M, Vincent JJ, Strausberg RL, Lee B, Pastan I (2006). High expression of a cytokeratin-associated protein in many cancers. Proc Natl. Acad. Sci. U. S. A 103, 5929-5934.
Ellinger J, El KN, Heukamp LC, Matthews S, Cubukluoz F, Kahl P, Perabo FG, Muller SC, Von RA, Bastian PJ (2008). Hypermethylation of cell-free serum DNA indicates worse outcome in patients with bladder cancer. J Urol. 179, 346-352.
Engel M, Maurel P, Margolis RU, Margolis RK (1996). Chondroitin sulfate proteoglycans in the developing central nervous system. I. cellular sites of synthesis of neurocan and phosphacan. J Comp Neurol.366, 34-43.
Erbel-Sieler C, Dudley C, Zhou Y, Wu X, Estill SJ, Han T, Diaz-Arrastia R, Brunskill EW, Potter SS, McKnight SL (2004). Behavioral and regulatory abnormalities in mice deficient in the NPAS1 and NPAS3 transcription factors. Proc. Natl. Acad. Sci. U. S. A 101, 13648-13653.
Escudero-Esparza A, Jiang WG, Martin TA (2012). Claudin-5 is involved in breast cancer cell motility through the N-WASP and ROCK signalling pathways. J Exp. Clin Cancer Res. 31, 43.
Etcheverry A, Aubry M, de TM, Vauleon E, Boniface R, Guenot F, Saikali S, Hamlat A, Riffaud L, Menei P, Quillien V, Mosser J (2010). DNA methylation in glioblastoma: impact on gene expression and clinical outcome. BMC. Genomics 11, 701.
Falk K, Rotzschke O, Stevanovic S, Jung G, Rammensee HG (1991). Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 351, 290-296.
Ferguson BW, Datta S (2011). Role of heparan sulfate 2-o-sulfotransferase in prostate cancer cell proliferation, invasion, and growth factor signaling. Prostate Cancer 2011, 893208.
Feyeux M, Bourgois-Rocha F, Redfern A, Giles P, Lefort N, Aubert S, Bonnefond C, Bugi A, Ruiz M, Deglon N, Jones L, Peschanski M, Allen ND, Perrier AL (2012). Early transcriptional changes linked to naturally occurring Huntington's disease mutations in neural derivatives of human embryonic stem cells. Hum. Mol. Genet.21, 3883-3895. Findeis-Hosey JJ, Xu H (2012). Insulin-like growth factor II-messenger RNA-binding protein-3 and lung cancer. Biotech. Histochem. 87, 24-29.
Findeis-Hosey JJ, Yang Q, Spaulding BO, Wang HL, Xu H (2010). IMP3 expression is correlated with histologic grade of lung adenocarcinoma. Hum. Pathol.41, 477-484. Fishman P, Bar-Yehuda S, Madi L, Cohn I (2002). A3 adenosine receptor as a target for cancer therapy. Anticancer Drugs 13, 437-443.
Fjorback AW, Muller HK, Wiborg O (2009). Membrane glycoprotein M6B interacts with the human serotonin transporter. J Mol. Neurosci.37, 191-200.
Flammiger A, Besch R, Cook AL, Maier T, Sturm RA, Berking C (2009). SOX9 and SOX10 but not BRN2 are required for nestin expression in human melanoma cells. J Invest Dermatol. 129, 945-953.
Flinterman MB, Mymryk JS, Klanrit P, Yousef AF, Lowe SW, Caldas C, Gaken J, Farzaneh F, Tavassoli M (2007). p400 function is required for the adenovirus E1A-mediated suppression of EGFR and tumour cell killing. Oncogene 26, 6863-6874.
Fode C, Ma Q, Casarosa S, Ang SL, Anderson DJ, Guillemot F (2000). A role for neural determination genes in specifying the dorsoventral identity of telencephalic neurons. Genes Dev. 14, 67-80.
Fong L, Hou Y, Rivas A, Benike C, Yuen A, Fisher GA, Davis MM, Engleman EG (2001). Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc. Natl. Acad. Sci. U. S. A 98, 8809-8814.
Frank M, Kemler R (2002). Protocadherins. Curr. Opin. Cell Biol.14, 557-562.
Fu J, Koul D, Yao J, Wang S, Yuan Y, Colman H, Sulman EP, Lang FF, Yung WK (2013). Novel HSP90 inhibitor NVP-HSP990 targets cell-cycle regulators to ablate Olig2-positive glioma tumor-initiating cells. Cancer Res.73, 3062-3074.
Fukasawa KM, Fukasawa K, Harada M (2000). Assignment of the dipeptidyl peptidase III gene (DPP3) to human chromosome 11 band q12-->q13.1 by in situ hybridization. Cytogenet. Cell Genet.88, 99-100.
Fukunaga-Kalabis M, Martinez G, Nguyen TK, Kim D, Santiago-Walker A, Roesch A, Herlyn M (2010). Tenascin-C promotes melanoma progression by maintaining the ABCB5-positive side population. Oncogene 29, 6115-6124.
Furic L, Rong L, Larsson O, Koumakpayi IH, Yoshida K, Brueschke A, Petroulakis E, Robichaud N, Pollak M, Gaboury LA, Pandolfi PP, Saad F, Sonenberg N (2010). eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression. Proc. Natl. Acad. Sci. U. S. A 107, 14134-14139.
Futerman AH, Riezman H (2005). The ins and outs of sphingolipid synthesis. Trends Cell Biol. 15, 312-318.
Galan SR, Kann PH (2013). Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma. Clin Endocrinol. (Oxf) 78, 165-175.
Gallucci M, Merola R, Farsetti A, Orlandi G, Sentinelli S, De CP, Leonardo C, Carlini P, Guadagni F, Sperduti I, Cianciulli AM (2006). Cytogenetic profiles as additional markers to pathological features in clinically localized prostate carcinoma. Cancer Lett. 237, 76-82.
Garagnani P, Bacalini MG, Pirazzini C, Gori D, Giuliani C, Mari D, Di Blasio AM, Gentilini D, Vitale G, Collino S, Rezzi S, Castellani G, Capri M, Salvioli S, Franceschi C (2012). Methylation of ELOVL2 gene as a new epigenetic marker of age. Aging Cell 11, 1132-1134.
Garrison KR, Shemilt I, Donell S, Ryder JJ, Mugford M, Harvey I, Song F, Alt V (2010). Bone morphogenetic protein (BMP) for fracture healing in adults. Cochrane. Database. Syst. Rev. CD006950.
Gary SC, Kelly GM, Hockfield S (1998). BEHAB/brevican: a brain-specific lectican implicated in gliomas and glial cell motility. Curr. Opin. Neurobiol.8, 576-581.
Gary SC, Zerillo CA, Chiang VL, Gaw JU, Gray G, Hockfield S (2000). cDNA cloning, chromosomal localization, and expression analysis of human BEHAB/brevican, a brain specific proteoglycan regulated during cortical development and in glioma. Gene 256, 139-147.
Gasnereau I, Herr P, Chia PZ, Basler K, Gleeson PA (2011). Identification of an endocytosis motif in an intracellular loop of Wntless protein, essential for its recycling and the control of Wnt protein signaling. J Biol. Chem. 286, 43324-43333.
Gattinoni L, Powell DJ, Jr., Rosenberg SA, Restifo NP (2006). Adoptive immunotherapy for cancer: building on success. Nat. Rev. Immunol.6, 383-393.
Geesink RG, Hoefnagels NH, Bulstra SK (1999). Osteogenic activity of OP-1 bone morphogenetic protein (BMP-7) in a human fibular defect. J Bone Joint Surg. Br.81, 710-718.
Gerhard DS et al (2004). The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res.14, 2121-2127.
Gessi S, Cattabriga E, Avitabile A, Gafa' R, Lanza G, Cavazzini L, Bianchi N, Gambari R, Feo C, Liboni A, Gullini S, Leung E, Mac-Lennan S, Borea PA (2004). Elevated expression of A3 adenosine receptors in human colorectal cancer is reflected in peripheral blood cells. Clin Cancer Res.10, 5895-5901.
Gessi S, Merighi S, Varani K, Leung E, Mac LS, Borea PA (2008). The A3 adenosine receptor: an enigmatic player in cell biology. Pharmacol. Ther.117, 123-140.
Ghosh S, Albitar L, LeBaron R, Welch WR, Samimi G, Birrer MJ, Berkowitz RS, Mok SC (2010). Up-regulation of stromal versican expression in advanced stage serous ovarian cancer. Gynecol. Oncol 119, 114-120.
Gilles C, Polette M, Mestdagt M, Nawrocki-Raby B, Ruggeri P, Birembaut P, Foidart JM (2003). Transactivation of vimentin by beta-catenin in human breast cancer cells. Cancer Res. 63, 26582664.
Gilles C, Polette M, Piette J, Delvigne AC, Thompson EW, Foidart JM, Birembaut P (1996). Vimentin expression in cervical carcinomas: association with invasive and migratory potential. J Pathol.180, 175-180.
Giri A, Bajpai S, Trenton N, Jayatilaka H, Longmore GD, Wirtz D (2013). The Arp2/3 complex mediates multigeneration dendritic protrusions for efficient 3-dimensional cancer cell migration. FASEB J.
Girotti MR, Pedersen M, Sanchez-Laorden B, Viros A, Turajlic S, Niculescu-Duvaz D, Zambon A, Sinclair J, Hayes A, Gore M, Lorigan P, Springer C, Larkin J, Jorgensen C, Marais R (2013). Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer Discov.3, 158-167.
Gnjatic S, Atanackovic D, Jager E, Matsuo M, Selvakumar A, Altorki NK, Maki RG, Dupont B, Ritter G, Chen YT, Knuth A, Old LJ (2003). Survey of naturally occurring CD4+ T cell responses against NY-ESO-1 in cancer patients: correlation with antibody responses. Proc Natl. Acad. Sci. U. S. A 100, 8862-8867.
Godbout R, Bisgrove DA, Shkolny D, Day RS, III (1998). Correlation of B-FABP and GFAP expression in malignant glioma. Oncogene 16, 1955-1962.
Gong D, Ferrell JE, Jr. (2010). The roles of cyclin A2, B1, and B2 in early and late mitotic events. Mol. Biol. Cell 21, 3149-3161.
Goodwin AC, Jadallah S, Toubaji A, Lecksell K, Hicks JL, Kowalski J, Bova GS, De Marzo AM, Netto GJ, Casero RA, Jr. (2008). Increased spermine oxidase expression in human prostate cancer and prostatic intraepithelial neoplasia tissues. Prostate 68, 766-772.
Gorivodsky M, Mukhopadhyay M, Wilsch-Braeuninger M, Phillips M, Teufel A, Kim C, Malik N, Huttner W, Westphal H (2009). Intraflagellar transport protein 172 is essential for primary cilia formation and plays a vital role in patterning the mammalian brain. Dev. Biol. 325, 24-32.
Gorka B, Skubis-Zegadlo J, Mikula M, Bardadin K, Paliczka E, Czarnocka B (2007). NrCAM, a neuronal system cell-adhesion molecule, is induced in papillary thyroid carcinomas. Br. J Cancer 97, 531-538.
Gorlov IP, Meyer P, Liloglou T, Myles J, Boettger MB, Cassidy A, Girard L, Minna JD, Fischer R, Duffy S, Spitz MR, Haeussinger K, Kammerer S, Cantor C, Dierkesmann R, Field JK, Amos CI (2007). Seizure 6-like (SEZ6L) gene and risk for lung cancer. Cancer Res. 67, 8406-8411.
Gorokhova S, Bibert S, Geering K, Heintz N (2007). A novel family of transmembrane proteins interacting with beta subunits of the Na,K-ATPase. Hum. Mol. Genet.16, 2394-2410.
Goto Y, Matsuzaki Y, Kurihara S, Shimizu A, Okada T, Yamamoto K, Murata H, Takata M, Aburatani H, Hoon DS, Saida T, Kawakami Y (2006). A new melanoma antigen fatty acidbinding protein 7, involved in proliferation and invasion, is a potential target for immunotherapy and molecular target therapy. Cancer Res.66, 4443-4449.
Graf F, Mosch B, Koehler L, Bergmann R, Wuest F, Pietzsch J (2010). Cyclin-dependent kinase 4/6 (cdk4/6) inhibitors: perspectives in cancer therapy and imaging. Mini. Rev. Med. Chem. 10, 527-539.
Grimwood J et al (2004). The DNA sequence and biology of human chromosome 19. Nature 428, 529-535.
Grumet M, Mauro V, Burgoon MP, Edelman GM, Cunningham BA (1991). Structure of a new nervous system glycoprotein, Nr-CAM, and its relationship to subgroups of neural cell adhesion molecules. J Cell Biol.113, 1399-1412.
Grumet M, Milev P, Sakurai T, Karthikeyan L, Bourdon M, Margolis RK, Margolis RU (1994). Interactions with tenascin and differential effects on cell adhesion of neurocan and phosphacan, two major chondroitin sulfate proteoglycans of nervous tissue. J Biol. Chem.
269, 12142-12146.
Grunda JM, Fiveash J, Palmer CA, Cantor A, Fathallah-Shaykh HM, Nabors LB, Johnson MR (2010). Rationally designed pharmacogenomic treatment using concurrent capecitabine and radiotherapy for glioblastoma; gene expression profiles associated with outcome. Clin Cancer Res.16, 2890-2898.
Grunda JM, Nabors LB, Palmer CA, Chhieng DC, Steg A, Mikkelsen T, Diasio RB, Zhang K, Allison D, Grizzle WE, Wang W, Gillespie GY, Johnson MR (2006). Increased expression of thymidylate synthetase (TS), ubiquitin specific protease 10 (USP10) and survivin is associated with poor survival in glioblastoma multiforme (GBM). J Neurooncol. 80, 261-274.
Grunder S, Geisler HS, Rainier S, Fink JK (2001). Acid-sensing ion channel (ASIC) 4 gene: physical mapping, genomic organisation, and evaluation as a candidate for paroxysmal dystonia. Eur. J Hum. Genet.9, 672-676.
Grunder S, Geissler HS, Bassler EL, Ruppersberg JP (2000). A new member of acidsensing ion channels from pituitary gland. Neuroreport 11, 1607-1611.
Gu L, Shigemasa K, Ohama K (2004). Increased expression of IGF II mRNA-binding protein 1 mRNA is associated with an advanced clinical stage and poor prognosis in patients with ovarian cancer. Int. J Oncol 24, 671-678.
Guerrero-Preston R, et al (2011). NID2 and HOXA9 promoter hypermethylation as biomarkers for prevention and early detection in oral cavity squamous cell carcinoma tissues and saliva. Cancer Prev. Res. (Phila) 4, 1061-1072.
Guillemot F, Lo LC, Johnson JE, Auerbach A, Anderson DJ, Joyner AL (1993). Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons. Cell 75, 463-476.
Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J (2000). Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 123 ( Pt 7), 1481-1494.
Gunther HS, Schmidt NO, Phillips HS, Kemming D, Kharbanda S, Soriano R, Modrusan Z, Meissner H, Westphal M, Lamszus K (2008). Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria. Oncogene 27, 28972909.
Gustmann C, Altmannsberger M, Osborn M, Griesser H, Feller AC (1991). Cytokeratin expression and vimentin content in large cell anaplastic lymphomas and other non-Hodgkin's lymphomas. Am. J Pathol.138, 1413-1422.
Guvenc H, Pavlyukov MS, Joshi K, Kurt H, Banasavadi-Siddegowda YK, Mao P, Hong C,
Yamada R, Kwon CH, Bhasin D, Chettiar S, Kitange G, Park IH, Sarkaria JN, Li C, Shakhparonov MI, Nakano I (2013). Impairment of Glioma Stem Cell Survival and Growth by a Novel Inhibitor for Survivin-Ran Protein Complex. Clin Cancer Res.
Hagemann C, Anacker J, Gerngras S, Kuhnel S, Said HM, Patel R, Kammerer U, Vordermark D,
Roosen K, Vince GH (2008). Expression analysis of the autosomal recessive primary microcephaly genes MCPH1 (microcephalin) and MCPH5 (ASPM, abnormal spindlelike, microcephaly associated) in human malignant gliomas. Oncol Rep.20, 301-308. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, . (1995). The molecular basis of Turcot's syndrome. N. Engl. J Med.
332, 839-847.
Han HJ, Tokino T, Nakamura Y (1998). CSR, a scavenger receptor-like protein with a protective role against cellular damage causedby UV irradiation and oxidative stress. Hum. Mol. Genet.7, 1039-1046.
Han J, Lee Y, Yeom KH, Nam JW, Heo I, Rhee JK, Sohn SY, Cho Y, Zhang BT, Kim VN (2006). Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell 125, 887-901.
Han Y, Liu Y, Gui Y, Cai Z (2013). Inducing cell proliferation inhibition and apoptosis via silencing Dicer, Drosha, and Exportin 5 in urothelial carcinoma of the bladder. J Surg. Oncol 107, 201-205.
Harada H, Omura K, Nakajima Y, Hasegawa S, Mogi S (2006). Cyclin B1 is useful to predict occult cervical lymph node metastases in tongue carcinoma. J Exp. Clin Cancer Res. 25, 351-356.
Harada T, Chelala C, Bhakta V, Chaplin T, Caulee K, Baril P, Young BD, Lemoine NR (2008). Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays. Oncogene 27, 1951-1960.
Harris ML, Baxter LL, Loftus SK, Pavan WJ (2010). Sox proteins in melanocyte development and melanoma. Pigment Cell Melanoma Res. 23, 496-513.
Harrison Pitner MK, Saavedra HI (2013). Cdk4 and nek2 signal binucleation and centrosome amplification in a her2+ breast cancer model. PLoS. ONE.8, e65971.
Hartomo TB, Kozaki A, Hasegawa D, Van Huyen PT, Yamamoto N, Saitoh A, Ishida T, Kawasaki K, Kosaka Y, Ohashi H, Yamamoto T, Morikawa S, Hirase S, Kubokawa I, Mori T, Yanai T, Hayakawa A, Takeshima Y, Iijima K, Matsuo M, Nishio H, Nishimura N (2013). Minimal residual disease monitoring in neuroblastoma patients based on the expression of a set of real-time RT-PCR markers in tumor-initiating cells. Oncol Rep.29, 1629-1636.
Harville HM, Held S, Diaz-Font A, Davis EE, Diplas BH, Lewis RA, Borochowitz ZU, Zhou W, Chaki M, MacDonald J, Kayserili H, Beales PL, Katsanis N, Otto E, Hildebrandt F (2010). Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping. J Med. Genet.47, 262-267.
Hawkins GA, Mychaleckyj JC, Zheng SL, Faith DA, Kelly B, Isaacs SD, Wiley KE, Chang BL, Ewing CM, Bujnovszky P, Bleecker ER, Walsh PC, Meyers DA, Isaacs WB, Xu J (2002). Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk. Cancer Genet. Cytogenet.137, 1-7.
Hay N (2010). Mnk earmarks eIF4E for cancer therapy. Proc. Natl. Acad. Sci. U. S. A 107, 13975-13976.
Hayashi YK, Chou FL, Engvall E, Ogawa M, Matsuda C, Hirabayashi S, Yokochi K, Ziober BL,
Kramer RH, Kaufman SJ, Ozawa E, Goto Y, Nonaka I, Tsukahara T, Wang JZ, Hoffman EP, Arahata K (1998). Mutations in the integrin alpha7 gene cause congenital myopathy. Nat Genet.19, 94-97.
He C, Qu X, Wan J, Rong R, Huang L, Cai C, Zhou K, Gu Y, Qian SY, Kang JX (2012). Inhibiting delta-6 desaturase activity suppresses tumor growth in mice. PLoS. ONE. 7, e47567.
He J, Liu Y, Xie X, Zhu T, Soules M, Dimeco F, Vescovi AL, Fan X, Lubman DM (2010). Identification of cell surface glycoprotein markers for glioblastoma-derived stem-like cells using a lectin microarray and LC-MS/MS approach. J Proteome. Res 9, 2565-2572. Hendrix MJ, Seftor EA, Chu YW, Seftor RE, Nagle RB, McDaniel KM, Leong SP, Yohem KH, Leibovitz AM, Meyskens FL, Jr., . (1992). Coexpression of vimentin and keratins by human melanoma tumor cells: correlation with invasive and metastatic potential. J Natl. Cancer Inst. 84, 165-174.
Heni M, Hennenlotter J, Scharpf M, Lutz SZ, Schwentner C, Todenhofer T, Schilling D, Kuhs U, Gerber V, Machicao F, Staiger H, Haring HU, Stenzl A (2012). Insulin receptor isoforms A and B as well as insulin receptor substrates-1 and -2 are differentially expressed in prostate cancer. PLoS. ONE.7, e50953.
Higgins J, Midgley C, Bergh AM, Bell SM, Askham JM, Roberts E, Binns RK, Sharif SM, Bennett C, Glover DM, Woods CG, Morrison EE, Bond J (2010). Human ASPM participates in spindle organisation, spindle orientation and cytokinesis. BMC. Cell Biol.
11, 85.
Hildebrandt F, Benzing T, Katsanis N (2011). Ciliopathies. N. Engl. J Med. 364, 1533-1543.
Hirama T, Miller CW, Koeffler HP (1999). Translocon-associated protein alpha transcripts are induced by granulocyte-macrophage colony-stimulating factor and exhibit complex alternative polyadenylation. FEBS Lett.455, 223-227.
Hirao K, Hata Y, Ide N, Takeuchi M, Irie M, Yao I, Deguchi M, Toyoda A, Sudhof TC, Takai Y (1998). A novel multiple PDZ domain-containing molecule interacting with N-methyl-Daspartate receptors and neuronal cell adhesion proteins. J Biol. Chem. 273, 21105-21110.
Hirayama T, Yagi T (2006). The role and expression of the protocadherin-alpha clusters in the CNS. Curr. Opin. Neurobiol.16, 336-342.
Hirokawa N, Noda Y (2008). Intracellular transport and kinesin superfamily proteins, KIFs: structure, function, and dynamics. Physiol Rev. 88, 1089-1118.
Hjelmqvist L, Tuson M, Marfany G, Herrero E, Balcells S, Gonzalez-Duarte R (2002). ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biol.3, RESEARCH0027.
Hlavac V, Brynychova V, Vaclavikova R, Ehrlichova M, Vrana D, Pecha V, Kozevnikovova R, Trnkova M, Gatek J, Kopperova D, Gut I, Soucek P (2013). The expression profile of ATPbinding cassette transporter genes in breast carcinoma. Pharmacogenomics. 14, 515-529.
Hlavata I, Mohelnikova-Duchonova B, Vaclavikova R, Liska V, Pitule P, Novak P, Bruha J, Vycital O, Holubec L, Treska V, Vodicka P, Soucek P (2012). The role of ABC transporters in progression and clinical outcome of colorectal cancer. Mutagenesis 27, 187-196.
Holden S, Raymond FL (2003). The human gene CXorf17 encodes a member of a novel family of putative transmembrane proteins: cDNA cloning and characterization of CXorf17 and its mouse ortholog orf34. Gene 318, 149-161.
Holtkamp N, Ziegenhagen N, Malzer E, Hartmann C, Giese A, von DA (2007). Characterization of the amplicon on chromosomal segment 4q12 in glioblastoma multiforme. Neuro Oncol 9, 291297.
Hood FE, Royle SJ (2011). Pulling it together: The mitotic function of TACC3. Bioarchitecture. 1, 105-109.
Hookham MB, O'Donovan HC, Church RH, Mercier-Zuber A, Luzi L, Curran SP, Carew RM, Droguett A, Mezzano S, Schubert M, White MF, Crean JK, Brazil DP (2013). Insulin receptor substrate-2 is expressed in kidney epithelium and up-regulated in diabetic nephropathy. FEBS J 280, 3232-3243.
Horvath S, Zhang B, Carlson M, Lu KV, Zhu S, Felciano RM, Laurance MF, Zhao W, Qi S, Chen
Z, Lee Y, Scheck AC, Liau LM, Wu H, Geschwind DH, Febbo PG, Kornblum HI, Cloughesy TF, Nelson SF, Mischel PS (2006). Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target. Proc Natl. Acad. Sci. U. S. A 103, 17402-17407.
Hu C, Xiong J, Zhang L, Huang B, Zhang Q, Li Q, Yang M, Wu Y, Wu Q, Shen Q, Gao Q, Zhang K, Sun Z, Liu J, Jin Y, Tan J (2004). PEG10 activation by co-stimulation of CXCR5 and CCR7 essentially contributes to resistance to apoptosis in CD19+CD34+ B cells from patients with B cell lineage acute and chronic lymphocytic leukemia. Cell Mol. Immunol. 1, 280-294.
Huang CC, Tu SH, Lien HH, Jeng JY, Huang CS, Huang CJ, Lai LC, Chuang EY (2013a). Concurrent gene signatures for han chinese breast cancers. PLoS. ONE.8, e76421.
Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA (2013b). Highly recurrent TERT promoter mutations in human melanoma. Science 339, 957-959.
Huang XP, Rong TH, Wu QL, Fu JH, Yang H, Zhao JM, Fang Y (2005). MCM4 expression in esophageal cancer from southern China and its clinical significance. J. Cancer Res. Clin. Oncol.131, 677-682.
Huxley C, Fried M (1990). The mouse rpL7a gene is typical of other ribosomal protein genes in it's 5' region but differs in being located in a tight cluster of CpG-rich islands. Nucleic Acids Res.18, 5353-5357.
Hwang ML, Lukens JR, Bullock TN (2007). Cognate memory CD4+ T cells generated with dendritic cell priming influence the expansion, trafficking, and differentiation of secondary CD8+ T cells and enhance tumor control. J Immunol. 179, 5829-5838.
Hwang YS, Park KK, Cha IH, Kim J, Chung WY (2012). Role of insulin-like growth factor-II mRNA-binding protein-3 in invadopodia formation and the growth of oral squamous cell carcinoma in athymic nude mice. Head Neck 34, 1329-1339.
Ideguchi H, Ueda A, Tanaka M, Yang J, Tsuji T, Ohno S, Hagiwara E, Aoki A, Ishigatsubo Y (2002). Structural and functional characterization of the USP11 deubiquitinating enzyme, which interacts with the RanGTP-associated protein RanBPM. Biochem. J 367, 87-95.
Ikenberg K et al (2010). Insulin-like growth factor II mRNA binding protein 3 (IMP3) is overexpressed in prostate cancer and correlates with higher Gleason scores. BMC. Cancer 10, 341.
Ikuerowo SO, Kuczyk MA, Mengel M, van der Heyde E, Shittu OB, Vaske B, Jonas U, Machtens S, Serth J (2006). Alteration of subcellular and cellular expression patterns of cyclin B1 in renal cell carcinoma is significantly related to clinical progression and survival of patients. Int. J Cancer 119, 867-874.
Ingley E, Hemmings BA (1994). Pleckstrin homology (PH) domains in signal transduction. J Cell Biochem.56, 436-443.
Ishida N, Kawakita M (2004). Molecular physiology and pathology of the nucleotide sugar transporter family (SLC35). Pflugers Arch. 447, 768-775.
Ishii H, Baffa R, Numata SI, Murakumo Y, Rattan S, Inoue H, Mori M, Fidanza V, Alder H, Croce CM (1999). The FEZ1 gene at chromosome 8p22 encodes a leucine-zipper protein, and its expression is altered in multiple human tumors. Proc. Natl. Acad. Sci. U. S. A 96, 3928-3933.
Ishii H, Vecchione A, Murakumo Y, Baldassarre G, Numata S, Trapasso F, Alder H, Baffa R, Croce CM (2001). FEZ1/LZTS1 gene at 8p22 suppresses cancer cell growth and regulates mitosis. Proc. Natl. Acad. Sci. U. S. A 98, 10374-10379.
Ishiuchi S (2009). [New roles of glutamate receptors in glias and gliomas]. Brain Nerve 61, 753764.
Ishiuchi S, Tsuzuki K, Yoshida Y, Yamada N, Hagimura N, Okado H, Miwa A, Kurihara H, Nakazato Y, Tamura M, Sasaki T, Ozawa S (2002). Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat. Med 8, 971-978.
Ishwad CS, Ferrell RE, Davare J, Meloni AM, Sandberg AA, Surti U (1995). Molecular and cytogenetic analysis of chromosome 7 in uterine leiomyomas. Genes Chromosomes. Cancer 14, 51-55.
Ito K, Takahashi A, Morita M, Suzuki T, Yamamoto T (2011). The role of the CNOT1 subunit of the CCR4-NOT complex in mRNA deadenylation and cell viability. Protein Cell 2, 755-763.
Jackson M, Song W, Liu MY, Jin L, Dykes-Hoberg M, Lin CI, Bowers WJ, Federoff HJ, Sternweis PC, Rothstein JD (2001). Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins. Nature 410, 89-93.
Jacobson SG, Cideciyan AV, Aleman TS, Pianta MJ, Sumaroka A, Schwartz SB, Smilko EE, Milam AH, Sheffield VC, Stone EM (2003). Crumbs homolog 1 (CRB1) mutations result in a thick human retina with abnormal lamination. Hum. Mol. Genet.12, 1073-1078. Jahr H, van DM, van Osch GJ, Weinans H, van Leeuwen JP (2005). Identification of acidsensing ion channels in bone. Biochem. Biophys. Res. Commun. 337, 349-354.
Jajoo S, Mukherjea D, Watabe K, Ramkumar V (2009). Adenosine A(3) receptor suppresses prostate cancer metastasis by inhibiting NADPH oxidase activity. Neoplasia.
11, 1132-1145.
Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T (2003). Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet.34, 27-29.
Jeng YM, Wang TH, Lu SH, Yuan RH, Hsu HC (2009). Prognostic significance of insulin-like growth factor II mRNA-binding protein 3 expression in gastric adenocarcinoma. Br. J Surg 96, 66-73.
Jiang JC, Kirchman PA, Zagulski M, Hunt J, Jazwinski SM (1998). Homologs of the yeast longevity gene LAG1 in Caenorhabditis elegans and human. Genome Res. 8, 1259-1272. Jiang SX, Kameya T, Asamura H, Umezawa A, Sato Y, Shinada J, Kawakubo Y, Igarashi T, Nagai K, Okayasu I (2004). hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors. Mod. Pathol.
17, 222-229.
Jiang W, Ren L, Jin N (2007). HIV-1 DNA vaccine efficacy is enhanced by coadministration with plasmid encoding IFN-alpha. J Virol. Methods 146, 266-273. Jiang Z, Chu PG, Woda BA, Rock KL, Liu Q, Hsieh CC, Li C, Chen W, Duan HO, McDougal S, Wu CL (2006). Analysis of RNA-binding protein IMP3 to predict metastasis and prognosis of renal-cell carcinoma: a retrospective study. Lancet Oncol 7, 556-564. Jin F, Zhao L, Zhao HY, Guo SG, Feng J, Jiang XB, Zhang SL, Wei YJ, Fu R, Zhao JS (2008). Comparison between cells and cancer stem-like cells isolated from glioblastoma and astrocytoma on expression of anti-apoptotic and multidrug resistance-associated protein genes. Neuroscience 154, 541-550.
Jin J, Kim JM, Hur YS, Cho WP, Lee KY, Ahn SI, Hong KC, Park IS (2012). Clinical significance of clusterin expression in pancreatic adenocarcinoma. World J Surg. Oncol 10, 146.
Jin KM, Lu M, Liu FF, Gu J, Du XJ, Xing BC (2013). N-WASP is highly expressed in hepatocellular carcinoma and associated with poor prognosis. Surgery 153, 518-525. Jin L, Seys AR, Zhang S, Erickson-Johnson MR, Roth CW, Evers BR, Oliveira AM, Lloyd RV (2010). Diagnostic utility of IMP3 expression in thyroid neoplasms: a quantitative RT-PCR study. Diagn. Mol. Pathol.19, 63-69.
Jogl G, Tong L (2003). Crystal structure of carnitine acetyltransferase and implications for the catalytic mechanism and fatty acid transport. Cell 112, 113-122.
Johnson MD, O'Connell MJ, Silberstein H, Korones D (2013). Differential Expression of Somatostatin Receptors, P44/42 MAPK, and mTOR Activation in Medulloblastomas and Primitive Neuroectodermal Tumors. Appl. Immunohistochem. Mol. Morphol.
Jung CK, Jung JH, Park GS, Lee A, Kang CS, Lee KY (2006). Expression of transforming acidic coiled-coil containing protein 3 is a novel independent prognostic marker in nonsmall cell lung cancer. Pathol. Int 56, 503-509.
Jung G, Ledbetter JA, Muller-Eberhard HJ (1987). Induction of cytotoxicity in resting human T lymphocytes bound to tumor cells by antibody heteroconjugates. Proc Natl Acad Sci U S A 84, 4611-4615.
Jung HM, Choi SJ, Kim JK (2009). Expression profiles of SV40-immortalizationassociated genes upregulated in various human cancers. J Cell Biochem.106, 703-713. Kabbarah O, Nogueira C, Feng B, Nazarian RM, Bosenberg M, Wu M, Scott KL, Kwong LN, Xiao Y, Cordon-Cardo C, Granter SR, Ramaswamy S, Golub T, Duncan LM, Wagner SN, Brennan C, Chin L (2010). Integrative genome comparison of primary and metastatic melanomas. PLoS. ONE.5, e10770.
Kajiwara Y, Yamasaki F, Hama S, Yahara K, Yoshioka H, Sugiyama K, Arita K, Kurisu K (2003). Expression of survivin in astrocytic tumors: correlation with malignant grade and prognosis. Cancer 97, 1077-1083.
Kallenbach S, Khantane S, Carroll P, Gayet O, Alonso S, Henderson CE, Dudley K (2003). Changes in subcellular distribution of protocadherin gamma proteins accompany maturation of spinal neurons. J Neurosci. Res.72, 549-556.
Kamalakaran S, Varadan V, Giercksky Russnes HE, Levy D, Kendall J, Janevski A, Riggs M,
Banerjee N, Synnestvedt M, Schlichting E, Karesen R, Shama PK, Rotti H, Rao R, Rao L, Eric
Tang MH, Satyamoorthy K, Lucito R, Wigler M, Dimitrova N, Naume B, Borresen-Dale AL, Hicks JB (2011). DNA methylation patterns in luminal breast cancers differ from nonluminal subtypes and can identify relapse risk independent of other clinical variables. Mol. Oncol 5, 7792.
Kamnasaran D, Muir WJ, Ferguson-Smith MA, Cox DW (2003). Disruption of the neuronal PAS3 gene in a family affected with schizophrenia. J Med. Genet. 40, 325-332.
Kang GH, Lee S, Cho NY, Gandamihardja T, Long TI, Weisenberger DJ, Campan M, Laird PW (2008). DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis. Lab Invest 88, 161-170.
Kang Y, Massague J (2004). Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 118, 277-279.
Kastan MB, Schlaffer E, Russo JE, Colvin OM, Civin CI, Hilton J (1990). Direct demonstration of elevated aldehyde dehydrogenase in human hematopoietic progenitor cells. Blood 75, 19471950.
Katoh Y, Katoh M (2005). Hedgehog signaling pathway and gastric cancer. Cancer Biol. Ther. 4, 1050-1054.
Kaur J, Demokan S, Tripathi SC, Macha MA, Begum S, Califano JA, Ralhan R (2010). Promoter hypermethylation in Indian primary oral squamous cell carcinoma. Int. J Cancer 127, 2367-2373.
Kawahara Y, Ito K, Sun H, Ito M, Kanazawa I, Kwak S (2004). GluR4c, an alternative splicing isoform of GluR4, is abundantly expressed in the adult human brain. Brain Res. Mol. Brain Res. 127, 150-155.
Kee Y, Yoo JS, Hazuka CD, Peterson KE, Hsu SC, Scheller RH (1997). Subunit structure of the mammalian exocyst complex. Proc. Natl. Acad. Sci. U. S. A 94, 14438-14443. Kennedy RC, Shearer MH, Watts AM, Bright RK (2003). CD4+ T lymphocytes play a critical role in antibody production and tumor immunity against simian virus 40 large tumor antigen. Cancer Res.63, 1040-1045.
Kenzelmann-Broz D, Tucker RP, Leachman NT, Chiquet-Ehrismann R (2010). The expression of teneurin-4 in the avian embryo: potential roles in patterning of the limb and nervous system. Int. J Dev. Biol.54, 1509-1516.
Kettunen E, Anttila S, Seppanen JK, Karjalainen A, Edgren H, Lindstrom I, Salovaara R, Nissen AM, Salo J, Mattson K, Hollmen J, Knuutila S, Wikman H (2004). Differentially expressed genes in nonsmall cell lung cancer: expression profiling of cancer-related genes in squamous cell lung cancer. Cancer Genet. Cytogenet. 149, 98-106.
Khalil BD, El-Sibai M (2012). Rho GTPases in primary brain tumor malignancy and invasion. J Neurooncol.108, 333-339.
Kikuno R, Nagase T, Ishikawa K, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (1999). Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res.6, 197-205.
Kim CH, Bak KH, Kim YS, Kim JM, Ko Y, Oh SJ, Kim KM, Hong EK (2000). Expression of tenascin-C in astrocytic tumors: its relevance to proliferation and angiogenesis. Surg Neurol. 54, 235-240.
Kim DH, Mohapatra G, Bollen A, Waldman FM, Feuerstein BG (1995). Chromosomal abnormalities in glioblastoma multiforme tumors and glioma cell lines detected by comparative genomic hybridization. Int. J Cancer 60, 812-819.
Kim EJ, Eom SJ, Hong JE, Lee JY, Choi MS, Park JH (2012a). Benzyl isothiocyanate inhibits basal and hepatocyte growth factor-stimulated migration of breast cancer cells. Mol. Cell Biochem. 359, 431-440.
Kim J, Reber HA, Hines OJ, Kazanjian KK, Tran A, Ye X, Amersi FF, Martinez SR, Dry SM, Bilchik AJ, Hoon DS (2006). The clinical significance of MAGEA3 expression in pancreatic cancer. Int. J Cancer 118, 2269-2275.
Kim KK, Park KS, Song SB, Kim KE (2010). Up regulation of GW112 Gene by NF kappaB promotes an antiapoptotic property in gastric cancer cells. Mol. Carcinog.49, 259-270.
Kim N, Yoo JC, Han JY, Hwang EM, Kim YS, Jeong EY, Sun CH, Yi GS, Roh GS, Kim HJ, Kang SS, Cho GJ, Park JY, Choi WS (2012b). Human nuclear clusterin mediates apoptosis by interacting with Bcl-XL through C-terminal coiled coil domain. J Cell Physiol 227, 1157-1167.
Kim TY, Bang YJ, Kim WS, Kang SH, Lee KU, Choe KJ, Kim NK (1997). Mutation of ras oncogene in gastric adenocarcinoma: association with histological phenotype. Anticancer Res 17, 1335-1339.
Kimchi ET, Posner MC, Park JO, Darga TE, Kocherginsky M, Karrison T, Hart J, Smith KD, Mezhir JJ, Weichselbaum RR, Khodarev NN (2005). Progression of Barrett's metaplasia to adenocarcinoma is associated with the suppression of the transcriptional programs of epidermal differentiation. Cancer Res.65, 3146-3154.
Kimura J, Kudoh T, Miki Y, Yoshida K (2011). Identification of dihydropyrimidinaserelated protein 4 as a novel target of the p53 tumor suppressor in the apoptotic response to DNA damage. Int. J Cancer 128, 1524-1531.
Kinsey M, Smith R, Lessnick SL (2006). NR0B1 is required for the oncogenic phenotype mediated by EWS/FLI in Ewing's sarcoma. Mol. Cancer Res.4, 851-859.
Klejnot M, Kozielski F (2012). Structural insights into human Kif7, a kinesin involved in Hedgehog signalling. Acta Crystallogr. D. Biol. Crystallogr.68, 154-159.
Klekner A, Varga I, Bognar L, Hutoczki G, Kenyeres A, Toth J, Hanzely Z, Scholtz B (2010). [Extracellular matrix of cerebral tumors with different invasiveness]. Ideggyogy. Sz 63, 38-43.
Knight HM, Pickard BS, Maclean A, Malloy MP, Soares DC, McRae AF, Condie A, White A,
Hawkins W, McGhee K, van BM, MacIntyre DJ, Starr JM, Deary IJ, Visscher PM, Porteous DJ, Cannon RE, St CD, Muir WJ, Blackwood DH (2009). A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression. Am J Hum. Genet.85, 833-846.
Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, Pai SK, Liu W, Fukuda K, Chambers C, Wilber A, Watabe K (2011). Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp. Med.208, 2641-2655.
Kobayashi H, Omiya R, Ruiz M, Huarte E, Sarobe P, Lasarte JJ, Herraiz M, Sangro B, Prieto J, Borras-Cuesta F, Celis E (2002). Identification of an antigenic epitope for helper T lymphocytes from carcinoembryonic antigen. Clin Cancer Res.8, 3219-3225.
Kobayashi K, Nishioka M, Kohno T, Nakamoto M, Maeshima A, Aoyagi K, Sasaki H, Takenoshita S, Sugimura H, Yokota J (2004). Identification of genes whose expression is upregulated in lung adenocarcinoma cells in comparison with type II alveolar cells and bronchiolar epithelial cells in vivo. Oncogene 23, 3089-3096.
Kohannim O, Hibar DP, Stein JL, Jahanshad N, Hua X, Rajagopalan P, Toga AW, Jack CR, Jr.,
Weiner MW, de Zubicaray GI, McMahon KL, Hansell NK, Martin NG, Wright MJ, Thompson PM (2012). Discovery and Replication of Gene Influences on Brain Structure Using LASSO Regression. Front Neurosci.6, 115.
Koide T, Banno M, Aleksic B, Yamashita S, Kikuchi T, Kohmura K, Adachi Y, Kawano N,
Kushima I, Nakamura Y, Okada T, Ikeda M, Ohi K, Yasuda Y, Hashimoto R, Inada T, Ujike H, Iidaka T, Suzuki M, Takeda M, Iwata N, Ozaki N (2012). Common variants in MAGI2 gene are associated with increased risk for cognitive impairment in schizophrenic patients. PLoS. ONE.7, e36836.
Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J, Traskelin AL, Perveen R, Kivitie-Kallio S, Norio R, Warburg M, Fryns JP, de la Chapelle A, Lehesjoki AE (2003). Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am. J Hum. Genet.72, 1359-1369.
Koon N, Schneider-Stock R, Sarlomo-Rikala M, Lasota J, Smolkin M, Petroni G, Zaika A, Boltze C, Meyer F, Andersson L, Knuutila S, Miettinen M, El-Rifai W (2004). Molecular targets for tumour progression in gastrointestinal stromal tumours. Gut 53, 235-240.
Kordes U, Cheng YC, Scotting PJ (2005). Sox group E gene expression distinguishes different types and maturational stages of glial cells in developing chick and mouse. Brain Res. Dev. Brain Res.157, 209-213.
Korn T, Magnus T, Jung S (2005). Autoantigen specific T cells inhibit glutamate uptake in astrocytes by decreasing expression of astrocytic glutamate transporter GLAST: a mechanism mediated by tumor necrosis factor-alpha. FASEB J 19, 1878-1880.
Kosari F, Parker AS, Kube DM, Lohse CM, Leibovich BC, Blute ML, Cheville JC, Vasmatzis G (2005). Clear cell renal cell carcinoma: gene expression analyses identify a potential signature for tumor aggressiveness. Clin Cancer Res.11, 5128-5139.
Kostenko S, Dumitriu G, Moens U (2012). Tumour promoting and suppressing roles of the atypical MAP kinase signalling pathway ERK3/4-MK5. J Mol. Signal. 7, 9.
Kovacs EM, Verma S, Ali RG, Ratheesh A, Hamilton NA, Akhmanova A, Yap AS (2011). NWASP regulates the epithelial junctional actin cytoskeleton through a non-canonical postnucleation pathway. Nat Cell Biol.13, 934-943.
Kraker J (2009). Treatment of anti-Ma2/Ta paraneoplastic syndrome. Curr. Treat. Options. Neurol. 11, 46-51.
Kramer RH, McDonald KA, Vu MP (1989). Human melanoma cells express a novel integrin receptor for laminin. J Biol. Chem.264, 15642-15649.
Kramer RH, Vu M, Cheng YF, Ramos DM (1991a). Integrin expression in malignant melanoma. Cancer Metastasis Rev.10, 49-59.
Kramer RH, Vu MP, Cheng YF, Ramos DM, Timpl R, Waleh N (1991b). Laminin-binding integrin alpha 7 beta 1: functional characterization and expression in normal and malignant melanocytes. Cell Regul.2, 805-817.
Krepela E, Dankova P, Moravcikova E, Krepelova A, Prochazka J, Cermak J, Schutzner J, Zatloukal P, Benkova K (2009). Increased expression of inhibitor of apoptosis proteins, survivin and XIAP, in non-small cell lung carcinoma. Int. J Oncol 35, 1449-1462.
Krieg AM (2006). Therapeutic potential of Toll-like receptor 9 activation. Nat. Rev. Drug Discov. 5, 471-484.
Kroes RA, Jastrow A, McLone MG, Yamamoto H, Colley P, Kersey DS, Yong VW, Mkrdichian E, Cerullo L, Leestma J, Moskal JR (2000). The identification of novel therapeutic targets for the treatment of malignant brain tumors. Cancer Lett.156, 191-198. Kunisada M, Yogianti F, Sakumi K, Ono R, Nakabeppu Y, Nishigori C (2011). Increased Expression of Versican in the Inflammatory Response to UVB- and Reactive Oxygen SpeciesInduced Skin Tumorigenesis. Am J Pathol.179, 3056-3065.
Kurimoto F, Gemma A, Hosoya Y, Seike M, Takenaka K, Uematsu K, Yoshimura A, Shibuya M, Kudoh S (2001). Unchanged frequency of loss of heterozygosity and size of the deleted region at 8p21-23 during metastasis of lung cancer. Int. J Mol. Med.8, 89-93. Kwak DH, Jin JW, Ryu JS, Ko K, Lee SD, Lee JW, Kim JS, Jung KY, Ko K, Ma JY, Hwang KA, Chang KT, Choo YK (2011). Regulatory roles of ganglioside GQ1b in neuronal cell differentiation of mouse embryonic stem cells. BMB. Rep.44, 799-804. Kwak JM, Min BW, Lee JH, Choi JS, Lee SI, Park SS, Kim J, Um JW, Kim SH, Moon HY (2007). The prognostic significance of E-cadherin and liver intestine-cadherin expression in colorectal cancer. Dis. Colon Rectum 50, 1873-1880.
Lamers F, van dP, I, Schild L, Ebus ME, Koster J, Hansen BR, Koch T, Versteeg R, Caron HN, Molenaar JJ (2011). Knockdown of survivin (BIRC5) causes apoptosis in neuroblastoma via mitotic catastrophe. Endocr. Relat Cancer 18, 657-668.
Lane J, Mansel RE, Jiang WG (2003). Expression of human delta-6-desaturase is associated with aggressiveness of human breast cancer. Int. J Mol. Med.12, 253-257. Langley RR, Fan D, Guo L, Zhang C, Lin Q, Brantley EC, McCarty JH, Fidler IJ (2009). Generation of an immortalized astrocyte cell line from H-2Kb-tsA58 mice to study the role of astrocytes in brain metastasis. Int. J Oncol 35, 665-672.
Laumonnier F, Bonnet-Brilhault F, Gomot M, Blanc R, David A, Moizard MP, Raynaud M,
Ronce N, Lemonnier E, Calvas P, Laudier B, Chelly J, Fryns JP, Ropers HH, Hamel BC, Andres C, Barthelemy C, Moraine C, Briault S (2004). X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum. Genet. 74, 552-557.
Lavedan C, Licamele L, Volpi S, Hamilton J, Heaton C, Mack K, Lannan R, Thompson A, Wolfgang CD, Polymeropoulos MH (2009). Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study. Mol. Psychiatry 14, 804-819.
Lawson-Yuen A, Saldivar JS, Sommer S, Picker J (2008). Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur. J Hum. Genet.16, 614-618. Lazarini M, Traina F, Machado-Neto JA, Barcellos KS, Moreira YB, Brandao MM, VerjovskiAlmeida S, Ridley AJ, Saad ST (2013). ARHGAP21 is a RhoGAP for RhoA and RhoC with a role in proliferation and migration of prostate adenocarcinoma cells. Biochim. Biophys. Acta 1832, 365-374.
Lee SY, Kim JW, Jeong MH, An JH, Jang SM, Song KH, Choi KH (2008a). Microtubuleassociated protein 1B light chain (MAP1B-LC1) negatively regulates the activity of tumor suppressor p53 in neuroblastoma cells. FEBS Lett.582, 2826-2832. Lee WR, Pan TL, Wang PW, Zhuo RZ, Huang CM, Fang JY (2008b). Erbium:YAG laser enhances transdermal peptide delivery and skin vaccination. J Control Release 128, 200-208.
Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S, Kim VN (2003). The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415-419.
Leja J, Essaghir A, Essand M, Wester K, Oberg K, Totterman TH, Lloyd R, Vasmatzis G, Demoulin JB, Giandomenico V (2009). Novel markers for enterochromaffin cells and gastrointestinal neuroendocrine carcinomas. Mod. Pathol.22, 261-272.
Leung E, Lim SP, Berg R, Yang Y, Ni J, Wang SX, Krissansen GW (1998). A novel extracellular domain variant of the human integrin alpha 7 subunit generated by alternative intron splicing. Biochem. Biophys. Res. Commun. 243, 317-325.
Lewis DA, Hashimoto T, Volk DW (2005). Cortical inhibitory neurons and schizophrenia. Nat Rev. Neurosci. 6, 312-324.
Li A, Walling J, Ahn S, Kotliarov Y, Su Q, Quezado M, Oberholtzer JC, Park J, Zenklusen JC, Fine HA (2009). Unsupervised analysis of transcriptomic profiles reveals six glioma subtypes. Cancer Res 69, 2091-2099.
Li C, Zota V, Woda BA, Rock KL, Fraire AE, Jiang Z, Lu D, Xu B, Dresser K, Lutman CV, Fischer AH (2007). Expression of a novel oncofetal mRNA-binding protein IMP3 in endometrial carcinomas: diagnostic significance and clinicopathologic correlations. Mod. Pathol. 20, 12631268.
Li H, Liu S, Zhu X, Yang S, Xiang J, Chen H (2010). Clusterin immunoexpression and its clinical significance in patients with non-small cell lung cancer. Lung 188, 423-431. Li HG, Han JJ, Huang ZQ, Wang L, Chen WL, Shen XM (2011a). IMP3 is a novel biomarker to predict metastasis and prognosis of tongue squamous cell carcinoma. J Craniofac. Surg. 22, 20222025.
Li J, Neumann I, Volkmer I, Staege MS (2011b). Down-regulation of achaete-scute complex homolog 1 (ASCL1) in neuroblastoma cells induces up-regulation of insulin-like growth factor 2 (IGF2). Mol. Biol. Rep.38, 1515-1521.
Li JQ, Kubo A, Wu F, Usuki H, Fujita J, Bandoh S, Masaki T, Saoo K, Takeuchi H, Kobayashi S, Imaida K, Maeta H, Ishida T, Kuriyama S (2003). Cyclin B1, unlike cyclin G1, increases significantly during colorectal carcinogenesis and during later metastasis to lymph nodes. Int. J Oncol 22, 1101-1110.
Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W (2002). Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416, 648-653. Li WQ, Hu N, Hyland PL, Gao Y, Wang ZM, Yu K, Su H, Wang CY, Wang LM, Chanock SJ, Burdett L, Ding T, Qiao YL, Fan JH, Wang Y, Xu Y, Shi JX, Gu F, Wheeler W, Xiong XQ, Giffen C, Tucker MA, Dawsey SM, Freedman ND, Abnet CC, Goldstein AM, Taylor PR (2013a). Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population. Carcinogenesis.
Li X, LI Z, Li N, Qi J, Fan K, Yin P, Zhao C, Liu Y, Yao W, Cai X, Wang L, Zha X (2013b). MAGI2 enhances the sensitivity of BEL-7404 human hepatocellular carcinoma cells to staurosporine-induced apoptosis by increasing PTEN stability. Int. J Mol. Med. Li Y, Fan S, Koo J, Yue P, Chen ZG, Owonikoko TK, Ramalingam SS, Khuri FR, Sun SY (2012a). Elevated expression of eukaryotic translation initiation factor 4E is associated with proliferation, invasion and acquired resistance to erlotinib in lung cancer. Cancer Biol. Ther.13, 272-280.
Li ZJ, Nieuwenhuis E, Nien W, Zhang X, Zhang J, Puviindran V, Wainwright BJ, Kim PC, Hui CC (2012b). Kif7 regulates Gli2 through Sufu-dependent and -independent functions during skin development and tumorigenesis. Development 139, 4152-4161. Liang Y, Diehn M, Watson N, Bollen AW, Aldape KD, Nicholas MK, Lamborn KR, Berger MS, Botstein D, Brown PO, Israel MA (2005). Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Proc. Natl. Acad. Sci. U. S. A 102, 58145819.
Liao B, Hu Y, Brewer G (2011). RNA-binding protein insulin-like growth factor mRNA-binding protein 3 (IMP-3) promotes cell survival via insulin-like growth factor II signaling after ionizing radiation. J Biol. Chem.286, 31145-31152.
Liao B, Hu Y, Herrick DJ, Brewer G (2005). The RNA-binding protein IMP-3 is a translational activator of insulin-like growth factor II leader-3 mRNA during proliferation of human K562 leukemia cells. J Biol. Chem.280, 18517-18524.
Lignitto L, Arcella A, Sepe M, Rinaldi L, Delle DR, Gallo A, Stefan E, Bachmann VA, Oliva
MA, Tiziana SC, L'Abbate A, Brunetti A, Gargiulo S, Gramanzini M, Insabato L, Garbi C, Gottesman ME, Feliciello A (2013). Proteolysis of MOB1 by the ubiquitin ligase praja2 attenuates Hippo signalling and supports glioblastoma growth. Nat Commun.4, 1822.
Ligon KL, Huillard E, Mehta S, Kesari S, Liu H, Alberta JA, Bachoo RM, Kane M, Louis DN, Depinho RA, Anderson DJ, Stiles CD, Rowitch DH (2007). Olig2-regulated lineagerestricted pathway controls replication competence in neural stem cells and malignant glioma. Neuron 53, 503-517.
Lin C, Meng S, Zhu T, Wang X (2010a). PDCD10/CCM3 acts downstream of {gamma}protocadherins to regulate neuronal survival. J Biol. Chem. 285, 41675-41685. Lin L, Zhang J, Wang Y, Zheng L, Lin Z, Cai Y (2013). [Expression of insulin-like growth factor 2 mRNA-binding protein 3 expression and analysis of prognosis in the patients with lung squamous cell carcinoma]. Xi. Bao. Yu Fen. Zi. Mian. Yi. Xue. Za Zhi.29, 694-697. Lin SY, Pan HW, Liu SH, Jeng YM, Hu FC, Peng SY, Lai PL, Hsu HC (2008). ASPM is a novel marker for vascular invasion, early recurrence, and poor prognosis of hepatocellular carcinoma. Clin Cancer Res 14, 4814-4820.
Lin Y, Mousa SS, Elshourbagy N, Mousa SA (2010b). Current status and future directions in lipid management: emphasizing low-density lipoproteins, high-density lipoproteins, and triglycerides as targets for therapy. Vasc. Health Risk Manag.6, 73-85.
Liu J, Yue P, Artym VV, Mueller SC, Guo W (2009). The role of the exocyst in matrix metalloproteinase secretion and actin dynamics during tumor cell invadopodia formation. Mol. Biol. Cell 20, 3763-3771.
Liu RZ, Graham K, Glubrecht DD, Lai R, Mackey JR, Godbout R (2012a). A fatty acidbinding protein 7/RXRbeta pathway enhances survival and proliferation in triple-negative breast cancer. J Pathol.228, 310-321.
Liu X, Chen N, Wang X, He Y, Chen X, Huang Y, Yin W, Zhou Q (2006). Apoptosis and proliferation markers in diffusely infiltrating astrocytomas: profiling of 17 molecules. J Neuropathol. Exp. Neurol.65, 905-913.
Liu Y, Li Q, Zhu L (2012b). Expression of the hepatocyte growth factor and c-Met in colon cancer: correlation with clinicopathological features and overall survival. Tumori 98, 105-112.
Lo ML, Staibano S, Pannone G, Mignogna MD, Mariggio A, Salvatore G, Chieffi P, Tramontano D, De RG, Altieri DC (2001). Expression of the apoptosis inhibitor survivin in aggressive squamous cell carcinoma. Exp. Mol. Pathol. 70, 249-254.
Lobas MA, Helsper L, Vernon CG, Schreiner D, Zhang Y, Holtzman MJ, Thedens DR, Weiner JA (2012). Molecular heterogeneity in the choroid plexus epithelium: the 22-member gammaprotocadherin family is differentially expressed, apically localized, and implicated in CSF regulation. J Neurochem.120, 913-927.
Losada A, Hirano T (2005). Dynamic molecular linkers of the genome: the first decade of SMC proteins. Genes Dev.19, 1269-1287.
Lossie AC, Nakamura H, Thomas SE, Justice MJ (2005). Mutation of l7Rn3 shows that Odz4 is required for mouse gastrulation. Genetics 169, 285-299.
Loyo M, Brait M, Kim MS, Ostrow KL, Jie CC, Chuang AY, Califano JA, Liegeois NJ, Begum S, Westra WH, Hoque MO, Tao Q, Sidransky D (2011). A survey of methylated candidate tumor suppressor genes in nasopharyngeal carcinoma. Int. J Cancer 128, 1393-1403.
Lu D, Yang X, Jiang NY, Woda BA, Liu Q, Dresser K, Mercurio AM, Rock KL, Jiang Z (2011). IMP3, a new biomarker to predict progression of cervical intraepithelial neoplasia into invasive cancer. Am. J Surg. Pathol.35, 1638-1645.
Lu KV, Jong KA, Kim GY, Singh J, Dia EQ, Yoshimoto K, Wang MY, Cloughesy TF, Nelson SF, Mischel PS (2005). Differential induction of glioblastoma migration and growth by two forms of pleiotrophin. J Biol Chem. 280, 26953-26964.
Lu QR, Park JK, Noll E, Chan JA, Alberta J, Yuk D, Alzamora MG, Louis DN, Stiles CD, Rowitch DH, Black PM (2001). Oligodendrocyte lineage genes (OLIG) as molecular markers for human glial brain tumors. Proc. Natl. Acad. Sci. U. S. A 98, 10851-10856.
Lu QR, Yuk D, Alberta JA, Zhu Z, Pawlitzky I, Chan J, McMahon AP, Stiles CD, Rowitch DH (2000). Sonic hedgehog--regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron 25, 317-329.
Lu Y, Lemon W, Liu PY, Yi Y, Morrison C, Yang P, Sun Z, Szoke J, Gerald WL, Watson M, Govindan R, You M (2006). A gene expression signature predicts survival of patients with stage I non-small cell lung cancer. PLoS. Med.3, e467.
Luksch H, Uckermann O, Stepulak A, Hendruschk S, Marzahn J, Bastian S, Staufner C, Temme A, Ikonomidou C (2011). Silencing of selected glutamate receptor subunits modulates cancer growth. Anticancer Res.31, 3181-3192.
Mackie EJ, Halfter W, Liverani D (1988). Induction of tenascin in healing wounds. J Cell Biol. 107, 2757-2767.
Mahlamaki EH, Barlund M, Tanner M, Gorunova L, Hoglund M, Karhu R, Kallioniemi A (2002). Frequent amplification of 8q24, 11q, 17q, and 20q-specific genes in pancreatic cancer. Genes Chromosomes. Cancer 35, 353-358.
Malagon MM, Cruz-Garcia D, Diaz-Ruiz A, Peinado JR, Pulido MR, Araujo J, Garcia-Navarro S, Gracia-Navarro F, Castano JP, Vazquez-Martinez R (2009). Identification of novel genes involved in the plasticity of pituitary melanotropes in amphibians. Ann N. Y. Acad. Sci.1163, 233-240.
Mao X, Boyd LK, Yanez-Munoz RJ, Chaplin T, Xue L, Lin D, Shan L, Berney DM, Young BD, Lu YJ (2011). Chromosome rearrangement associated inactivation of tumour suppressor genes in prostate cancer. Am. J Cancer Res. 1, 604-617.
Marchand M, Van BN, Weynants P, Brichard V, Dreno B, Tessier MH, Rankin E, Parmiani G,
Arienti F, Humblet Y, Bourlond A, Vanwijck R, Lienard D, Beauduin M, Dietrich PY, Russo V,
Kerger J, Masucci G, Jager E, De GJ, Atzpodien J, Brasseur F, Coulie PG, van der BP, Boon T
(1999). Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1. Int. J. Cancer 80, 219230.
Marchand M, Weynants P, Rankin E, Arienti F, Belli F, Parmiani G, Cascinelli N, Bourlond A, Vanwijck R, Humblet Y, . (1995). Tumor regression responses in melanoma patients treated with a peptide encoded by gene MAGE-3. Int. J Cancer 63, 883-885.
Mardilovich K, Pankratz SL, Shaw LM (2009). Expression and function of the insulin receptor substrate proteins in cancer. Cell Commun. Signal.7, 14.
Marei HE, Ahmed AE, Michetti F, Pescatori M, Pallini R, Casalbore P, Cenciarelli C, Elhadidy M (2012). Gene expression profile of adult human olfactory bulb and embryonic neural stem cell suggests distinct signaling pathways and epigenetic control. PLoS. ONE.
7, e33542.
Marie SK, Okamoto OK, Uno M, Hasegawa AP, Oba-Shinjo SM, Cohen T, Camargo AA, Kosoy A, Carlotti CG, Jr., Toledo S, Moreira-Filho CA, Zago MA, Simpson AJ, Caballero OL (2008). Maternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomas. Int J Cancer 122, 807-815.
Marie Y, Sanson M, Mokhtari K, Leuraud P, Kujas M, Delattre JY, Poirier J, Zalc B, Hoang-Xuan K (2001). OLIG2 as a specific marker of oligodendroglial tumour cells. Lancet 358, 298-300.
Marquardt A, Stohr H, White K, Weber BH (2000). cDNA cloning, genomic structure, and chromosomal localization of three members of the human fatty acid desaturase family. Genomics 66, 175-183.
Martineau Y, Azar R, Muller D, Lasfargues C, El KS, Anesia R, Pelletier J, Bousquet C, Pyronnet S (2013). Pancreatic tumours escape from translational control through 4E-BP1 loss. Oncogene.
Marzo AL, Kinnear BF, Lake RA, Frelinger JJ, Collins EJ, Robinson BW, Scott B (2000). Tumor-specific CD4+ T cells have a major "post-licensing" role in CTL mediated antitumor immunity. J Immunol. 165, 6047-6055.
Masuda H, Fukabori Y, Nakano K, Shimizu N, Yamanaka H (2004). Expression of bone morphogenetic protein-7 (BMP-7) in human prostate. Prostate 59, 101-106.
Mathew RM, Vandenberghe R, Garcia-Merino A, Yamamoto T, Landolfi JC, Rosenfeld MR, Rossi JE, Thiessen B, Dropcho EJ, Dalmau J (2007). Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis. Neurology 68, 900-905.
Mattera L, Escaffit F, Pillaire MJ, Selves J, Tyteca S, Hoffmann JS, Gourraud PA, ChevillardBriet M, Cazaux C, Trouche D (2009). The p400/Tip60 ratio is critical for colorectal cancer cell proliferation through DNA damage response pathways. Oncogene 28, 1506-1517.
McCarthy PL, Mercer FC, Savicky MW, Carter BA, Paterno GD, Gillespie LL (2008). Changes in subcellular localisation of MI-ER1 alpha, a novel oestrogen receptor-alpha interacting protein, is associated with breast cancer progression. Br. J Cancer 99, 639-646. McInroy L, Maatta A (2007). Down-regulation of vimentin expression inhibits carcinoma cell migration and adhesion. Biochem. Biophys. Res. Commun. 360, 109-114.
McManus KJ, Barrett IJ, Nouhi Y, Hieter P (2009). Specific synthetic lethal killing of RAD54Bdeficient human colorectal cancer cells by FEN1 silencing. Proc. Natl. Acad. Sci. U. S. A 106, 3276-3281.
McMillan DR, Kayes-Wandover KM, Richardson JA, White PC (2002). Very large G proteincoupled receptor-1, the largest known cell surface protein, is highly expressed in the developing central nervous system. J Biol. Chem. 277, 785-792.
Megumi K, Ishigami S, Uchikado Y, Kita Y, Okumura H, Matsumoto M, Uenosono Y, Arigami T, Kijima Y, Kitazono M, Shinchi H, Ueno S, Natsugoe S (2012). Clinicopathological significance of BMP7 expression in esophageal squamous cell carcinoma. Ann Surg. Oncol 19, 2066-2071.
Mehrle A, Rosenfelder H, Schupp I, del VC, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S (2006). The LIFEdb database in 2006. Nucleic Acids Res.34, D415-D418.
Mellai M, Caldera V, Patrucco A, Annovazzi L, Schiffer D (2008). Survivin expression in glioblastomas correlates with proliferation, but not with apoptosis. Anticancer Res. 28, 109-118.
Melrose J, Numata Y, Ghosh P (1996). Biotinylated hyaluronan: a versatile and highly sensitive probe capable of detecting nanogram levels of hyaluronan binding proteins (hyaladherins) on electroblots by a novel affinity detection procedure. Electrophoresis 17, 205-212.
Mendez MG, Kojima S, Goldman RD (2010). Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J 24, 1838-1851.
Mendiola M, Carrillo J, Garcia E, Lalli E, Hernandez T, de AE, Tirode F, Delattre O, GarciaMiguel P, Lopez-Barea F, Pestana A, Alonso J (2006). The orphan nuclear receptor DAX1 is upregulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. Int. J Cancer 118, 1381-1389.
Merighi S, Mirandola P, Varani K, Gessi S, Leung E, Baraldi PG, Tabrizi MA, Borea PA (2003). A glance at adenosine receptors: novel target for antitumor therapy. Pharmacol. Ther. 100, 31-48.
Merritt WM, et al. (2008). Dicer, Drosha, and outcomes in patients with ovarian cancer. N. Engl. J Med.359, 2641-2650.
Meunier L, Puiffe ML, Le PC, Filali-Mouhim A, Chevrette M, Tonin PN, Provencher DM, MesMasson AM (2010). Effect of ovarian cancer ascites on cell migration and gene expression in an epithelial ovarian cancer in vitro model. Transl. Oncol 3, 230-238.
Meyer-Puttlitz B, Junker E, Margolis RU, Margolis RK (1996). Chondroitin sulfate proteoglycans in the developing central nervous system. II. Immunocytochemical localization of neurocan and phosphacan. J Comp Neurol.366, 44-54.
Midorikawa Y, Tsutsumi S, Taniguchi H, Ishii M, Kobune Y, Kodama T, Makuuchi M, Aburatani H (2002). Identification of genes associated with dedifferentiation of hepatocellular carcinoma with expression profiling analysis. Jpn. J Cancer Res. 93, 636-643.
Miki M, Ball DW, Linnoila RI (2012). Insights into the achaete-scute homolog-1 gene (hASH1) in normal and neoplastic human lung. Lung Cancer 75, 58-65.
Milev P, Friedlander DR, Sakurai T, Karthikeyan L, Flad M, Margolis RK, Grumet M, Margolis RU (1994). Interactions of the chondroitin sulfate proteoglycan phosphacan, the extracellular domain of a receptor-type protein tyrosine phosphatase, with neurons, glia, and neural cell adhesion molecules. J Cell Biol.127, 1703-1715.
Milkereit P, Strauss D, Bassler J, Gadal O, Kuhn H, Schutz S, Gas N, Lechner J, Hurt E, Tschochner H (2003). A Noc complex specifically involved in the formation and nuclear export of ribosomal 40 S subunits. J Biol. Chem. 278, 4072-4081.
Min J, Mesika A, Sivaguru M, Van Veldhoven PP, Alexander H, Futerman AH, Alexander S (2007). (Dihydro)ceramide synthase 1 regulated sensitivity to cisplatin is associated with the activation of p38 mitogen-activated protein kinase and is abrogated by sphingosine kinase 1. Mol. Cancer Res.5, 801-812.
Minde DP, Anvarian Z, Rudiger SG, Maurice MM (2011). Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer? Mol. Cancer 10, 101.
Mita R, Coles JE, Glubrecht DD, Sung R, Sun X, Godbout R (2007). B-FABP-expressing radial glial cells: the malignant glioma cell of origin? Neoplasia.9, 734-744.
Miyamoto K, Fukutomi T, Akashi-Tanaka S, Hasegawa T, Asahara T, Sugimura T, Ushijima T (2005). Identification of 20 genes aberrantly methylated in human breast cancers. Int. J Cancer 116, 407-414.
Mobius W, Patzig J, Nave KA, Werner HB (2008). Phylogeny of proteolipid proteins: divergence, constraints, and the evolution of novel functions in myelination and neuroprotection. Neuron Glia Biol.4, 111-127.
Mohamed A, Gonzalez RS, Lawson D, Wang J, Cohen C (2012). SOX10 Expression in Malignant Melanoma, Carcinoma, and Normal Tissues. Appl. Immunohistochem. Mol. Morphol.
Morales G, Hubert M, Brummendorf T, Treubert U, Tarnok A, Schwarz U, Rathjen FG (1993). Induction of axonal growth by heterophilic interactions between the cell surface recognition proteins F11 and Nr-CAM/Bravo. Neuron 11, 1113-1122.
Moreira F, Kiehl TR, So K, Ajeawung NF, Honculada C, Gould P, Pieper RO, Kamnasaran D (2011). NPAS3 demonstrates features of a tumor suppressive role in driving the progression of Astrocytomas. Am. J Pathol.179, 462-476.
Morello S, Petrella A, Festa M, Popolo A, Monaco M, Vuttariello E, Chiappetta G, Parente L, Pinto A (2008). Cl-IB-MECA inhibits human thyroid cancer cell proliferation independently of A3 adenosine receptor activation. Cancer Biol. Ther.7, 278-284.
Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian
SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA (2006). Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes. Science.
Mori M, Beatty PG, Graves M, Boucher KM, Milford EL (1997). HLA gene and haplotype frequencies in the North American population: the National Marrow Donor Program Donor Registry. Transplantation 64, 1017-1027.
Morishita H, Yagi T (2007). Protocadherin family: diversity, structure, and function. Curr. Opin. Cell Biol.19, 584-592.
Mortara L, Castellani P, Meazza R, Tosi G, De Lerma BA, Procopio FA, Comes A, Zardi L, Ferrini S, Accolla RS (2006). CIITA-induced MHC class II expression in mammary adenocarcinoma leads to a Th1 polarization of the tumor microenvironment, tumor rejection, and specific antitumor memory. Clin Cancer Res.12, 3435-3443.
Mosavi LK, Cammett TJ, Desrosiers DC, Peng ZY (2004). The ankyrin repeat as molecular architecture for protein recognition. Protein Sci.13, 1435-1448.
Motoyama K, Tanaka F, Kosaka Y, Mimori K, Uetake H, Inoue H, Sugihara K, Mori M (2008). Clinical significance of BMP7 in human colorectal cancer. Ann Surg. Oncol 15, 1530-1537.
Mu J, Roach PJ (1998). Characterization of human glycogenin-2, a self-glucosylating initiator of liver glycogen metabolism. J Biol. Chem.273, 34850-34856.
Mueller LN, Rinner O, Schmidt A, Letarte S, Bodenmiller B, Brusniak MY, Vitek O, Aebersold R, Muller M (2007). SuperHirn - a novel tool for high resolution LC-MS-based peptide/protein profiling. Proteomics.7, 3470-3480.
Muir K, Hazim A, He Y, Peyressatre M, Kim DY, Song X, Beretta L (2013). Proteomic and Lipidomic Signatures of Lipid Metabolism in NASH-Associated Hepatocellular Carcinoma. Cancer Res.73, 4722-4731.
Mulholland PJ, Fiegler H, Mazzanti C, Gorman P, Sasieni P, Adams J, Jones TA, Babbage JW,
Vatcheva R, Ichimura K, East P, Poullikas C, Collins VP, Carter NP, Tomlinson IP, Sheer D (2006). Genomic profiling identifies discrete deletions associated with translocations in glioblastoma multiforme. Cell Cycle 5, 783-791.
Muller S, Kunkel P, Lamszus K, Ulbricht U, Lorente GA, Nelson AM, von SD, Chin DJ, Lohr SC, Westphal M, Melcher T (2003). A role for receptor tyrosine phosphatase zeta in glioma cell migration. Oncogene 22, 6661-6668.
Murray-Stewart T, Wang Y, Devereux W, Casero RA, Jr. (2002). Cloning and characterization of multiple human polyamine oxidase splice variants that code for isoenzymes with different biochemical characteristics. Biochem. J 368, 673-677.
Musacchio A, Gibson T, Rice P, Thompson J, Saraste M (1993). The PH domain: a common piece in the structural patchwork of signalling proteins. Trends Biochem. Sci.18, 343-348.
Mykytyn K, Nishimura DY, Searby CC, Beck G, Bugge K, Haines HL, Cornier AS, Cox GF, Fulton AB, Carmi R, Iannaccone A, Jacobson SG, Weleber RG, Wright AF, Riise R, Hennekam RC, Luleci G, Berker-Karauzum S, Biesecker LG, Stone EM, Sheffield VC (2003). Evaluation of complex inheritance involving the most common Bardet-Biedl syndrome locus (BBS1). Am. J Hum. Genet.72, 429-437.
Myung PS, Takeo M, Ito M, Atit RP (2013). Epithelial Wnt ligand secretion is required for adult hair follicle growth and regeneration. J Invest Dermatol.133, 31-41.
Na YR, Seok SH, Kim DJ, Han JH, Kim TH, Jung H, Lee BH, Park JH (2009). Bone morphogenetic protein 7 induces mesenchymal-to-epithelial transition in melanoma cells, leading to inhibition of metastasis. Cancer Sci.100, 2218-2225.
Nagai M, Ichimiya S, Ozaki T, Seki N, Mihara M, Furuta S, Ohira M, Tomioka N, Nomura N,
Sakiyama S, Kubo O, Takakura K, Hori T, Nakagawara A (2000). Identification of the full-length KIAA0591 gene encoding a novel kinesin-related protein which is mapped to the neuroblastoma suppressor gene locus at 1p36.2. Int. J Oncol 16, 907-916.
Nakada Y, Hunsaker TL, Henke RM, Johnson JE (2004). Distinct domains within Mash1 and Math1 are required for function in neuronal differentiation versus neuronal cell-type specification. Development 131, 1319-1330.
Nakamura Y, Suzuki T, Arai Y, Sasano H (2009). Nuclear receptor DAX1 in human prostate cancer: a novel independent biological modulator. Endocr. J 56, 39-44.
Nakayama J, Hamano K, Iwasaki N, Nakahara S, Horigome Y, Saitoh H, Aoki T, Maki T, Kikuchi M, Migita T, Ohto T, Yokouchi Y, Tanaka R, Hasegawa M, Matsui A, Hamaguchi H, Arinami T (2000). Significant evidence for linkage of febrile seizures to chromosome 5q14-q15. Hum. Mol. Genet.9, 87-91.
Nakayama M, Miyake T, Gahara Y, Ohara O, Kitamura T (1995). A novel RING-H2 motif protein downregulated by axotomy: its characteristic localization at the postsynaptic density of axosomatic synapse. J Neurosci.15, 5238-5248.
Nara Y, Kato Y, Torii Y, Tsuji Y, Nakagaki S, Goto S, Isobe H, Nakashima N, Takeuchi J (1997). Immunohistochemical localization of extracellular matrix components in human breast tumours with special reference to PG-M/versican. Histochem. J 29, 21-30.
Nasr Z, Robert F, Porco JA, Jr., Muller WJ, Pelletier J (2013). eIF4F suppression in breast cancer affects maintenance and progression. Oncogene 32, 861-871.
Need AC, Keefe RS, Ge D, Grossman I, Dickson S, McEvoy JP, Goldstein DB (2009). Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis. Eur. J Hum. Genet.17, 946-957.
Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G, Schadendorf D (1998). Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med.4, 328-332.
Niakan KK, McCabe ER (2005). DAX1 origin, function, and novel role. Mol. Genet. Metab 86, 70-83.
Nibbe RK, Markowitz S, Myeroff L, Ewing R, Chance MR (2009). Discovery and scoring of protein interaction subnetworks discriminative of late stage human colon cancer. Mol. Cell Proteomics. 8, 827-845.
Nichols AC, Chan-Seng-Yue M, Yoo J, Xu W, Dhaliwal S, Basmaji J, Szeto CC, Dowthwaite S,
Todorovic B, Starmans MH, Lambin P, Palma DA, Fung K, Franklin JH, Wehrli B, Kwan K,
Koropatnick J, Mymryk JS, Boutros P, Barrett JW (2012). A Pilot Study Comparing HPVPositive and HPV-Negative Head and Neck Squamous Cell Carcinomas by Whole Exome Sequencing. ISRN. Oncol 2012, 809370.
Nigg EA, Raff JW (2009). Centrioles, centrosomes, and cilia in health and disease. Cell 139, 663678.
Nikkila H, McMillan DR, Nunez BS, Pascoe L, Curnow KM, White PC (2000). Sequence similarities between a novel putative G protein-coupled receptor and Na+/Ca2+ exchangers define a cation binding domain. Mol. Endocrinol.14, 1351-1364.
Nishioka M, Kohno T, Takahashi M, Niki T, Yamada T, Sone S, Yokota J (2000). Identification of a 428-kb homozygously deleted region disrupting the SEZ6L gene at 22q12.1 in a lung cancer cell line. Oncogene 19, 6251-6260.
Niu Z, Li X, Hu B, Li R, Wang L, Wu L, Wang X (2012). Small interfering RNA targeted to secretory clusterin blocks tumor growth, motility, and invasion in breast cancer. Acta Biochim. Biophys. Sin. (Shanghai) 44, 991-998.
Novak P, Jensen T, Oshiro MM, Watts GS, Kim CJ, Futscher BW (2008). Agglomerative epigenetic aberrations are a common event in human breast cancer. Cancer Res.68, 8616-8625.
Nurmi EL, Dowd M, Tadevosyan-Leyfer O, Haines JL, Folstein SE, Sutcliffe JS (2003). Exploratory subsetting of autism families based on savant skills improves evidence of genetic linkage to 15q11-q13. J Am. Acad. Child Adolesc. Psychiatry 42, 856-863.
Nwankwo JO, Spector AA, Domann FE (2003). A nucleotide insertion in the transcriptional regulatory region of FADS2 gives rise to human fatty acid delta-6-desaturase deficiency. J Lipid Res.44, 2311-2319.
Oda T, Tian T, Inoue M, Ikeda J, Qiu Y, Okumura M, Aozasa K, Morii E (2009). Tumorigenic role of orphan nuclear receptor NR0B1 in lung adenocarcinoma. Am. J Pathol. 175, 1235-1245.
Ohira M, et al. (2000). Identification and characterization of a 500-kb homozygously deleted region at 1p36.2-p36.3 in a neuroblastoma cell line. Oncogene 19, 4302-4307.
Ohmae S, Takemoto-Kimura S, Okamura M, Adachi-Morishima A, Nonaka M, Fuse T, Kida S, Tanji M, Furuyashiki T, Arakawa Y, Narumiya S, Okuno H, Bito H (2006). Molecular identification and characterization of a family of kinases with homology to Ca2+/calmodulindependent protein kinases I/IV. J Biol. Chem.281, 20427-20439.
Ohtomo R, Mori T, Shibata S, Tsuta K, Maeshima AM, Akazawa C, Watabe Y, Honda K, Yamada T, Yoshimoto S, Asai M, Okano H, Kanai Y, Tsuda H (2013). SOX10 is a novel marker of acinus and intercalated duct differentiation in salivary gland tumors: a clue to the histogenesis for tumor diagnosis. Mod. Pathol.26, 1041-1050.
Okada K, Fujiwara Y, Nakamura Y, Takiguchi S, Nakajima K, Miyata H, Yamasaki M, Kurokawa Y, Takahashi T, Mori M, Doki Y (2012). Oncofetal protein, IMP-3, a potential marker for prediction of postoperative peritoneal dissemination in gastric adenocarcinoma. J Surg. Oncol 105, 780-785.
Olsen ML, Sontheimer H (2008). Functional implications for Kir4.1 channels in glial biology: from K+ buffering to cell differentiation. J Neurochem.107, 589-601.
Osada H, Tatematsu Y, Yatabe Y, Horio Y, Takahashi T (2005). ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features. Cancer Res. 65, 10680-10685.
Ostrow KL, Park HL, Hoque MO, Kim MS, Liu J, Argani P, Westra W, Van CW, Sidransky D (2009). Pharmacologic unmasking of epigenetically silenced genes in breast cancer. Clin Cancer Res.15, 1184-1191.
Otey CA, Pavalko FM, Burridge K (1990). An interaction between alpha-actinin and the beta 1 integrin subunit in vitro. J Cell Biol.111, 721-729.
Ou XM, Chen K, Shih JC (2006). Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway. Proc. Natl. Acad. Sci. U. S. A 103, 10923-10928.
Ozerdem U (2006). Targeting of pericytes diminishes neovascularization and lymphangiogenesis in prostate cancer. Prostate 66, 294-304.
Panico F, Casali C, Rossi G, Rizzi F, Morandi U, Bettuzzi S, Davalli P, Corbetta L, Storelli ES, Corti A, Fabbri LM, Astancolle S, Luppi F (2013). Prognostic role of clusterin in resected adenocarcinomas of the lung. Lung Cancer 79, 294-299.
Pannuti A, Lanfrancone L, Pascucci A, Pelicci PG, La MG, Lania L (1988). Isolation of cDNAs encoding finger proteins and measurement of the corresponding mRNA levels during myeloid terminal differentiation. Nucleic Acids Res.16, 4227-4237.
Papachristou DJ, Korpetinou A, Giannopoulou E, Antonacopoulou AG, Papadaki H, Grivas P, Scopa CD, Kalofonos HP (2011). Expression of the ribonucleases Drosha, Dicer, and Ago2 in colorectal carcinomas. Virchows Arch.459, 431-440.
Parisi M, Glass I (1993). Joubert Syndrome and Related Disorders.
Park WJ, Kothapalli KS, Lawrence P, Brenna JT (2011). FADS2 function loss at the cancer hotspot 11q13 locus diverts lipid signaling precursor synthesis to unusual eicosanoid fatty acids. PLoS. ONE.6, e28186.
Paron I, Berchtold S, Voros J, Shamarla M, Erkan M, Hofler H, Esposito I (2011). Tenascin-C enhances pancreatic cancer cell growth and motility and affects cell adhesion through activation of the integrin pathway. PLoS. ONE.6, e21684.
Pascolo S, Ginhoux F, Laham N, Walter S, Schoor O, Probst J, Rohrlich P, Obermayr F, Fisch P, Danos O, Ehrlich R, Lemonnier FA, Rammensee HG (2005). The non-classical HLA class I molecule HFE does not influence the NK-like activity contained in fresh human PBMCs and does not interact with NK cells. Int. Immunol. 17, 117-122.
Passon N, Gerometta A, Puppin C, Lavarone E, Puglisi F, Tell G, Di LC, Damante G (2012). Expression of Dicer and Drosha in triple-negative breast cancer. J Clin Pathol.65, 320-326.
Paterno GD, Ding Z, Lew YY, Nash GW, Mercer FC, Gillespie LL (2002). Genomic organization of the human mi-er1 gene and characterization of alternatively spliced isoforms: regulated use of a facultative intron determines subcellular localization. Gene 295, 79-88.
Paterno GD, Li Y, Luchman HA, Ryan PJ, Gillespie LL (1997). cDNA cloning of a novel, developmentally regulated immediate early gene activated by fibroblast growth factor and encoding a nuclear protein. J Biol. Chem.272, 25591-25595.
Pattani KM, et al. (2010). Endothelin receptor type B gene promoter hypermethylation in salivary rinses is independently associated with risk of oral cavity cancer and premalignancy. Cancer Prev. Res. (Phila) 3, 1093-1103.
Pattyn A, Guillemot F, Brunet JF (2006). Delays in neuronal differentiation in Mash1/Ascl1 mutants. Dev. Biol.295, 67-75.
Pegoraro E, Cepollaro F, Prandini P, Marin A, Fanin M, Trevisan CP, El-Messlemani AH, Tarone G, Engvall E, Hoffman EP, Angelini C (2002). Integrin alpha 7 beta 1 in muscular dystrophy/myopathy of unknown etiology. Am. J Pathol. 160, 2135-2143.
Pellikka M, Tanentzapf G, Pinto M, Smith C, McGlade CJ, Ready DF, Tepass U (2002). Crumbs, the Drosophila homologue of human CRB1/RP12, is essential for photoreceptor morphogenesis. Nature 416, 143-149.
Pender-Cudlip MC, Krag KJ, Martini D, Yu J, Guidi A, Skinner SS, Zhang Y, Qu X, He C, Xu Y, Qian SY, Kang JX (2013). Delta-6-desaturase activity and arachidonic acid synthesis are increased in human breast cancer tissue. Cancer Sci.104, 760-764.
Perrin FE, Rathjen FG, Stoeckli ET (2001). Distinct subpopulations of sensory afferents require F11 or axonin-1 for growth to their target layers within the spinal cord of the chick. Neuron 30, 707-723.
Piesche M, Hildebrandt Y, Zettl F, Chapuy B, Schmitz M, Wulf G, Trumper L, Schroers R (2007). Identification of a promiscuous HLA DR-restricted T-cell epitope derived from the inhibitor of apoptosis protein survivin. Hum. Immunol. 68, 572-576.
Pinheiro PS, Perrais D, Coussen F, Barhanin J, Bettler B, Mann JR, Malva JO, Heinemann SF, Mulle C (2007). GluR7 is an essential subunit of presynaptic kainate autoreceptors at hippocampal mossy fiber synapses. Proc. Natl. Acad. Sci. U. S. A 104, 12181-12186.
Poomsawat S, Buajeeb W, Khovidhunkit SO, Punyasingh J (2010). Alteration in the expression of cdk4 and cdk6 proteins in oral cancer and premalignant lesions. J Oral Pathol. Med.39, 793799.
Populo H, Lopes JM, Soares P (2012). The mTOR Signalling Pathway in Human Cancer. Int. J Mol. Sci.13, 1886-1918.
Prades C, Arnould I, Annilo T, Shulenin S, Chen ZQ, Orosco L, Triunfol M, Devaud C, Maintoux-Larois C, Lafargue C, Lemoine C, Denefle P, Rosier M, Dean M (2002). The human ATP binding cassette gene ABCA13, located on chromosome 7p12.3, encodes a 5058 amino acid protein with an extracellular domain encoded in part by a 4.8-kb conserved exon. Cytogenet. Genome Res 98, 160-168.
Prajapati SC, Chauhan SS (2011). Dipeptidyl peptidase III: a multifaceted oligopeptide N-end cutter. FEBS J 278, 3256-3276.
Prakash S, Sarran L, Socci N, DeMatteo RP, Eisenstat J, Greco AM, Maki RG, Wexler LH, LaQuaglia MP, Besmer P, Antonescu CR (2005). Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. J Pediatr. Hematol. Oncol 27, 179-187.
Prieto JL, McStay B (2007). Recruitment of factors linking transcription and processing of prerRNA to NOR chromatin is UBF-dependent and occurs independent of transcription in human cells. Genes Dev.21, 2041-2054.
Pritchett J, Athwal V, Roberts N, Hanley NA, Hanley KP (2011). Understanding the role of SOX9 in acquired diseases: lessons from development. Trends Mol. Med.17, 166-174. Pryor JG, Bourne PA, Yang Q, Spaulding BO, Scott GA, Xu H (2008). IMP-3 is a novel progression marker in malignant melanoma. Mod. Pathol.21, 431-437.
Puyol M, Martin A, Dubus P, Mulero F, Pizcueta P, Khan G, Guerra C, Santamaria D, Barbacid M (2010). A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18, 63-73. Qiao Y, Liu X, Harvard C, Hildebrand MJ, Rajcan-Separovic E, Holden JJ, Lewis ME (2008). Autism-associated familial microdeletion of Xp11.22. Clin Genet.74, 134-144. Qin Z, Blankenstein T (2000). CD4+ T cell--mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFN gamma receptor expression by nonhematopoietic cells. Immunity. 12, 677-686.
Qin Z, Schwartzkopff J, Pradera F, Kammertoens T, Seliger B, Pircher H, Blankenstein T (2003). A critical requirement of interferon gamma-mediated angiostasis for tumor rejection by CD8+ T cells. Cancer Res.63, 4095-4100.
Raji OY, Agbaje OF, Duffy SW, Cassidy A, Field JK (2010). Incorporation of a genetic factor into an epidemiologic model for prediction of individual risk of lung cancer: the Liverpool Lung Project. Cancer Prev. Res. (Phila) 3, 664-669.
Rammensee HG, Bachmann J, Emmerich NP, Bachor OA, Stevanovic S (1999). SYFPEITHI:
database for MHC ligands and peptide motifs. Immunogenetics 50, 213-219.
Rammensee HG, Bachmann J, Stevanovic S (1997). MHC Ligands and Peptide Motifs. (Heidelberg, Germany: Springer-Verlag).
Ramos S, Khademi F, Somesh BP, Rivero F (2002). Genomic organization and expression profile of the small GTPases of the RhoBTB family in human and mouse. Gene 298, 147-157.
Rao P, Fuller GN, Prieto VG (2010). Expression of Sox-9 in metastatic melanoma--a potential diagnostic pitfall. Am. J Dermatopathol.32, 262-266.
Rapa I, Ceppi P, Bollito E, Rosas R, Cappia S, Bacillo E, Porpiglia F, Berruti A, Papotti M, Volante M (2008). Human ASH1 expression in prostate cancer with neuroendocrine differentiation. Mod. Pathol.21, 700-707.
Rauch U (2004). Extracellular matrix components associated with remodeling processes in brain. Cell Mol. Life Sci.61, 2031-2045.
Raverot G, Wierinckx A, Dantony E, Auger C, Chapas G, Villeneuve L, Brue T, FigarellaBranger D, Roy P, Jouanneau E, Jan M, Lachuer J, Trouillas J (2010). Prognostic factors in prolactin pituitary tumors: clinical, histological, and molecular data from a series of 94 patients with a long postoperative follow-up. J Clin Endocrinol. Metab 95, 1708-1716.
Reamy AA, Wolfgang MJ (2011). Carnitine palmitoyltransferase-1c gain-of-function in the brain results in postnatal microencephaly. J Neurochem.118, 388-398.
Reilly PT, Mak TW (2012). Molecular pathways: tumor cells Co-opt the brain-specific metabolism gene CPT1C to promote survival. Clin Cancer Res. 18, 5850-5855.
Reinert T, Modin C, Castano FM, Lamy P, Wojdacz TK, Hansen LL, Wiuf C, Borre M, Dyrskjot L, ORntoft TF (2011). Comprehensive genome methylation analysis in bladder cancer: identification and validation of novel methylated genes and application of these as urinary tumor markers. Clin Cancer Res.17, 5582-5592.
Ren B, Yu YP, Tseng GC, Wu C, Chen K, Rao UN, Nelson J, Michalopoulos GK, Luo JH (2007). Analysis of integrin alpha7 mutations in prostate cancer, liver cancer, glioblastoma multiforme, and leiomyosarcoma. J Natl. Cancer Inst.99, 868-880.
Renkonen S, Heikkila P, Haglund C, Makitie AA, Hagstrom J (2012). Tenascin-C, GLUT-1, and syndecan-2 expression in juvenile nasopharyngeal angiofibroma: Correlations to vessel density and tumor stage. Head Neck.
Rheinbay E, Suva ML, Gillespie SM, Wakimoto H, Patel AP, Shahid M, Oksuz O, Rabkin SD,
Martuza RL, Rivera MN, Louis DN, Kasif S, Chi AS, Bernstein BE (2013). An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma. Cell Rep.3, 1567-1579.
Richiardi L, Fiano V, Grasso C, Zugna D, Delsedime L, Gillio-Tos A, Merletti F (2013). Methylation of APC and GSTP1 in Non-Neoplastic Tissue Adjacent to Prostate Tumour and Mortality from Prostate Cancer. PLoS. ONE.8, e68162.
Richter P, Umbreit C, Franz M, Berndt A, Grimm S, Uecker A, Bohmer FD, Kosmehl H, Berndt A (2011). EGF/TGFbeta1 co-stimulation of oral squamous cell carcinoma cells causes an epithelial-mesenchymal transition cell phenotype expressing laminin 332. J Oral Pathol. Med.40, 46-54.
Riener MO (2011). [Diagnosis of tumours of the liver and the biliary tract: new tissue and serum markers]. Pathologe 32 Suppl 2, 304-309.
Righi L, Rapa I, Votta A, Papotti M, Sapino A (2012). Human achaete-scute homolog-1 expression in neuroendocrine breast carcinoma. Virchows Arch. 460, 415-421.
Rimkus C, Friederichs J, Boulesteix AL, Theisen J, Mages J, Becker K, Nekarda H, Rosenberg R, Janssen KP, Siewert JR (2008). Microarray-based prediction of tumor response to neoadjuvant radiochemotherapy of patients with locally advanced rectal cancer. Clin Gastroenterol. Hepatol.6, 53-61.
Rini BI, Weinberg V, Fong L, Conry S, Hershberg RM, Small EJ (2006). Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy. Cancer 107, 67-74.
Rivero F, Dislich H, Glockner G, Noegel AA (2001). The Dictyostelium discoideum family of Rho-related proteins. Nucleic Acids Res.29, 1068-1079.
Rodenko B, Toebes M, Hadrup SR, van Esch WJ, Molenaar AM, Schumacher TN, Ovaa H (2006). Generation of peptide-MHC class I complexes through UV-mediated ligand exchange. Nat. Protoc.1, 1120-1132.
Rodriguez-Martinez A, Alarmo EL, Saarinen L, Ketolainen J, Nousiainen K, Hautaniemi S, Kallioniemi A (2011). Analysis of BMP4 and BMP7 signaling in breast cancer cells unveils timedependent transcription patterns and highlights a common synexpression group of genes. BMC. Med. Genomics 4, 80.
Rodriguez-Pineiro AM, Garcia-Lorenzo A, Blanco-Prieto S, Alvarez-Chaver P, RodriguezBerrocal FJ, Cadena MP, Martinez-Zorzano VS (2012). Secreted clusterin in colon tumor cell models and its potential as diagnostic marker for colorectal cancer. Cancer Invest 30, 72-78.
Rose A, Meier I (2004). Scaffolds, levers, rods and springs: diverse cellular functions of long coiled-coil proteins. Cell Mol. Life Sci.61, 1996-2009.
Rose A, Schraegle SJ, Stahlberg EA, Meier I (2005). Coiled-coil protein composition of 22 proteomes--differences and common themes in subcellular infrastructure and traffic control. BMC. Evol. Biol. 5, 66.
Ross MT, et al (2005). The DNA sequence of the human X chromosome. Nature 434, 325-337.
Rostomily RC, Born DE, Beyer RP, Jin J, Alvord EC, Jr., Mikheev AM, Matthews RT, Pan C, Khorasani L, Sonnen JA, Montine TJ, Shi M, Zhang J (2010). Quantitative proteomic analysis of oligodendrogliomas with and without 1p/19q deletion. J Proteome. Res. 9, 2610-2618.
Rothhammer T, Wild PJ, Meyer S, Bataille F, Pauer A, Klinkhammer-Schalke M, Hein R, Hofstaedter F, Bosserhoff AK (2007). Bone morphogenetic protein 7 (BMP7) expression is a potential novel prognostic marker for recurrence in patients with primary melanoma. Cancer Biomark. 3, 111-117.
Rotunno M, Hu N, Su H, Wang C, Goldstein AM, Bergen AW, Consonni D, Pesatori AC, Bertazzi PA, Wacholder S, Shih J, Caporaso NE, Taylor PR, Landi MT (2011). A gene expression signature from peripheral whole blood for stage I lung adenocarcinoma. Cancer Prev. Res (Phila) 4, 1599-1608.
Rotunno M, Zhao Y, Bergen AW, Koshiol J, Burdette L, Rubagotti M, Linnoila RI, Marincola FM, Bertazzi PA, Pesatori AC, Caporaso NE, McShane LM, Wang E, Landi MT (2010). Inherited polymorphisms in the RNA-mediated interference machinery affect microRNA expression and lung cancer survival. Br. J Cancer 103, 1870-1874.
Rousseau A, Nutt CL, Betensky RA, Iafrate AJ, Han M, Ligon KL, Rowitch DH, Louis DN (2006). Expression of oligodendroglial and astrocytic lineage markers in diffuse gliomas: use of YKL-40, ApoE, ASCL1, and NKX2-2. J Neuropathol. Exp. Neurol. 65, 1149-1156.
Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, Munemitsu S, Polakis P (1993). Association of the APC gene product with beta-catenin. Science 262, 1731-1734.
Saadoun S, Papadopoulos MC, Krishna S (2003). Water transport becomes uncoupled from K+ siphoning in brain contusion, bacterial meningitis, and brain tumours: immunohistochemical case review. J Clin Pathol.56, 972-975.
Saarikangas J, Hakanen J, Mattila PK, Grumet M, Salminen M, Lappalainen P (2008). ABBA regulates plasma-membrane and actin dynamics to promote radial glia extension. J Cell Sci.121, 1444-1454.
Saddoughi SA, Ogretmen B (2013). Diverse functions of ceramide in cancer cell death and proliferation. Adv. Cancer Res.117, 37-58.
Sadeque A, Serao NV, Southey BR, Delfino KR, Rodriguez-Zas SL (2012). Identification and characterization of alternative exon usage linked glioblastoma multiforme survival. BMC. Med. Genomics 5, 59.
Sahashi K, Sakai K, Mano K, Hirose G (2003). Anti-Ma2 antibody related paraneoplastic limbic/brain stem encephalitis associated with breast cancer expressing Ma1, Ma2, and Ma3 mRNAs. J Neurol. Neurosurg. Psychiatry 74, 1332-1335.
Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA (1988). Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239, 487-491.
Saito S, Ito K, Suzuki T, Utsunomiya H, Akahira J, Sugihashi Y, Niikura H, Okamura K, Yaegashi N, Sasano H (2005). Orphan nuclear receptor DAX-1 in human endometrium and its disorders. Cancer Sci.96, 645-652.
Saito T, Arifin MT, Hama S, Kajiwara Y, Sugiyama K, Yamasaki F, Hidaka T, Arita K, Kurisu K (2007). Survivin subcellular localization in high-grade astrocytomas: simultaneous expression in both nucleus and cytoplasm is negative prognostic marker. J Neurooncol. 82, 193-198.
Sakurai T, Friedlander DR, Grumet M (1996). Expression of polypeptide variants of receptortype protein tyrosine phosphatase beta: the secreted form, phosphacan, increases dramatically during embryonic development and modulates glial cell behavior in vitro. J Neurosci. Res. 43, 694-706.
Sakurai T, Lustig M, Babiarz J, Furley AJ, Tait S, Brophy PJ, Brown SA, Brown LY, Mason CA, Grumet M (2001). Overlapping functions of the cell adhesion molecules Nr-CAM and L1 in cerebellar granule cell development. J Cell Biol.154, 1259-1273.
Sakurai T, Lustig M, Nativ M, Hemperly JJ, Schlessinger J, Peles E, Grumet M (1997). Induction of neurite outgrowth through contactin and Nr-CAM by extracellular regions of glial receptor tyrosine phosphatase beta. J Cell Biol.136, 907-918.
Salsano E, Paterra R, Figus M, Menghi F, Maderna E, Pollo B, Solero CL, Massimi L, Finocchiaro G (2012). Expression profile of frizzled receptors in human medulloblastomas. J Neurooncol.106, 271-280.
Samanta S, Sharma VM, Khan A, Mercurio AM (2012). Regulation of IMP3 by EGFR signaling and repression by ERbeta: implications for triple-negative breast cancer. Oncogene 31, 46894697.
Samuelson AV, Narita M, Chan HM, Jin J, de SE, McCurrach ME, Narita M, Fuchs M, Livingston DM, Lowe SW (2005). p400 is required for E1A to promote apoptosis. J Biol. Chem. 280, 21915-21923.
Sarai N, Kagawa W, Fujikawa N, Saito K, Hikiba J, Tanaka K, Miyagawa K, Kurumizaka H, Yokoyama S (2008). Biochemical analysis of the N-terminal domain of human RAD54B. Nucleic Acids Res.36, 5441-5450.
Sarria AJ, Panini SR, Evans RM (1992). A functional role for vimentin intermediate filaments in the metabolism of lipoprotein-derived cholesterol in human SW-13 cells. J Biol. Chem. 267, 19455-19463.
Sasaki A, Masuda Y, Iwai K, Ikeda K, Watanabe K (2002a). A RING finger protein Praja1 regulates Dlx5-dependent transcription through its ubiquitin ligase activity for the Dlx/Msxinteracting MAGE/Necdin family protein, Dlxin-1. J Biol. Chem. 277, 22541-22546.
Sasaki T, Lopes MB, Hankins GR, Helm GA (2002b). Expression of survivin, an inhibitor of apoptosis protein, in tumors of the nervous system. Acta Neuropathol.104, 105-109.
Satish L, O'Gorman DB, Johnson S, Raykha C, Gan BS, Wang JH, Kathju S (2013). Increased CCT-eta expression is a marker of latent and active disease and a modulator of fibroblast contractility in Dupuytren's contracture. Cell Stress. Chaperones. 18, 397-404.
Sato F, Abraham JM, Yin J, Kan T, Ito T, Mori Y, Hamilton JP, Jin Z, Cheng Y, Paun B, Berki AT, Wang S, Shimada Y, Meltzer SJ (2006). Polo-like kinase and survivin are esophageal tumorspecific promoters. Biochem. Biophys. Res. Commun. 342, 465-471.
Schaefer C, Grouse L, Buetow K, Strausberg RL (2001). A new cancer genome anatomy project web resource for the community. Cancer J 7, 52-60.
Schaeffer DF, Owen DR, Lim HJ, Buczkowski AK, Chung SW, Scudamore CH, Huntsman DG, Ng SS, Owen DA (2010). Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) overexpression in pancreatic ductal adenocarcinoma correlates with poor survival. BMC. Cancer 10, 59.
Schietke R, Brohl D, Wedig T, Mucke N, Herrmann H, Magin TM (2006). Mutations in vimentin disrupt the cytoskeleton in fibroblasts and delay execution of apoptosis. Eur. J Cell Biol.85, 1-10.
Schoenfeld AR, Apgar S, Dolios G, Wang R, Aaronson SA (2004). BRCA2 is ubiquitinated in vivo and interacts with USP11, a deubiquitinating enzyme that exhibits prosurvival function in the cellular response to DNA damage. Mol. Cell Biol. 24, 7444-7455.
Scholey JM, Anderson KV (2006). Intraflagellar transport and cilium-based signaling. Cell 125, 439-442.
Schuller M, Jenne D, Voltz R (2005). The human PNMA family: novel neuronal proteins implicated in paraneoplastic neurological disease. J Neuroimmunol.169, 172-176.
Seeger FH, Schirle M, Gatfield J, Arnold D, Keilholz W, Nickolaus P, Rammensee HG, Stevanovic S (1999). The HLA-A*6601 peptide motif: prediction by pocket structure and verification by peptide analysis. Immunogenetics 49, 571-576.
Sehgal A, Boynton AL, Young RF, Vermeulen SS, Yonemura KS, Kohler EP, Aldape HC, Simrell CR, Murphy GP (1998). Cell adhesion molecule Nr-CAM is over-expressed in human brain tumors. Int J Cancer 76, 451-458.
Sehgal A, Ricks S, Warrick J, Boynton AL, Murphy GP (1999). Antisense human neuroglia related cell adhesion molecule hNr-CAM, reduces the tumorigenic properties of human glioblastoma cells. Anticancer Res.19, 4947-4953.
Seifert W, Kuhnisch J, Maritzen T, Horn D, Haucke V, Hennies HC (2011). Cohen syndromeassociated protein, COH1, is a novel, giant Golgi matrix protein required for Golgi integrity. J Biol. Chem.286, 37665-37675.
Seki N, Ohira M, Nagase T, Ishikawa K, Miyajima N, Nakajima D, Nomura N, Ohara O (1997). Characterization of cDNA clones in size-fractionated cDNA libraries from human brain. DNA Res. 4, 345-349.
Senkal CE, Ponnusamy S, Rossi MJ, Bialewski J, Sinha D, Jiang JC, Jazwinski SM, Hannun YA, Ogretmen B (2007). Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas. Mol. Cancer Ther.6, 712-722.
Sentelle RD, Senkal CE, Jiang W, Ponnusamy S, Gencer S, Selvam SP, Ramshesh VK, Peterson YK, Lemasters JJ, Szulc ZM, Bielawski J, Ogretmen B (2012). Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat Chem. Biol. 8, 831-838.
Seo M, Lee WH, Suk K (2010). Identification of novel cell migration-promoting genes by a functional genetic screen. FASEB J 24, 464-478.
Separovic D, Breen P, Joseph N, Bielawski J, Pierce JS, VAN BE, Gudz TI (2012). siRNAmediated down-regulation of ceramide synthase 1 leads to apoptotic resistance in human head and neck squamous carcinoma cells after photodynamic therapy. Anticancer Res. 32, 2479-2485.
Shaw LM (2011). The insulin receptor substrate (IRS) proteins: at the intersection of metabolism and cancer. Cell Cycle 10, 1750-1756.
Shedlock DJ, Shen H (2003). Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300, 337-339.
Shida T, Furuya M, Nikaido T, Kishimoto T, Koda K, Oda K, Nakatani Y, Miyazaki M, Ishikura H (2005). Aberrant expression of human achaete-scute homologue gene 1 in the gastrointestinal neuroendocrine carcinomas. Clin Cancer Res. 11, 450-458.
Shiota M, Zardan A, Takeuchi A, Kumano M, Beraldi E, Naito S, Zoubeidi A, Gleave ME (2012). Clusterin mediates TGF-beta-induced epithelial-mesenchymal transition and metastasis via Twist1 in prostate cancer cells. Cancer Res. 72, 5261-5272.
Shirahata A, Sakata M, Sakuraba K, Goto T, Mizukami H, Saito M, Ishibashi K, Kigawa G, Nemoto H, Sanada Y, Hibi K (2009). Vimentin methylation as a marker for advanced colorectal carcinoma. Anticancer Res.29, 279-281.
Shiras A, Bhosale A, Shepal V, Shukla R, Baburao VS, Prabhakara K, Shastry P (2003). A unique model system for tumor progression in GBM comprising two developed human neuro-epithelial cell lines with differential transforming potential and coexpressing neuronal and glial markers. Neoplasia.5, 520-532.
Shoji H, Tsuchida K, Kishi H, Yamakawa N, Matsuzaki T, Liu Z, Nakamura T, Sugino H (2000). Identification and characterization of a PDZ protein that interacts with activin type II receptors. J Biol. Chem. 275, 5485-5492.
Simaga S, Abramic M, Osmak M, Babic D, Ilic-Forko J (2008). Total tissue lactate dehydrogenase activity in endometrial carcinoma. Int. J Gynecol. Cancer 18, 1272-1278.
Simaga S, Babic D, Osmak M, Ilic-Forko J, Vitale L, Milicic D, Abramic M (1998). Dipeptidyl peptidase III in malignant and non-malignant gynaecological tissue. Eur. J Cancer 34, 399-405.
Simaga S, Babic D, Osmak M, Sprem M, Abramic M (2003). Tumor cytosol dipeptidyl peptidase III activity is increased with histological aggressiveness of ovarian primary carcinomas. Gynecol. Oncol 91, 194-200.
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004). Identification of human brain tumour initiating cells. Nature 432, 396-401.
Singh-Jasuja H, Emmerich NP, Rammensee HG (2004). The Tubingen approach: identification, selection, and validation of tumor-associated HLA peptides for cancer therapy. Cancer Immunol. Immunother. 53, 187-195.
Siow DL, Wattenberg BW (2012). Mammalian ORMDL proteins mediate the feedback response in ceramide biosynthesis. J Biol. Chem.287, 40198-40204.
Siu A, Lee C, Pham E, Ramos DM (2012). Revisiting epithelial-to-mesenchymal transition through adenoid cystic carcinoma. Anticancer Res.32, 3683-3688.
Sivasankaran B, Degen M, Ghaffari A, Hegi ME, Hamou MF, Ionescu MC, Zweifel C, Tolnay M,
Wasner M, Mergenthaler S, Miserez AR, Kiss R, Lino MM, Merlo A, Chiquet-Ehrismann R, Boulay JL (2009). Tenascin-C is a novel RBPJkappa-induced target gene for Notch signaling in gliomas. Cancer Res 69, 458-465.
Skaletsky H, et al. (2003). The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 423, 825-837.
Slack FJ, Weidhaas JB (2008). MicroRNA in cancer prognosis. N. Engl. J Med.359, 2720-2722.
Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM (2006). Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol.24, 3089-3094.
Smith JA, White EA, Sowa ME, Powell ML, Ottinger M, Harper JW, Howley PM (2010). Genome-wide siRNA screen identifies SMCX, EP400, and Brd4 as E2-dependent regulators of human papillomavirus oncogene expression. Proc. Natl. Acad. Sci. U. S. A 107, 3752-3757.
Soderholm H, Ortoft E, Johansson I, Ljungberg J, Larsson C, Axelson H, Pahlman S (1999). Human achaete-scute homologue 1 (HASH-1) is downregulated in differentiating neuroblastoma cells. Biochem. Biophys. Res. Commun. 256, 557-563.
Somasundaram K, Reddy SP, Vinnakota K, Britto R, Subbarayan M, Nambiar S, Hebbar A, Samuel C, Shetty M, Sreepathi HK, Santosh V, Hegde AS, Hegde S, Kondaiah P, Rao MR (2005). Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma. Oncogene 24, 7073-7083.
Song Y, Zhao C, Dong L, Fu M, Xue L, Huang Z, Tong T, Zhou Z, Chen A, Yang Z, Lu N, Zhan Q (2008). Overexpression of cyclin B1 in human esophageal squamous cell carcinoma cells induces tumor cell invasive growth and metastasis. Carcinogenesis 29, 307-315.
Soon PS, Gill AJ, Benn DE, Clarkson A, Robinson BG, McDonald KL, Sidhu SB (2009). Microarray gene expression and immunohistochemistry analyses of adrenocortical tumors identify IGF2 and Ki-67 as useful in differentiating carcinomas from adenomas. Endocr. Relat Cancer 16, 573-583.
Span PN, Sweep FC, Wiegerinck ET, Tjan-Heijnen VC, Manders P, Beex LV, de Kok JB (2004). Survivin is an independent prognostic marker for risk stratification of breast cancer patients. Clin Chem.50, 1986-1993.
Splinter PL, Lazaridis KN, Dawson PA, LaRusso NF (2006). Cloning and expression of SLC10A4, a putative organic anion transport protein. World J Gastroenterol. 12, 6797-6805.
Srour M, Hamdan FF, Schwartzentruber JA, Patry L, Ospina LH, Shevell MI, Desilets V, Dobrzeniecka S, Mathonnet G, Lemyre E, Massicotte C, Labuda D, Amrom D, Andermann E, Sebire G, Maranda B, Rouleau GA, Majewski J, Michaud JL (2012). Mutations in TMEM231 cause Joubert syndrome in French Canadians. J Med. Genet.49, 636-641.
Staehler M, Stenzl A, Dietrich PY, Eisen T, Haferkamp A, Beck J, Mayer A, Walter S, SinghJasuja H, Stief C (2007). A phase I study to evaluate safety, immunogenicity and anti-tumor activity of the multi-peptide vaccine IMA901 in renal cell carcinoma patients (RCC). Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I, Vol 25, No.18S (June 20 Supplement), 2007: 5098 (Abstract).
Stepulak A, Luksch H, Gebhardt C, Uckermann O, Marzahn J, Sifringer M, Rzeski W, Staufner C, Brocke KS, Turski L, Ikonomidou C (2009). Expression of glutamate receptor subunits in human cancers. Histochem. Cell Biol.132, 435-445.
Stoeckli ET, Landmesser LT (1995). Axonin-1, Nr-CAM, and Ng-CAM play different roles in the in vivo guidance of chick commissural neurons. Neuron 14, 1165-1179. Stolt CC, Lommes P, Friedrich RP, Wegner M (2004). Transcription factors Sox8 and Sox10 perform non-equivalent roles during oligodendrocyte development despite functional redundancy. Development 131, 2349-2358.
Sugito N, Ishiguro H, Kuwabara Y, Kimura M, Mitsui A, Kurehara H, Ando T, Mori R, Takashima N, Ogawa R, Fujii Y (2006). RNASEN regulates cell proliferation and affects survival in esophageal cancer patients. Clin Cancer Res.12, 7322-7328.
Sugiyama T, Sadzuka Y, Tanaka K, Sonobe T (2001). Inhibition of glutamate transporter by theanine enhances the therapeutic efficacy of doxorubicin. Toxicol. Lett.121, 89-96. Sulzbacher I, Birner P, Trieb K, Pichlbauer E, Lang S (2002). The expression of bone morphogenetic proteins in osteosarcoma and its relevance as a prognostic parameter. J Clin Pathol.55, 381-385.
Sun C, Cheng MC, Qin R, Liao DL, Chen TT, Koong FJ, Chen G, Chen CH (2011). Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia. Hum. Mol. Genet.20, 3042-3051.
Sun JC, Bevan MJ (2003). Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300, 339-342.
Sunavala-Dossabhoy G, Palaniyandi S, Clark C, Nathan CO, Abreo FW, Caldito G (2011). Analysis of eIF4E and 4EBP1 mRNAs in head and neck cancer. Laryngoscope 121, 2136-2141.
Suvasini R, Shruti B, Thota B, Shinde SV, Friedmann-Morvinski D, Nawaz Z, Prasanna KV,
Thennarasu K, Hegde AS, Arivazhagan A, Chandramouli BA, Santosh V, Somasundaram K (2011). Insulin growth factor-2 binding protein 3 (IGF2BP3) is a glioblastoma-specific marker that activates phosphatidylinositol 3-kinase/mitogen-activated protein kinase (PI3K/MAPK) pathways by modulating IGF-2. J Biol. Chem.286, 25882-25890.
Suzuki H, Gabrielson E, Chen W, Anbazhagan R, Van EM, Weijenberg MP, Herman JG, Baylin SB (2002). A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet.31, 141-149.
Suzuki N, Fukushi M, Kosaki K, Doyle AD, de VS, Yoshizaki K, Akazawa C, Arikawa-Hirasawa E, Yamada Y (2012). Teneurin-4 is a novel regulator of oligodendrocyte differentiation and myelination of small-diameter axons in the CNS. J Neurosci. 32, 11586-11599.
Suzuki T, Urano T, Miki Y, Moriya T, Akahira J, Ishida T, Horie K, Inoue S, Sasano H (2007). Nuclear cyclin B1 in human breast carcinoma as a potent prognostic factor. Cancer Sci. 98, 644651.
Svendsen A, et al. (2011). Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma. Acta Neuropathol.122, 495-510.
Tagawa H, Miura I, Suzuki R, Suzuki H, Hosokawa Y, Seto M (2002). Molecular cytogenetic analysis of the breakpoint region at 6q21-22 in T-cell lymphoma/leukemia cell lines. Genes Chromosomes. Cancer 34, 175-185.
Takebayashi H, Yoshida S, Sugimori M, Kosako H, Kominami R, Nakafuku M, Nabeshima Y (2000). Dynamic expression of basic helix-loop-helix Olig family members: implication of Olig2 in neuron and oligodendrocyte differentiation and identification of a new member, Olig3. Mech. Dev.99, 143-148.
Tan G, Sun SQ, Yuan DL (2008). Expression of Kir 4.1 in human astrocytic tumors: correlation with pathologic grade. Biochem. Biophys. Res. Commun. 367, 743-747.
Tan HY, Liu J, Wu SM, Luo HS (2005). Expression of a novel apoptosis inhibitor-survivin in colorectal carcinoma. World J Gastroenterol.11, 4689-4692.
Tatenhorst L, Senner V, Puttmann S, Paulus W (2004). Regulators of G-protein signaling 3 and 4 (RGS3, RGS4) are associated with glioma cell motility. J Neuropathol. Exp. Neurol. 63, 210-222.
Taylor TE, Furnari FB, Cavenee WK (2012). Targeting EGFR for treatment of glioblastoma: molecular basis to overcome resistance. Curr. Cancer Drug Targets.12, 197-209.
Tchernitsa O, Kasajima A, Schafer R, Kuban RJ, Ungethum U, Gyorffy B, Neumann U, Simon E, Weichert W, Ebert MP, Rocken C (2010). Systematic evaluation of the miRNA-ome and its downstream effects on mRNA expression identifies gastric cancer progression. J Pathol.222, 310-319.
Teratani T, Domoto T, Kuriki K, Kageyama T, Takayama T, Ishikawa A, Ozono S, Nozawa R (2007). Detection of transcript for brain-type fatty Acid-binding protein in tumor and urine of patients with renal cell carcinoma. Urology 69, 236-240.
Thompson DM, Gill GN (1985). The EGF receptor: structure, regulation and potential role in malignancy. Cancer Surv.4, 767-788.
Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N, Iwata KK, Gibson N, Haley JD (2005). Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res.65, 9455-9462.
Thurner B, et al. (1999). Vaccination with mage-3A1 peptide-pulsed mature, monocytederived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp. Med 190, 1669-1678.
Tina E, Lindqvist BM, Gabrielson M, Lubovac Z, Wegman P, Wingren S (2012). The mitochondrial transporter SLC25A43 is frequently deleted and may influence cell proliferation in HER2-positive breast tumors. BMC. Cancer 12, 350.
Torres A, Torres K, Paszkowski T, Jodlowska-Jedrych B, Radomanski T, Ksiazek A, Maciejewski R (2011). Major regulators of microRNAs biogenesis Dicer and Drosha are down-regulated in endometrial cancer. Tumour. Biol.32, 769-776.
Toyooka S, Fukuyama Y, Wistuba II, Tockman MS, Minna JD, Gazdar AF (2002). Differential expression of FEZ1/LZTS1 gene in lung cancers and their cell cultures. Clin Cancer Res. 8, 2292-2297.
Tsai JR, Chong IW, Chen YH, Yang MJ, Sheu CC, Chang HC, Hwang JJ, Hung JY, Lin SR (2007). Differential expression profile of MAGE family in non-small-cell lung cancer. Lung Cancer 56, 185-192.
Tsavachidou-Fenner D, Tannir N, Tamboli P, Liu W, Petillo D, Teh B, Mills GB, Jonasch E (2010). Gene and protein expression markers of response to combined antiangiogenic and epidermal growth factor targeted therapy in renal cell carcinoma. Ann Oncol 21, 1599-1606.
Tsourlakis MC, Walter E, Quaas A, Graefen M, Huland H, Simon R, Sauter G, Steurer S, Schlomm T, Minner S (2013). High Nr-CAM expression is associated with favorable phenotype and late PSA recurrence in prostate cancer treated by prostatectomy. Prostate Cancer Prostatic. Dis.
Tsuritani K, Irie T, Yamashita R, Sakakibara Y, Wakaguri H, Kanai A, Mizushima-Sugano J, Sugano S, Nakai K, Suzuki Y (2007). Distinct class of putative "non-conserved" promoters in humans: comparative studies of alternative promoters of human and mouse genes. Genome Res.17, 1005-1014.
Tucker RP, Chiquet-Ehrismann R (2006). Teneurins: a conserved family of transmembrane proteins involved in intercellular signaling during development. Dev. Biol. 290, 237-245.
Turashvili G, Bouchal J, Baumforth K, Wei W, Dziechciarkova M, Ehrmann J, Klein J, Fridman E, Skarda J, Srovnal J, Hajduch M, Murray P, Kolar Z (2007). Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. BMC. Cancer 7, 55.
Tuy FP, Saillour Y, Kappeler C, Chelly J, Francis F (2008). Alternative transcripts of Dclk1 and Dclk2 and their expression in doublecortin knockout mice. Dev. Neurosci.30, 171-186.
Uematsu M, Ohsawa I, Aokage T, Nishimaki K, Matsumoto K, Takahashi H, Asoh S, Teramoto A, Ohta S (2005). Prognostic significance of the immunohistochemical index of survivin in glioma: a comparative study with the MIB-1 index. J Neurooncol.72, 231-238. Ulbricht U, Brockmann MA, Aigner A, Eckerich C, Muller S, Fillbrandt R, Westphal M, Lamszus K (2003). Expression and function of the receptor protein tyrosine phosphatase zeta and its ligand pleiotrophin in human astrocytomas. J Neuropathol. Exp. Neurol. 62, 1265-1275.
Ulbricht U, Eckerich C, Fillbrandt R, Westphal M, Lamszus K (2006). RNA interference targeting protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta suppresses glioblastoma growth in vitro and in vivo. J Neurochem. 98, 1497-1506. Unger T, Lakowa N, Bette S, Engele J (2012). Transcriptional regulation of the GLAST/EAAT-1 gene in rat and man. Cell Mol. Neurobiol.32, 539-547.
Upton MP, Hirohashi S, Tome Y, Miyazawa N, Suemasu K, Shimosato Y (1986). Expression of vimentin in surgically resected adenocarcinomas and large cell carcinomas of lung. Am. J Surg. Pathol.10, 560-567.
Urban P, Bilecova-Rabajdova M, Stefekova Z, Ostro A, Marekova M (2011). [Overview of potential oncomarkers for detection of early stages of ovarian cancer]. Klin. Onkol.24, 106-111.
Usadel H, Brabender J, Danenberg KD, Jeronimo C, Harden S, Engles J, Danenberg PV, Yang S, Sidransky D (2002). Quantitative adenomatous polyposis coli promoter methylation analysis in tumor tissue, serum, and plasma DNA of patients with lung cancer. Cancer Res. 62, 371-375.
Utreras E, Jimenez-Mateos EM, Contreras-Vallejos E, Tortosa E, Perez M, Rojas S, Saragoni L, Maccioni RB, Avila J, Gonzalez-Billault C (2008). Microtubule-associated protein 1B interaction with tubulin tyrosine ligase contributes to the control of microtubule tyrosination. Dev. Neurosci.30, 200-210.
Vaarala MH, Porvari KS, Kyllonen AP, Mustonen MV, Lukkarinen O, Vihko PT (1998). Several genes encoding ribosomal proteins are over-expressed in prostate-cancer cell lines: confirmation of L7a and L37 over-expression in prostate-cancer tissue samples. Int. J Cancer 78, 27-32.
Valiente M, Andres-Pons A, Gomar B, Torres J, Gil A, Tapparel C, Antonarakis SE, Pulido R (2005). Binding of PTEN to specific PDZ domains contributes to PTEN protein stability and phosphorylation by microtubule-associated serine/threonine kinases. J Biol. Chem. 280, 2893628943.
van de Pavert SA, Sanz AS, Aartsen WM, Vos RM, Versteeg I, Beck SC, Klooster J, Seeliger MW, Wijnholds J (2007). Crb1 is a determinant of retinal apical Muller glia cell features. Glia 55, 1486-1497.
van AM, Schepens M, de BD, Janssen B, Merkx G, Geurts van KA (2000). Construction of a 350-kb sequence-ready 11q13 cosmid contig encompassing the markers D11S4933 and D11S546: mapping of 11 genes and 3 tumor-associated translocation breakpoints. Genomics 66, 35-42.
Van CE, Rivera F, Berry S, Kretzschmar A, Michael M, DiBartolomeo M, Mazier MA, Canon JL, Georgoulias V, Peeters M, Bridgewater J, Cunningham D (2009). Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 20, 1842-1847.
Van dA, I, et al. (2008). Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter is associated with the inflammatory breast cancer phenotype. Br. J Cancer 99, 17351742.
Varga I, Hutoczki G, Petras M, Scholtz B, Miko E, Kenyeres A, Toth J, Zahuczky G, Bognar L, Hanzely Z, Klekner A (2010). Expression of invasion-related extracellular matrix molecules in human glioblastoma versus intracerebral lung adenocarcinoma metastasis. Cent. Eur. Neurosurg. 71, 173-180.
Varga I, Hutoczki G, Szemcsak CD, Zahuczky G, Toth J, Adamecz Z, Kenyeres A, Bognar L, Hanzely Z, Klekner A (2012). Brevican, neurocan, tenascin-C and versican are mainly responsible for the invasiveness of low-grade astrocytoma. Pathol. Oncol Res. 18, 413-420.
Vasquez K, Kuizon S, Junaid M, Idrissi AE (2013). The effect of folic acid on GABA(A)-B 1 receptor subunit. Adv. Exp. Med. Biol.775, 101-109.
Vecchione A, Ishii H, Baldassarre G, Bassi P, Trapasso F, Alder H, Pagano F, Gomella LG, Croce CM, Baffa R (2002). FEZ1/LZTS1 is down-regulated in high-grade bladder cancer, and its restoration suppresses tumorigenicity in transitional cell carcinoma cells. Am. J Pathol. 160, 1345-1352.
Vecchione A, Ishii H, Shiao YH, Trapasso F, Rugge M, Tamburrino JF, Murakumo Y, Alder H, Croce CM, Baffa R (2001). Fez1/lzts1 alterations in gastric carcinoma. Clin Cancer Res. 7, 15461552.
Vignier N, Moghadaszadeh B, Gary F, Beckmann J, Mayer U, Guicheney P (1999). Structure, genetic localization, and identification of the cardiac and skeletal muscle transcripts of the human integrin alpha7 gene (ITGA7). Biochem. Biophys. Res. Commun.
260, 357-364.
Visnyei K, Onodera H, Damoiseaux R, Saigusa K, Petrosyan S, De VD, Ferrari D, Saxe J,
Panosyan EH, Masterman-Smith M, Mottahedeh J, Bradley KA, Huang J, Sabatti C, Nakano I, Kornblum HI (2011). A molecular screening approach to identify and characterize inhibitors of glioblastoma stem cells. Mol. Cancer Ther.10, 1818-1828.
Vissers JH, Nicassio F, van LM, Di Fiore PP, Citterio E (2008). The many faces of ubiquitinated histone H2A: insights from the DUBs. Cell Div.3, 8.
Volkmer H, Leuschner R, Zacharias U, Rathjen FG (1996). Neurofascin induces neurites by heterophilic interactions with axonal NrCAM while NrCAM requires F11 on the axonal surface to extend neurites. J Cell Biol.135, 1059-1069.
Voltz R, Gultekin SH, Rosenfeld MR, Gerstner E, Eichen J, Posner JB, Dalmau J (1999). A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N. Engl. J Med.340, 1788-1795.
Vranic S, Gurjeva O, Frkovic-Grazio S, Palazzo J, Tawfik O, Gatalica Z (2011). IMP3, a proposed novel basal phenotype marker, is commonly overexpressed in adenoid cystic carcinomas but not in apocrine carcinomas of the breast. Appl. Immunohistochem. Mol. Morphol. 19, 413-416.
Vulcani-Freitas TM, Saba-Silva N, Cappellano A, Cavalheiro S, Marie SK, Oba-Shinjo SM, Malheiros SM, de Toledo SR (2011). ASPM gene expression in medulloblastoma. Childs Nerv. Syst.27, 71-74.
Wachter DL, Kristiansen G, Soll C, Hellerbrand C, Breuhahn K, Fritzsche F, Agaimy A, Hartmann A, Riener MO (2012). Insulin-like growth factor II mRNA-binding protein 3 (IMP3) expression in hepatocellular carcinoma. A clinicopathological analysis with emphasis on diagnostic value. Histopathology 60, 278-286.
Wachter DL, Schlabrakowski A, Hoegel J, Kristiansen G, Hartmann A, Riener MO (2011). Diagnostic value of immunohistochemical IMP3 expression in core needle biopsies of pancreatic ductal adenocarcinoma. Am. J Surg. Pathol.35, 873-877.
Walia S, Fishman GA, Jacobson SG, Aleman TS, Koenekoop RK, Traboulsi EI, Weleber RG, Pennesi ME, Heon E, Drack A, Lam BL, Allikmets R, Stone EM (2010). Visual acuity in patients with Leber's congenital amaurosis and early childhood-onset retinitis pigmentosa. Ophthalmology 117, 1190-1198.
Wang J, Svendsen A, Kmiecik J, Immervoll H, Skaftnesmo KO, Planaguma J, Reed RK, Bjerkvig R, Miletic H, Enger PO, Rygh CB, Chekenya M (2011a). Targeting the NG2/CSPG4 proteoglycan retards tumour growth and angiogenesis in preclinical models of GBM and melanoma. PLoS. ONE.6, e23062.
Wang JC, Livingstone AM (2003). Cutting edge: CD4+ T cell help can be essential for primary CD8+ T cell responses in vivo. J Immunol.171, 6339-6343.
Wang KS, Liu X, Aragam N, Jian X, Mullersman JE, Liu Y, Pan Y (2011b). Family-based association analysis of alcohol dependence in the COGA sample and replication in the Australian twin-family study. J Neural Transm.118, 1293-1299.
Wang L, He S, Yuan J, Mao X, Cao Y, Zong J, Tu Y, Zhang Y (2012a). Oncogenic role of SOX9 expression in human malignant glioma. Med. Oncol 29, 3484-3490.
Wang L, Li HG, Xia ZS, Lu J, Peng TS (2010). IMP3 is a novel biomarker to predict metastasis and prognosis of gastric adenocarcinoma: a retrospective study. Chin Med. J (Engl. ) 123, 35543558.
Wang R, Ferrell LD, Faouzi S, Maher JJ, Bishop JM (2001). Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice. J. Cell Biol.153, 1023-1034.
Wang S, Pang T, Gao M, Kang H, Ding W, Sun X, Zhao Y, Zhu W, Tang X, Yao Y, Hu X (2013). HPV E6 induces eIF4E transcription to promote the proliferation and migration of cervical cancer. FEBS Lett.587, 690-697.
Wang X, Su H, Bradley A (2002). Molecular mechanisms governing Pcdh-gamma gene expression: evidence for a multiple promoter and cis-alternative splicing model. Genes Dev. 16, 1890-1905.
Wang XL, Cai HP, Ge JH, Su XF (2012b). Detection of eukaryotic translation initiation factor 4E and its clinical significance in hepatocellular carcinoma. World J Gastroenterol.
18, 2540-2544.
Wang XZ, Kuroda M, Sok J, Batchvarova N, Kimmel R, Chung P, Zinszner H, Ron D (1998). Identification of novel stress-induced genes downstream of chop. EMBO J 17, 3619-3630.
Wang Y, Cheong D, Chan S, Hooi SC (2000). Ribosomal protein L7a gene is upregulated but not fused to the tyrosine kinase receptor as chimeric trk oncogene in human colorectal carcinoma. Int. J Oncol 16, 757-762.
Warth A, Mittelbronn M, Wolburg H (2005). Redistribution of the water channel protein aquaporin-4 and the K+ channel protein Kir4.1 differs in low- and high-grade human brain tumors. Acta Neuropathol. (Berl) 109, 418-426.
Watabe-Uchida M, John KA, Janas JA, Newey SE, Van AL (2006). The Rac activator DOCK7 regulates neuronal polarity through local phosphorylation of stathmin/Op18. Neuron 51, 727-739.
Weake VM, Workman JL (2008). Histone ubiquitination: triggering gene activity. Mol. Cell 29, 653-663.
Wegner AM, Nebhan CA, Hu L, Majumdar D, Meier KM, Weaver AM, Webb DJ (2008). Nwasp and the arp2/3 complex are critical regulators of actin in the development of dendritic spines and synapses. J Biol. Chem.283, 15912-15920.
Weiskirchen R, Erdel M, Utermann G, Bister K (1997). Cloning, structural analysis, and chromosomal localization of the human CSRP2 gene encoding the LIM domain protein CRP2. Genomics 44, 83-93.
Wellstein A (2012). ALK receptor activation, ligands and therapeutic targeting in glioblastoma and in other cancers. Front Oncol 2, 192.
Werner H, Dimou L, Klugmann M, Pfeiffer S, Nave KA (2001). Multiple splice isoforms of proteolipid M6B in neurons and oligodendrocytes. Mol. Cell Neurosci.18, 593-605. Wheater MJ, Johnson PW, Blaydes JP (2010). The role of MNK proteins and eIF4E phosphorylation in breast cancer cell proliferation and survival. Cancer Biol. Ther. 10, 728-735.
White MF (2002). IRS proteins and the common path to diabetes. Am. J Physiol Endocrinol. Metab 283, E413-E422.
Wiame E, Tyteca D, Pierrot N, Collard F, Amyere M, Noel G, Desmedt J, Nassogne MC, Vikkula M, Octave JN, Vincent MF, Courtoy PJ, Boltshauser E, van SE (2010). Molecular identification of aspartate N-acetyltransferase and its mutation in hypoacetylaspartia. Biochem. J 425, 127-136.
Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sultmann H, Poustka A (2004). From ORFeome to biology: a functional genomics pipeline. Genome Res.14, 2136-2144.
Wikman H, Kettunen E, Seppanen JK, Karjalainen A, Hollmen J, Anttila S, Knuutila S (2002). Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array. Oncogene 21, 5804-5813.
Williams AA, Higgins JP, Zhao H, Ljunberg B, Brooks JD (2009). CD 9 and vimentin distinguish clear cell from chromophobe renal cell carcinoma. BMC. Clin Pathol.9, 9. Williamson SM, Silva DA, Richey E, Qin H (2012). Probing the role of IFT particle complex A and B in flagellar entry and exit of IFT-dynein in Chlamydomonas. Protoplasma 249, 851-856.
Willoughby V, Sonawala A, Werlang-Perurena A, Donner LR (2008). A comparative immunohistochemical analysis of small round cell tumors of childhood: utility of peripherin and alpha-internexin as markers for neuroblastomas. Appl. Immunohistochem. Mol. Morphol.16, 344-348.
Wiltshire TD, Lovejoy CA, Wang T, Xia F, O'Connor MJ, Cortez D (2010). Sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition identifies ubiquitin-specific peptidase 11 (USP11) as a regulator of DNA double-strand break repair. J Biol. Chem. 285, 14565-14571.
Winkler GS, Mulder KW, Bardwell VJ, Kalkhoven E, Timmers HT (2006). Human Ccr4-Not complex is a ligand-dependent repressor of nuclear receptor-mediated transcription. EMBO J 25, 3089-3099.
Wolfgang MJ, Kurama T, Dai Y, Suwa A, Asaumi M, Matsumoto S, Cha SH, Shimokawa T, Lane MD (2006). The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis. Proc. Natl. Acad. Sci. U. S. A 103, 7282-7287.
Wood JD, Yuan J, Margolis RL, Colomer V, Duan K, Kushi J, Kaminsky Z, Kleiderlein JJ, Sharp AH, Ross CA (1998). Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins. Mol. Cell Neurosci. 11, 149-160.
Wool IG (1996). Extraribosomal functions of ribosomal proteins. Trends Biochem. Sci.
21, 164165.
Wu A, Wu B, Guo J, Luo W, Wu D, Yang H, Zhen Y, Yu X, Wang H, Zhou Y, Liu Z, Fang W, Yang Z (2011). Elevated expression of CDK4 in lung cancer. J Transl. Med. 9, 38.
Wu H, Xu H, Miraglia LJ, Crooke ST (2000). Human RNase III is a 160-kDa protein involved in preribosomal RNA processing. J Biol. Chem.275, 36957-36965.
Wu M, Liu Y, Di X, Kang H, Zeng H, Zhao Y, Cai K, Pang T, Wang S, Yao Y, Hu X (2013). EIF4E over-expresses and enhances cell proliferation and cell cycle progression in nasopharyngeal carcinoma. Med. Oncol 30, 400.
Xiao L, Rao JN, Zou T, Liu L, Marasa BS, Chen J, Turner DJ, Passaniti A, Wang JY (2007). Induced JunD in intestinal epithelial cells represses CDK4 transcription through its proximal promoter region following polyamine depletion. Biochem. J 403, 573-581. Xie D, Zeng YX, Wang HJ, Wen JM, Tao Y, Sham JS, Guan XY (2006). Expression of cytoplasmic and nuclear Survivin in primary and secondary human glioblastoma. Br. J Cancer 94, 108-114.
Xin WJ, Weng HR, Dougherty PM (2009). Plasticity in expression of the glutamate transporters GLT-1 and GLAST in spinal dorsal horn glial cells following partial sciatic nerve ligation. Mol. Pain 5, 15.
Xu C, Mullersman JE, Wang L, Bin SB, Mao C, Posada Y, Camarillo C, Mao Y, Escamilla MA, Wang KS (2013). Polymorphisms in seizure 6-like gene are associated with bipolar disorder I: evidence of gene x gender interaction. J Affect. Disord.145, 95-99.
Yamada A, Irie K, Deguchi-Tawarada M, Ohtsuka T, Takai Y (2003). Nectin-dependent localization of synaptic scaffolding molecule (S-SCAM) at the puncta adherentia junctions formed between the mossy fibre terminals and the dendrites of pyramidal cells in the CA3 area of the mouse hippocampus. Genes Cells 8, 985-994.
Yamamoto K, Murata H, Putranto EW, Kataoka K, Motoyama A, Hibino T, Inoue Y, Sakaguchi M, Huh NH (2013). DOCK7 is a critical regulator of the RAGE-Cdc42 signaling axis that induces formation of dendritic pseudopodia in human cancer cells. Oncol Rep.29, 1073-1079.
Yamamoto Y, Izumi K, Otsuka H (1992). An immunohistochemical study of epithelial membrane antigen, cytokeratin, and vimentin in papillary thyroid carcinoma. Recognition of lethal and favorable prognostic types. Cancer 70, 2326-2333.
Yamashita S, Masuda Y, Kurizaki T, Haga Y, Murayama T, Ikei S, Kamei M, Takeno S, Kawahara K (2007). Survivin expression predicts early recurrence in early-stage breast cancer. Anticancer Res.27, 2803-2808.
Yamauchi J, Miyamoto Y, Chan JR, Tanoue A (2008). ErbB2 directly activates the exchange factor Dock7 to promote Schwann cell migration. J Cell Biol.181, 351-365.
Yan J, Feng J, Schroer R, Li W, Skinner C, Schwartz CE, Cook EH, Jr., Sommer SS (2008). Analysis of the neuroligin 4Y gene in patients with autism. Psychiatr. Genet.18, 204-207.
Yan Y, Lagenaur C, Narayanan V (1993). Molecular cloning of M6: identification of a PLP/DM20 gene family. Neuron 11, 423-431.
Yang GF, Li XM, Xie D (2009). Overexpression of clusterin in ovarian cancer is correlated with impaired survival. Int. J Gynecol. Cancer 19, 1342-1346.
Yang H, Li LW, Shi M, Wang JH, Xiao F, Zhou B, Diao LQ, Long XL, Liu XL, Xu L (2012a). In vivo study of breast carcinoma radiosensitization by targeting eIF4E. Biochem. Biophys. Res. Commun. 423, 878-883.
Yang HY, Lieska N, Shao D, Kriho V, Pappas GD (1994). Proteins of the intermediate filament cytoskeleton as markers for astrocytes and human astrocytomas. Mol. Chem. Neuropathol. 21, 155-176.
Yang HY, Xue LY, Xing LX, Wang J, Wang JL, Yan X, Zhang XH (2013). Putative role of the mTOR/4E-BP1 signaling pathway in the carcinogenesis and progression of gastric cardiac adenocarcinoma. Mol. Med. Rep.7, 537-542.
Yang Y, Wang F, Shi C, Zou Y, Qin H, Ma Y (2012b). Cyclin D1 G870A Polymorphism Contributes to Colorectal Cancer Susceptibility: Evidence from a Systematic Review of 22 CaseControl Studies. PLoS. ONE.7, e36813.
Yantiss RK, Cosar E, Fischer AH (2008). Use of IMP3 in identification of carcinoma in fine needle aspiration biopsies of pancreas. Acta Cytol.52, 133-138.
Yasukawa M, Ishida K, Yuge Y, Hanaoka M, Minami Y, Ogawa M, Sasaki T, Saito M, Tsuji T (2013). Dpysl4 is involved in tooth germ morphogenesis through growth regulation, polarization and differentiation of dental epithelial cells. Int. J Biol. Sci.9, 382-390.
Yau C, Esserman L, Moore DH, Waldman F, Sninsky J, Benz CC (2010). A multigene predictor of metastatic outcome in early stage hormone receptor-negative and triplenegative breast cancer. Breast Cancer Res 12, R85.
Yeh IT, Lenci RE, Qin Y, Buddavarapu K, Ligon AH, Leteurtre E, Do CC, Cardot-Bauters C, Pigny P, Dahia PL (2008). A germline mutation of the KIF1B beta gene on 1p36 in a family with neural and nonneural tumors. Hum. Genet. 124, 279-285.
Yi HJ, Zhang BQ, Guo W, Zhao LD, Yang SM (2012). The role of molecular margins as prognostic factors in laryngeal carcinoma in Chinese patients. Acta Otolaryngol.132, 874-878.
Ylisaukko-oja T, Rehnstrom K, Auranen M, Vanhala R, Alen R, Kempas E, Ellonen P, Turunen JA, Makkonen I, Riikonen R, Nieminen-von WT, von WL, Peltonen L, Jarvela I (2005). Analysis of four neuroligin genes as candidates for autism. Eur. J Hum. Genet.13, 1285-1292.
Yokoi K, Thaker PH, Yazici S, Rebhun RR, Nam DH, He J, Kim SJ, Abbruzzese JL, Hamilton SR, Fidler IJ (2005). Dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation by AEE788 reduces growth and metastasis of human colon carcinoma in an orthotopic nude mouse model. Cancer Res. 65, 3716-3725.
Yokota S, Yanagi H, Yura T, Kubota H (2001). Cytosolic chaperonin-containing tcomplex polypeptide 1 changes the content of a particular subunit species concomitant with substrate binding and folding activities during the cell cycle. Eur. J Biochem. 268, 4664-4673.
Yoon H, Liyanarachchi S, Wright FA, Davuluri R, Lockman JC, de la CA, Pellegata NS (2002). Gene expression profiling of isogenic cells with different TP53 gene dosage reveals numerous genes that are affected by TP53 dosage and identifies CSPG2 as a direct target of p53. Proc Natl. Acad. Sci. U. S. A 99, 15632-15637.
Yue Y, Stout K, Grossmann B, Zechner U, Brinckmann A, White C, Pilz DT, Haaf T (2006). Disruption of TCBA1 associated with a de novo t(1;6)(q32.2;q22.3) presenting in a child with developmental delay and recurrent infections. J Med. Genet.43, 143-147.
yuso-Sacido A, Graham C, Greenfield JP, Boockvar JA (2006). The duality of epidermal growth factor receptor (EGFR) signaling and neural stem cell phenotype: cell enhancer or cell transformer? Curr. Stem Cell Res. Ther. 1, 387-394.
Zacharias U, Norenberg U, Rathjen FG (1999). Functional interactions of the immunoglobulin superfamily member F11 are differentially regulated by the extracellular matrix proteins tenascinR and tenascin-C. J Biol. Chem.274, 24357-24365.
Zadravec D, Tvrdik P, Guillou H, Haslam R, Kobayashi T, Napier JA, Capecchi MR, Jacobsson A (2011). ELOVL2 controls the level of n-6 28:5 and 30:5 fatty acids in testis, a prerequisite for male fertility and sperm maturation in mice. J Lipid Res. 52, 245-255.
Zangen I, Kneitz S, Monoranu CM, Rutkowski S, Hinkes B, Vince GH, Huang B, Roggendorf W (2007). Ependymoma gene expression profiles associated with histological subtype, proliferation, and patient survival. Acta Neuropathol.113, 325-337.
Zaremba S, Barzaga E, Zhu M, Soares N, Tsang KY, Schlom J (1997). Identification of an enhancer agonist cytotoxic T lymphocyte peptide from human carcinoembryonic antigen. Cancer Res.57, 4570-4577.
Zekri AR, Hassan ZK, Bahnassy AA, Sherif GM, ELdahshan D, Abouelhoda M, Ali A, Hafez MM (2012). Molecular prognostic profile of Egyptian HCC cases infected with hepatitis C virus. Asian Pac. J Cancer Prev.13, 5433-5438.
Zelano J, Mikulovic S, Patra K, Kuhnemund M, Larhammar M, Emilsson L, Leao R, Kullander K (2013). The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants. Exp. Neurol. 239, 73-81.
Zhai L, Mu J, Zong H, DePaoli-Roach AA, Roach PJ (2000). Structure and chromosomal localization of the human glycogenin-2 gene GYG2. Gene 242, 229-235.
Zhang H, Baader SL, Sixt M, Kappler J, Rauch U (2004). Neurocan-GFP fusion protein: a new approach to detect hyaluronan on tissue sections and living cells. J Histochem. Cytochem. 52, 915-922.
Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH, Wang XZ, Zhao YW, Wei YQ (2012). Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS. ONE.7, e50946.
Zhao C, Ma H, Bu X, Wang W, Zhang N (2012a). SFRP5 inhibits gastric epithelial cell migration induced by macrophage-derived Wnt5a. Carcinogenesis.
Zhao J, He H, Zhou K, Ren Y, Shi Z, Wu Z, Wang Y, Lu Y, Jiao J (2012b). Neuronal transcription factors induce conversion of human glioma cells to neurons and inhibit tumorigenesis. PLoS. ONE.7, e41506.
Zhao M, Kim YT, Yoon BS, Kim SW, Kang MH, Kim SH, Kim JH, Kim JW, Park YW (2006). Expression profiling of cyclin B1 and D1 in cervical carcinoma. Exp. Oncol 28, 44-48.
Zhao W, Yue L, Zhou F, Xu C, Liang W, Sui A, Ding A, Qiu W (2013). Clinical significance of vimentin expression and Her-2 status in patients with gastric carcinoma. Clin Transl. Sci.6, 184190.
Zhen HN, Zhang X, Hu PZ, Yang TT, Fei Z, Zhang JN, Fu LA, He XS, Ma FC, Wang XL (2005). Survivin expression and its relation with proliferation, apoptosis, and angiogenesis in brain gliomas. Cancer 104, 2775-2783.
Zheng D, Gu S, Li Y, Ji C, Xie Y, Mao Y (2011). A global genomic view on LNX siRNAmediated cell cycle arrest. Mol. Biol. Rep.38, 2771-2783.
Zheng D, Niu S, Yu D, Zhan XH, Zeng X, Cui B, Chen Y, Yoon J, Martin SS, Lu X, Zhan X
(2010). Abba promotes PDGF-mediated membrane ruffling through activation of the small GTPase Rac1. Biochem. Biophys. Res. Commun.401, 527-532.
Zheng PS, Wen J, Ang LC, Sheng W, Viloria-Petit A, Wang Y, Wu Y, Kerbel RS, Yang BB (2004). Versican/PG-M G3 domain promotes tumor growth and angiogenesis. FASEB J 18, 754756.
Zheng SE, Yao Y, Dong Y, Lin F, Zhao H, Shen Z, Sun YJ, Tang LN (2009). Downregulation of ribosomal protein L7A in human osteosarcoma. J Cancer Res. Clin Oncol 135, 1025-1031.
Zhou D, Yang L, Zheng L, Ge W, Li D, Zhang Y, Hu X, Gao Z, Xu J, Huang Y, Hu H, Zhang H, Zhang H, Liu M, Yang H, Zheng L, Zheng S (2013). Exome capture sequencing of adenoma reveals genetic alterations in multiple cellular pathways at the early stage of colorectal tumorigenesis. PLoS. ONE.8, e53310.
Zhou L, Picard D, Ra YS, Li M, Northcott PA, Hu Y, Stearns D, Hawkins C, Taylor MD, Rutka J, Der SD, Huang A (2010). Silencing of thrombospondin-1 is critical for mycinduced metastatic phenotypes in medulloblastoma. Cancer Res.70, 8199-8210.
Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC, Osawa M, Nakauchi H, Sorrentino BP (2001). The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat. Med 7, 1028-1034.
Zhu ZH, Yu YP, Shi YK, Nelson JB, Luo JH (2009). CSR1 induces cell death through inactivation of CPSF3. Oncogene 28, 41-51.
Zimmermann DR, Dours-Zimmermann MT, Schubert M, Bruckner-Tuderman L, Heitz PU (1994). [Expression of the extracellular matrix proteoglycan, versican, in human skin]. Verh. Dtsch. Ges. Pathol.78, 481-484.
Zimmermann G, Moghaddam A, Wagner C, Vock B, Wentzensen A (2006). [Clinical experience with bone morphogenetic protein 7 (BMP 7) in nonunions of long bones]. Unfallchirurg 109, 528-537.
Zindy P, Berge Y, Allal B, Filleron T, Pierredon S, Cammas A, Beck S, Mhamdi L, Fan L, Favre G, Delord JP, Roche H, Dalenc F, Lacroix-Triki M, Vagner S (2011). Formation of the eIF4F translation-initiation complex determines sensitivity to anticancer drugs targeting the EGFR and HER2 receptors. Cancer Res.71, 4068-4073.
Zody MC, et al. (2006). DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage. Nature 440, 1045-1049.
Zou JX, Revenko AS, Li LB, Gemo AT, Chen HW (2007). ANCCA, an estrogen-regulated AAA+ ATPase coactivator for ERalpha, is required for coregulator occupancy and chromatin modification. Proc Natl. Acad. Sci. U. S. A 104, 18067-18072.
Zuo L, Wang K, Zhang XY, Krystal JH, Li CS, Zhang F, Zhang H, Luo X (2013). NKAIN1SERINC2 is a functional, replicable and genome-wide significant risk gene region specific for alcohol dependence in subjects of European descent. Drug Alcohol Depend. 129, 254-264.
Zuo X, Zhang J, Zhang Y, Hsu SC, Zhou D, Guo W (2006). Exo70 interacts with the Arp2/3 complex and regulates cell migration. Nat Cell Biol.8, 1383-1388.
Seibold P, Hein R, Schmezer P, Hall P, Liu J, Dahmen N, Flesch-Janys D, Popanda O, ChangClaude J (2011). Polymorphisms in oxidative stress-related genes and postmenopausal breast cancer risk. Int. J Cancer 129, 1467-1476.
Song JS, Cho HH, Lee BJ, Bae YC, Jung JS (2011). Role of thioredoxin 1 and thioredoxin 2 on proliferation of human adipose tissue-derived mesenchymal stem cells. Stem Cells Dev. 20, 15291537.144 -Tanaka T, Hosoi F, Yamaguchi-Iwai Y, Nakamura H, Masutani H, Ueda S, Nishiyama A, Takeda S, Wada H, Spyrou G, Yodoi J (2002). Thioredoxin-2 (TRX-2) is an essential gene regulating mitochondria-dependent apoptosis. EMBO J 21, 1695-1703.

Claims (1)

  1. PATENTNI ZAHTEVI
    1. Peptid koji sadrži ID BR. SEKV 28, ili njegovu farmaceutski prihvatljivu so.
    2. In vitro metod za proizvodnju aktiviranih citotoksičnih T limfocita (CTL), pri čemu se metod sastoji od dovođenja u kontakt in vitro CTL sa humanim MHC molekulima klase I sa ubačenim antigenom eksprimiranim na površini prikladne antigen-prezentujuće ćelije ili veštačkog konstrukta koji imitira antigen-prezentujuću ćeliju u toku vremenskog perioda koji je dovoljan da se navedeni CTL aktiviraju na antigen-specifičan način, naznačeno time što je navedeni antigen peptid u skladu sa patentnim zahtevom 1.
    3. Aktivirani citotoksični T limfocit (CTL), proizveden metodom u skladu sa patentnim zahtevom 3, koji selektivno prepoznaje ćeliju koja aberantno eksprimira polipeptid koji sadrži aminokiselinsku sekvencu navedenu u patentnom zahtevu 1.
    5 Antitelo koje specifično prepoznaje peptid u skladu sa patentnim zahtevima 1 ili 2, ili navedeni peptid kada je vezan sa MHC molekulom.
    6 T-ćelijski receptor koji je reaktivan sa HLA ligandom koji sadrži aminokiselinsku sekvencu ID BR. SEKV 28.
    7. Nukleinska kiselina koja kodira peptid u skladu sa bilo kojim od patentnih zahteva 1 ili 2, aktivirani citotoksični T limfocit u skladu sa patentnim zahtevom 4, antitelo u skladu sa patentnim zahtevom 5, ili T-ćelijski receptor u skladu sa patentnim zahtevom 6, opciono vezana sa heterolognom promoterskom sekvencom, ili vektor ekspresije koji eksprimira navedenu nukleinsku kiselinu.
    8 Ćelija domaćin koja sadrži nukleinsku kiselinu ili vektor ekspresije u skladu sa patentnim zahtevom 7.
    9 Ćelija domaćin u skladu sa patentnim zahtevom 8, naznačeno time što je navedena ćelija domaćin antigen-prezentujuća ćelija ili dendritična ćelija.
    10 Peptid u skladu sa bilo kojim od patentnih zahteva od 1 ili 2, aktivirani citotoksi čni T limfocit u skladu sa patentnim zahtevom 4, antitelo u skladu sa patentnim zahtevom 5, T-ćelijski receptor u skladu sa patentnim zahtevom 6, nukleinska kiselina ili vektor ekspresije u skladu sa patentnim zahtevom 7, ili ćelija u skladu sa patentnim zahtevom 8 ili 9, za upotrebu u lečenju bolesti.
    11 Peptid, aktivirani citotoksični T limfocit, antitelo, T-ćelijski receptor, nukleinska kiselina ili vektor ekspresije, ili ćelija za upotrebu u skladu sa patentnim zahtevom 10, naznačeno time što je navedena bolest maligna bolest, poželjno u obliku farmaceutske smeše, npr. vakcine.
    12 Farmaceutska smeša za upotrebu u skladu sa patentnim zahtevom 11, naznačeno time što je navedeni maligni tumor odabran iz sledeće grupe: astrocitom, pilocitni astrocitom, disembrioplastični neuroepitelijalni tumor, oligodendrogliomi, ependimom, glioblastoma multiforme, mešoviti gliomi, oligoastrocitomi, meduloblastom, retinoblastom, neuroblastom, germinom, teratom, gangliogliomi, gangliocitom, centralni gangliocitom, primitivni neuroektodermalni tumori (PNET, npr. meduloblastom, meduloepiteliom, neuroblastom, retinoblastom, ependimoblastom), tumori parenhima epifize (npr. pineocitom, pineoblastom), tumori ependimalnih ćelija, tumori horoidnog pleksusa, neuroepitelijalni tumori nejasnog porekla (npr. gliomatoza mozga, astroblastom), glioblastom, tumor prostate, karcinom dojke, karcinom jednjaka, kolorektalni karcinom, svetloćelijski karcinom bubrežnih ćelija, karcinom pluća, CNS-a, jajnika, melanom, karcinom pankreasa, skvamocelularni karcinom, leukemija, meduloblastom, karcinom kolona, rektuma, želuca, bubrega, pluća, pankreasa, prostate i kože.
    13 Komplet koji se sastoji od:
    (a) posude koja sadrži farmaceutsku smešu koja sadrži peptid u skladu sa bilo kojim od patentnih zahteva od 1 ili 2, aktivirani citotoksični T limfocit u skladu sa patentnim zahtevom 4, antitelo u skladu sa patentnim zahtevom 5, T-ćelijski receptor u skladu sa patentnim zahtevom 6, nukleinsku kiselinu ili vektor ekspresije u skladu sa patentnim zahtevom 7, ili ćeliju u skladu sa patentnim zahtevom 8 ili 9, u rastvoru ili liofiliziranom obliku,
    (b) druge posude koja sadrži rastvarač ili rastvor za rekonstituciju za liofiliziranu formulaciju;
    i
    (c) opciono, uputstva za (i) upotrebu rastvora ili (ii) rekonstituciju i/ili upotrebu liofilizirane formulacije.
    14 Komplet u skladu sa patentnim zahtevom 13, dalje se sastoji od:
    (d) najmanje jednog ili više peptida izabranih iz grupe koju čine ID BR. SEKV 1 do ID BR.
    SEKV 27, i ID BR. SEKV 29 do ID BR. SEKV 131.
RS20190775A 2013-11-04 2014-11-03 Personalizovana imunoterapija protiv nekoliko tumora nervnih ćelija i mozga RS59031B1 (sr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201361899680P 2013-11-04 2013-11-04
GBGB1319446.9A GB201319446D0 (en) 2013-11-04 2013-11-04 Personalized immunotherapy against several neuronal and brain tumors
PCT/EP2014/073588 WO2015063302A2 (en) 2013-11-04 2014-11-03 Personalized immunotherapy against several neuronal and brain tumors
EP14792834.5A EP3066115B1 (en) 2013-11-04 2014-11-03 Personalized immunotherapy against several neuronal and brain tumors

Publications (1)

Publication Number Publication Date
RS59031B1 true RS59031B1 (sr) 2019-08-30

Family

ID=49767624

Family Applications (1)

Application Number Title Priority Date Filing Date
RS20190775A RS59031B1 (sr) 2013-11-04 2014-11-03 Personalizovana imunoterapija protiv nekoliko tumora nervnih ćelija i mozga

Country Status (27)

Country Link
US (9) US10946064B2 (sr)
EP (3) EP4253401A3 (sr)
JP (2) JP6632982B2 (sr)
KR (3) KR102414447B1 (sr)
CN (3) CN111303244B (sr)
AU (3) AU2014343599B2 (sr)
BR (1) BR112016009402A2 (sr)
CA (1) CA2929445A1 (sr)
CU (1) CU20160060A7 (sr)
CY (1) CY1121691T1 (sr)
DK (1) DK3066115T3 (sr)
EA (1) EA036517B1 (sr)
ES (1) ES2733517T3 (sr)
GB (1) GB201319446D0 (sr)
HR (1) HRP20191009T1 (sr)
HU (1) HUE045038T2 (sr)
LT (1) LT3066115T (sr)
ME (1) ME03458B (sr)
MX (1) MX379423B (sr)
PL (1) PL3066115T3 (sr)
PT (1) PT3066115T (sr)
RS (1) RS59031B1 (sr)
SG (2) SG10201900727QA (sr)
SI (1) SI3066115T1 (sr)
TR (1) TR201909021T4 (sr)
UA (1) UA124048C2 (sr)
WO (1) WO2015063302A2 (sr)

Families Citing this family (89)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10704021B2 (en) 2012-03-15 2020-07-07 Flodesign Sonics, Inc. Acoustic perfusion devices
TWI714869B (zh) * 2013-08-05 2021-01-01 德商伊瑪提克斯生物科技有限公司 新穎肽類，細胞及其用於治療多種腫瘤的用途，其製造方法及包含其等之醫藥組成物
MX2019013161A (es) * 2013-11-04 2020-02-03 Immatics Biotechnologies Gmbh Inmunoterapia personalizada contra diversos tumores cerebrales y neuronales.
US9725710B2 (en) 2014-01-08 2017-08-08 Flodesign Sonics, Inc. Acoustophoresis device with dual acoustophoretic chamber
US10000533B2 (en) * 2014-06-20 2018-06-19 Immatics Biotechnologies Gmbh Immunotherapy against several tumors of the blood, in particular chronic lymphoid leukemia (CLL)
HUE052106T2 (hu) * 2015-04-27 2021-04-28 Cancer Research Tech Ltd Eljárás rák kezelésére
US11708572B2 (en) 2015-04-29 2023-07-25 Flodesign Sonics, Inc. Acoustic cell separation techniques and processes
US11377651B2 (en) 2016-10-19 2022-07-05 Flodesign Sonics, Inc. Cell therapy processes utilizing acoustophoresis
GB201507719D0 (en) 2015-05-06 2015-06-17 Immatics Biotechnologies Gmbh Novel peptides and combination of peptides and scaffolds thereof for use in immunotherapy against colorectal carcinoma (CRC) and other cancers
PH12021550910A1 (en) 2015-05-06 2022-03-07 Immatics Biotechnologies Gmbh Novel peptides and combination of peptides and scaffolds thereof for use in immunotherapy against colorectal carcinoma (crc) and other cancers
JP2018518956A (ja) * 2015-06-19 2018-07-19 イマティクス バイオテクノロジーズ ゲーエムベーハー 免疫療法で使用するための新規ペプチドおよびペプチド組み合わせおよび膵臓がんおよびその他のがんに対して使用するためにスキャフォールドを作製する方法
MA51531A (fr) * 2015-07-06 2020-11-11 Immatics Biotechnologies Gmbh Nouveaux peptides et nouvelle combinaison de peptides à utiliser dans l'immunothérapie du cancer de l' oesophage et d'autres cancers
MY189596A (en) * 2015-07-15 2022-02-18 Immatics Biotechnologies Gmbh A novel peptides for use in immunotherapy against epithelial ovarian cancer and other cancers
CN105092859B (zh) * 2015-08-04 2016-09-14 中国农业大学 Net49蛋白作为糖尿病生物标记物及治疗靶点的应用
GB201513921D0 (en) 2015-08-05 2015-09-23 Immatics Biotechnologies Gmbh Novel peptides and combination of peptides for use in immunotherapy against prostate cancer and other cancers
GB201516047D0 (en) 2015-09-10 2015-10-28 Cancer Rec Tech Ltd Method
HK1258386A1 (zh) 2015-10-05 2019-11-08 Immatics Biotechnologies Gmbh 用於小细胞肺癌和其他癌症免疫治疗的肽和肽组合物
GB201520550D0 (en) 2015-11-23 2016-01-06 Immunocore Ltd & Adaptimmune Ltd Peptides
GB201520568D0 (en) 2015-11-23 2016-01-06 Immunocore Ltd Peptides
GB201520567D0 (en) * 2015-11-23 2016-01-06 Immunocore Ltd & Adaptimmune Ltd Peptides
WO2017095632A1 (en) 2015-11-30 2017-06-08 Mayo Foundation For Medical Education And Research Heatr1 as a marker for chemoresistance
GB201521746D0 (en) 2015-12-10 2016-01-27 Immatics Biotechnologies Gmbh Novel peptides and combination of peptides for use in immunotherapy against CLL and other cancers
US10383896B2 (en) 2015-12-11 2019-08-20 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against various cancers
GB201521894D0 (en) 2015-12-11 2016-01-27 Immatics Biotechnologies Gmbh Novel peptides and combination of peptides for use in immunotherapy against various cancers
HK1255541A1 (zh) 2015-12-11 2019-08-23 Immatics Biotechnologies Gmbh 用於多种癌症免疫治疗的新型肽和肽组合物
US20170199961A1 (en) 2015-12-16 2017-07-13 Gritstone Oncology, Inc. Neoantigen Identification, Manufacture, and Use
GB201522667D0 (en) * 2015-12-22 2016-02-03 Immatics Biotechnologies Gmbh Novel peptides and combination of peptides for use in immunotherapy against breast cancer and other cancers
SG10202111399YA (en) 2015-12-22 2021-11-29 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against breast cancer and other cancers
GB201603568D0 (en) * 2016-03-01 2016-04-13 Immatics Biotechnologies Gmbh Efficient treatment options including peptides and combination of peptide and cell based medicaments for use in immunotherapy against urinary bladder cancer
GB201603987D0 (en) 2016-03-08 2016-04-20 Immatics Biotechnologies Gmbh Uterine cancer treatments
DK3430037T3 (da) 2016-03-16 2022-11-21 Immatics Biotechnologies Gmbh Transficerede t-celler og t-cellereceptorer til anvendelse i immunterapi mod cancere
GB201604458D0 (en) * 2016-03-16 2016-04-27 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against cancers
GB201604490D0 (en) * 2016-03-16 2016-04-27 Immatics Biotechnologies Gmbh Peptides combination of peptides for use in immunotherapy against cancers
GB201604494D0 (en) * 2016-03-16 2016-04-27 Immatics Biotechnologies Gmbh Transfected T-Cells and T-Cell receptors for use in immunotherapy against cancers
US11214789B2 (en) 2016-05-03 2022-01-04 Flodesign Sonics, Inc. Concentration and washing of particles with acoustics
WO2017194170A1 (en) 2016-05-13 2017-11-16 Biontech Rna Pharmaceuticals Gmbh Methods for predicting the usefulness of proteins or protein fragments for immunotherapy
JP7075125B2 (ja) 2016-05-25 2022-05-25 イマティクス バイオテクノロジーズ ゲーエムベーハー 標的としてのおよび胆嚢がんおよび胆管がんおよびその他のがんに対する免疫療法で使用するための新規ペプチド、ペプチド組み合わせ
GB201609193D0 (en) * 2016-05-25 2016-07-06 Immatics Biotechnologies Gmbh Novel peptides, combination of peptides as targets for use in immunotherapy against gallbladder cancer and cholangiocarcinoma and other cancers
TW202304970A (zh) * 2016-08-26 2023-02-01 德商英麥提克生物技術股份有限公司 用於頭頸鱗狀細胞癌和其他癌症免疫治療的新型肽和支架
MX2019006010A (es) * 2016-11-23 2019-12-05 Gritstone Oncology Inc Administracion viral de neoantigenos.
DE102016123893A1 (de) 2016-12-08 2018-06-14 Immatics Biotechnologies Gmbh T-Zellrezeptoren mit verbesserter Bindung
KR102379955B1 (ko) 2016-12-08 2022-03-29 이매틱스 바이오테크놀로지스 게엠베하 짝짓기가 향상된 t 세포 수용체
WO2018138257A1 (en) * 2017-01-27 2018-08-02 Immatics Biotechnologies Gmbh Novel peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancers
EA201991444A1 (ru) 2017-01-27 2019-12-30 Имматикс Байотекнолоджиз Гмбх Новые пептиды и комбинации пептидов для применения в иммунотерапии рака яичника и других видов рака
ES2946584T3 (es) 2017-01-27 2023-07-21 Immatics Biotechnologies Gmbh Nuevos péptidos y nuevas combinaciones de péptidos para el uso en la inmunoterapia contra el cáncer de ovario y otros tipos de cáncer
WO2018144775A1 (en) 2017-02-01 2018-08-09 Modernatx, Inc. Immunomodulatory therapeutic mrna compositions encoding activating oncogene mutation peptides
CR20190509A (es) 2017-04-10 2020-01-08 Immatics Biotechnologies Gmbh Péptidos y combinaciones de péptidos para el uso en la inmunoterapia contra la leucemia y otros tipos de cáncer
TW201841934A (zh) 2017-04-10 2018-12-01 德商英麥提克生物技術股份有限公司 用於治療癌症免疫治療的新穎肽及其肽組合物
AU2018251839B2 (en) 2017-04-10 2022-06-30 Immatics Biotechnologies Gmbh Peptides and combination thereof for use in the immunotherapy against cancers
EA201992416A1 (ru) 2017-04-10 2020-02-25 Имматикс Байотекнолоджиз Гмбх Пептиды и комбинации пептидов для применения в иммунотерапии лейкозов и других видов рака
MX2019013259A (es) 2017-05-08 2020-01-13 Gritstone Oncology Inc Vectores de neoantigeno de alfavirus.
JPWO2018212237A1 (ja) * 2017-05-16 2020-03-19 伊東　恭悟 テーラーメイド型ペプチドワクチン剤に対する脳腫瘍患者の適格性を判定する方法
EP4316597A3 (en) 2017-07-07 2024-11-06 immatics biotechnologies GmbH Novel peptides and combination of peptides for use in immunotherapy against lung cancer, including nsclc, sclc and other cancers
US10800823B2 (en) 2017-07-07 2020-10-13 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against lung cancer, including NSCLC, SCLC and other cancers
ES3029080T3 (en) 2017-10-10 2025-06-23 Seattle Project Corp Neoantigen identification using hotspots
US11885815B2 (en) 2017-11-22 2024-01-30 Gritstone Bio, Inc. Reducing junction epitope presentation for neoantigens
JP2021507561A (ja) 2017-12-14 2021-02-22 フロデザイン ソニックス， インク．Ｆｌｏｄｅｓｉｇｎ Ｓｏｎｉｃｓ， Ｉｎｃ． 音響トランスデューサドライバ及びコントローラ
EP4495597A3 (en) 2018-01-04 2025-04-30 Iconic Therapeutics LLC Anti-tissue factor antibodies, antibody-drug conjugates, and related methods
DE102018107224A1 (de) 2018-02-21 2019-08-22 Immatics Biotechnologies Gmbh Peptide und Kombinationen von Peptiden nicht-kanonischen Ursprungs zur Verwendung in der Immuntherapie gegen verschiedene Krebsarten
CN108623661B (zh) * 2018-05-14 2021-04-27 中国医学科学院肿瘤医院 一种靶向胰腺癌肿瘤细胞的双特异性多肽分子探针及应用
TW202016131A (zh) 2018-05-16 2020-05-01 德商英麥提克生物技術股份有限公司 用於抗癌免疫治療的肽
WO2019222708A2 (en) 2018-05-17 2019-11-21 Meso Scale Technologies, Llc. Methods for isolating surface marker displaying agents
DE102018115865A1 (de) * 2018-06-29 2020-02-20 Immatics Biotechnologies Gmbh A*03-restringierte Peptide zur Verwendung in der Immuntherapie gegen Krebs und verwandte Verfahren
US10925947B2 (en) 2018-06-29 2021-02-23 Immatics Biotechnologies Gmbh A*03 restricted peptides for use in immunotherapy against cancers and related methods
WO2020020444A1 (en) * 2018-07-24 2020-01-30 Biontech Rna Pharmaceuticals Gmbh Individualized vaccines for cancer
US11945850B2 (en) 2018-09-17 2024-04-02 Immatics Biotechnologies Gmbh B*44 restricted peptides for use in immunotherapy against cancers and related methods
TW202024121A (zh) 2018-09-18 2020-07-01 德商英麥提克生物技術股份有限公司 A*01 限制肽和肽組合物在抗癌免疫治療中的用途和相關方法
TW202039535A (zh) 2018-12-18 2020-11-01 德商英麥提克生物技術股份有限公司 B*08限制肽和肽組合物抗癌免疫治療和相關方法
CN109706065A (zh) * 2018-12-29 2019-05-03 深圳裕策生物科技有限公司 肿瘤新生抗原负荷检测装置及存储介质
CN109750040B (zh) * 2019-03-05 2023-05-12 上海市第七人民医院 Heatr1基因或蛋白的抑制剂在制备抗肿瘤药物中的应用
JP7457733B2 (ja) 2019-05-30 2024-03-28 グリットストーン バイオ インコーポレイテッド 改変アデノウイルス
US12036204B2 (en) 2019-07-26 2024-07-16 Eisai R&D Management Co., Ltd. Pharmaceutical composition for treating tumor
US20230204565A1 (en) * 2020-01-02 2023-06-29 The Regents Of The University Of California Methods for Culturing Cancer Cells and for Inhibiting Invasion of Cancer
GR1010022B (el) * 2020-03-17 2021-06-01 Πανεπιστημιο Πατρων Μεθοδοι για προσδιορισμο της προγνωσης της επιβιωσης ενος ατομου με αδενοκαρκινωμα πνευμονα και της ανταποκρισης στη θεραπεια
CN113493835A (zh) * 2020-03-20 2021-10-12 上海鹍远健康科技有限公司 通过检测bcan基因区域的甲基化状态筛查大肠瘤的方法和试剂盒
EP4192496A4 (en) 2020-08-06 2025-01-01 Gritstone bio, Inc. MULTIEPITOP VACCINE CASSETTES
CN112053785A (zh) * 2020-09-02 2020-12-08 北京小白世纪网络科技有限公司 基于冠心病诊断神经网络模型冠心病诊断方法及系统
WO2022051481A2 (en) * 2020-09-04 2022-03-10 Meso Scale Technologies, Llc. Methods for isolating central nervous system surface marker displaying agents
CN112946279A (zh) * 2021-03-17 2021-06-11 扬州大学 一种基于油水界面自组装的三明治sers免疫传感器检测宫颈癌患者血清生物标志物方法
CN114022472B (zh) * 2021-11-17 2022-05-20 深圳裕策生物科技有限公司 一种肿瘤浸润淋巴细胞分析方法、装置和存储介质
CN114231494B (zh) * 2021-11-29 2023-09-05 中国科学院动物研究所 USP10基因和/或Ascl1基因在诱导成纤维细胞转分化为神经元细胞的应用及方法
CN114146180B (zh) * 2021-12-22 2022-12-23 首都医科大学附属北京地坛医院 抑制chchd2活性的物质在制备治疗nash和肝损伤所致肝纤维化的产品中的应用
JP2025507447A (ja) * 2022-02-01 2025-03-18 ４ディー・パス・インコーポレイテッド 画像に基づく疾患特性評価のためのシステム及び方法
WO2023213904A1 (en) * 2022-05-04 2023-11-09 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts T cell receptor derived binding polypeptides
EP4382121A1 (en) 2022-12-07 2024-06-12 Altevax Vaccines against ptprz1-positive tumors
EP4709378A1 (en) * 2023-05-10 2026-03-18 Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. Compounds for nos-related cancers and methods of use
CN116808017B (zh) * 2023-07-19 2025-10-17 清华大学 非瑟酮在预防/治疗kif1a相关的神经疾病中的用途
WO2025103803A1 (en) * 2023-11-13 2025-05-22 CureVac SE Immunotherapy against neuronal and brain tumors
CN119827767B (zh) * 2025-01-14 2025-10-28 重庆医科大学 泛素特异性蛋白酶usp4在治疗急性肺损伤/急性呼吸窘迫综合征中的应用

Family Cites Families (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2000E (fr) 1901-04-20 1903-11-24 Albert Lagarde Cadre pliant en fer pour le transport en wagons des fruits et primeurs
US3119139A (en) 1961-02-06 1964-01-28 Taylor Mfg Bottle case inverter
DE2148469A1 (de) 1971-09-28 1973-04-05 Ullrich G Messwerkzeug Kg Wasserwaage mit einer im winkel einstellbaren libelle
US4440859A (en) 1977-05-27 1984-04-03 The Regents Of The University Of California Method for producing recombinant bacterial plasmids containing the coding sequences of higher organisms
US4704362A (en) 1977-11-08 1987-11-03 Genentech, Inc. Recombinant cloning vehicle microbial polypeptide expression
IE53176B1 (en) 1978-12-22 1988-08-17 Biogen Nv Recombinant dna molecules and their method of production
US4530901A (en) 1980-01-08 1985-07-23 Biogen N.V. Recombinant DNA molecules and their use in producing human interferon-like polypeptides
US4342566A (en) 1980-02-22 1982-08-03 Scripps Clinic & Research Foundation Solid phase anti-C3 assay for detection of immune complexes
US4678751A (en) 1981-09-25 1987-07-07 Genentech, Inc. Hybrid human leukocyte interferons
US4766075A (en) 1982-07-14 1988-08-23 Genentech, Inc. Human tissue plasminogen activator
US4582800A (en) 1982-07-12 1986-04-15 Hoffmann-La Roche Inc. Novel vectors and method for controlling interferon expression
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4757006A (en) 1983-10-28 1988-07-12 Genetics Institute, Inc. Human factor VIII:C gene and recombinant methods for production
US4677063A (en) 1985-05-02 1987-06-30 Cetus Corporation Human tumor necrosis factor
US4810648A (en) 1986-01-08 1989-03-07 Rhone Poulenc Agrochimie Haloarylnitrile degrading gene, its use, and cells containing the gene
US4897445A (en) 1986-06-27 1990-01-30 The Administrators Of The Tulane Educational Fund Method for synthesizing a peptide containing a non-peptide bond
ATE183513T1 (de) 1993-06-03 1999-09-15 Therapeutic Antibodies Inc Herstellung von antikörperfragmenten
AUPM322393A0 (en) 1993-12-24 1994-01-27 Austin Research Institute, The Mucin carbohydrate compounds and their use in immunotherapy
ES2203782T3 (es) 1996-01-17 2004-04-16 Imperial College Innovations Limited Inmunoterapia que utiliza linfocitos t citotoxicos (ctl).
US5849589A (en) 1996-03-11 1998-12-15 Duke University Culturing monocytes with IL-4, TNF-α and GM-CSF TO induce differentiation to dendric cells
US6406705B1 (en) 1997-03-10 2002-06-18 University Of Iowa Research Foundation Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant
US6514935B1 (en) * 1997-03-14 2003-02-04 President And Fellows Of Harvard Methods of treating hypertension
US7030235B1 (en) * 1998-09-29 2006-04-18 The Brigham & Women's Hospital, Inc. Compositions to detect lesions associated with hearing loss in the cochlear gene, COCH5B2
AU3087801A (en) * 2000-02-04 2001-08-14 Molecular Dynamics Inc Human genome-derived single exon nucleic acid probes useful for analysis of geneexpression in human breast and hbl 100 cells
CA2404489A1 (en) 2000-03-27 2001-10-04 Technion Research And Development Foundation Ltd. Single chain class i major histo-compatibility complexes, constructs encoding same and methods of generating same
US20040191260A1 (en) 2003-03-26 2004-09-30 Technion Research & Development Foundation Ltd. Compositions capable of specifically binding particular human antigen presenting molecule/pathogen-derived antigen complexes and uses thereof
US20030144474A1 (en) 2000-06-05 2003-07-31 Sunol Molecular Corporation T cell receptor fusions and conjugates and methods of use thereof
GB0017512D0 (en) * 2000-07-17 2000-08-30 Smithkline Beecham Biolog Novel compounds
WO2002076510A1 (en) * 2001-03-23 2002-10-03 Agy Therapeutics Use of biomolecular targets in the treatment and visualization of brain tumors
US7803915B2 (en) * 2001-06-20 2010-09-28 Genentech, Inc. Antibody compositions for the diagnosis and treatment of tumor
EP1992643A3 (en) 2001-06-20 2008-12-10 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
AU2002324700A1 (en) * 2001-08-14 2003-03-03 Bayer Ag Nucleic acid and amino acid sequences involved in pain
US6992176B2 (en) 2002-02-13 2006-01-31 Technion Research & Development Foundation Ltd. Antibody having a T-cell receptor-like specificity, yet higher affinity, and the use of same in the detection and treatment of cancer, viral infection and autoimmune disease
US20030223994A1 (en) 2002-02-20 2003-12-04 Hoogenboom Henricus Renerus Jacobus Mattheus MHC-peptide complex binding ligands
NZ539225A (en) 2002-10-09 2006-09-29 Avidex Ltd Single chain recombinant T cell receptors
ES2327229T3 (es) 2002-11-09 2009-10-27 Immunocore Ltd. Presentacion del receptor de linfocitos t.
GB0304068D0 (en) 2003-02-22 2003-03-26 Avidex Ltd Substances
JP2005245430A (ja) 2003-08-25 2005-09-15 Medeinetto:Kk Ｃｔｌの誘導方法
WO2006034334A2 (en) 2004-09-21 2006-03-30 University Of Pittsburgh Of The Commonwealth System Of Higher Education Peptide analogs capable of enhancing stimulation of a glioma-specific ctl response
JP2008532014A (ja) * 2005-02-24 2008-08-14 セマインズ，インコーポレイティド 生物試料を分類するための組成物及び方法
ATE461215T1 (de) 2005-09-05 2010-04-15 Immatics Biotechnologies Gmbh Tumor-assoziierte peptide, welche an unterschiedliche menschliche leukozytenantigene der klasse ii binden
ATE473350T1 (de) 2006-05-09 2010-07-15 Comacchio Internat S A Bohrmaschine mit karussell-bohrschaft und mantelrohrlader
RS54147B1 (sr) 2007-07-27 2015-12-31 Immatics Biotechnologies Gmbh Nova imunoterapija protiv tumora mozga
KR101351195B1 (ko) * 2007-07-27 2014-01-14 이매틱스 바이오테크놀로지스 게엠베하 면역 치료를 위한 새로운 면역원성 에피톱
UA104572C2 (ru) * 2008-04-24 2014-02-25 Имматикс Байотекнолоджиз Гмбх Новые композиции опухолеассоциированных пептидов, которые связываются с молекулами i или ii класса лейкоцитарного антигена человека (hla) для разработки вакцин
SI2113253T1 (sl) 2008-04-30 2010-06-30 Immatics Biotechnologies Gmbh Nove formulacije s tumorjem povezanih peptidov ki se vežejo na molekule humanega levkocitnega antigena HLA razreda I ali II za cepiva
PL2119726T5 (pl) 2008-05-14 2018-04-30 Immatics Biotechnologies Gmbh Nowe i silne peptydy MHC klasy II pochodzące z surwiwiny i neurokanu
PL2172211T3 (pl) 2008-10-01 2015-05-29 Immatics Biotechnologies Gmbh Kompozycja związanych z guzem peptydów i związana z tym szczepionka przeciwrakowa do leczenia glejaka (GBM) i innych rodzajów raka
US20120322075A1 (en) * 2009-10-26 2012-12-20 Externautics S.P.A. Lung Tumor Markers and Methods of Use Thereof
US20130022983A1 (en) * 2009-10-26 2013-01-24 Externautics S.P.A. Colon and Rectal Tumor Markers and Methods of Use Thereof
GB201006360D0 (en) 2010-04-16 2010-06-02 Immatics Biotechnologies Gmbh Method for differentially quantifying naturally processed HLA-restricted peptides for cancer, autoimmune and infectious diseases immunotherapy development
US20130310266A1 (en) * 2010-09-03 2013-11-21 Immport Therapeutics, Inc. Methods and Compositions For The Diagnosis And Treatment Of Cancer and Autoimmune Disorders
EP2632955A1 (en) 2010-10-26 2013-09-04 Technion Research & Development Foundation Ltd. Antibodies which bind soluble t-cell receptor ligands
US9103183B2 (en) 2011-08-03 2015-08-11 Vetco Gray Inc. Method and apparatus for launching multiple balls in a well
WO2013057586A1 (en) 2011-10-19 2013-04-25 Oslo Universitetssykehus Hf Compositions and methods for producing soluble t - cell receptors
WO2013071295A2 (en) * 2011-11-10 2013-05-16 Rutgers, The State University Of New Jersey Transcript optimized expression enhancement for high-level production of proteins and protein domains
CN114057895A (zh) * 2014-05-28 2022-02-18 诺诺公司 TAT-NR2B9c的氯盐
DE102016123893A1 (de) 2016-12-08 2018-06-14 Immatics Biotechnologies Gmbh T-Zellrezeptoren mit verbesserter Bindung

Also Published As

Publication number Publication date
MX379423B (es) 2025-03-11
LT3066115T (lt) 2019-06-10
EP4253401A3 (en) 2023-11-22
KR20220100705A (ko) 2022-07-15
PL3066115T3 (pl) 2020-01-31
AU2014343599B2 (en) 2018-12-20
CN105793280A (zh) 2016-07-20
US11524059B2 (en) 2022-12-13
EA201690868A1 (ru) 2016-08-31
US11529400B1 (en) 2022-12-20
JP7426972B2 (ja) 2024-02-02
JP2021192610A (ja) 2021-12-23
BR112016009402A2 (pt) 2017-09-19
US20210369826A1 (en) 2021-12-02
AU2019201558B2 (en) 2021-02-11
US20230263873A1 (en) 2023-08-24
JP6632982B2 (ja) 2020-01-22
EP3539979A2 (en) 2019-09-18
US11890334B2 (en) 2024-02-06
US11759507B2 (en) 2023-09-19
EA036517B1 (ru) 2020-11-18
JP2017502076A (ja) 2017-01-19
KR20160079102A (ko) 2016-07-05
KR102651028B1 (ko) 2024-03-25
KR102414447B1 (ko) 2022-07-04
US20220362363A1 (en) 2022-11-17
TR201909021T4 (tr) 2019-07-22
CN111303244A (zh) 2020-06-19
US20220362362A1 (en) 2022-11-17
US20230089882A1 (en) 2023-03-23
CN111303244B (zh) 2024-07-16
SG11201603299PA (en) 2016-05-30
US20150125477A1 (en) 2015-05-07
WO2015063302A3 (en) 2015-10-29
EP3066115B1 (en) 2019-04-03
NZ719767A (en) 2021-11-26
EP4253401A2 (en) 2023-10-04
AU2020273312A1 (en) 2020-12-17
ES2733517T3 (es) 2019-11-29
CN105793280B (zh) 2020-02-11
EP3539979A3 (en) 2020-01-01
CN118852353A (zh) 2024-10-29
US11529401B2 (en) 2022-12-20
KR20210068615A (ko) 2021-06-09
US20210228697A1 (en) 2021-07-29
PT3066115T (pt) 2019-07-12
ME03458B (me) 2020-01-20
SI3066115T1 (sl) 2019-07-31
DK3066115T3 (da) 2019-06-11
MX2016005866A (es) 2016-12-09
US11607446B2 (en) 2023-03-21
US20210393754A1 (en) 2021-12-23
EP3066115A2 (en) 2016-09-14
WO2015063302A2 (en) 2015-05-07
SG10201900727QA (en) 2019-02-27
GB201319446D0 (en) 2013-12-18
KR102415748B1 (ko) 2022-07-05
HRP20191009T1 (hr) 2019-08-23
HUE045038T2 (hu) 2019-12-30
CA2929445A1 (en) 2015-05-07
AU2014343599A1 (en) 2016-05-26
AU2019201558A1 (en) 2019-03-28
UA124048C2 (uk) 2021-07-14
AU2020273312B2 (en) 2022-05-26
CU20160060A7 (es) 2017-02-02
CY1121691T1 (el) 2020-07-31
US10946064B2 (en) 2021-03-16
US11890333B2 (en) 2024-02-06

Similar Documents

Publication Publication Date Title
JP7426972B2 (ja) 数種の神経細胞腫瘍および脳腫瘍に対する個別化免疫療法
JP6646017B2 (ja) Ｎｓｃｌｃをはじめとする肺がんなどの数種の腫瘍に対する新規免疫療法
JP2016527293A (ja) Ｎｓｃｌｃをはじめとする肺がんなどの数種の腫瘍に対する新規免疫療法
JP6963836B2 (ja) 数種の神経細胞腫瘍および脳腫瘍に対する個別化免疫療法
HK40013092A (en) Personalized immunotherapy against several neuronal and brain tumors
HK1227420B (en) Personalized immunotherapy against several neuronal and brain tumors
HK1227420A1 (en) Personalized immunotherapy against several neuronal and brain tumors
EA044260B1 (ru) Персонализированная иммунотерапия нескольких видов нейрональных опухолей и опухолей головного мозга
NZ719767B2 (en) Personalized immunotherapy against several neuronal and brain tumors