CN101918836B - 诊断和治疗前列腺癌和肺癌的方法 - Google Patents
诊断和治疗前列腺癌和肺癌的方法 Download PDFInfo
- Publication number
- CN101918836B CN101918836B CN200880023852.5A CN200880023852A CN101918836B CN 101918836 B CN101918836 B CN 101918836B CN 200880023852 A CN200880023852 A CN 200880023852A CN 101918836 B CN101918836 B CN 101918836B
- Authority
- CN
- China
- Prior art keywords
- gpr110
- antibody
- sample
- level
- epi
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 208000000236 Prostatic Neoplasms Diseases 0.000 title claims abstract description 95
- 206010060862 Prostate cancer Diseases 0.000 title claims abstract description 94
- 206010058467 Lung neoplasm malignant Diseases 0.000 title claims abstract description 79
- 208000020816 lung neoplasm Diseases 0.000 title claims abstract description 74
- 201000005202 lung cancer Diseases 0.000 title claims abstract description 72
- 238000000034 method Methods 0.000 title claims abstract description 69
- 210000002307 prostate Anatomy 0.000 title abstract description 9
- 101000718228 Homo sapiens Adhesion G-protein coupled receptor F1 Proteins 0.000 claims abstract description 210
- 102100026443 Adhesion G-protein coupled receptor F1 Human genes 0.000 claims abstract description 205
- 238000001514 detection method Methods 0.000 claims description 87
- 206010028980 Neoplasm Diseases 0.000 claims description 70
- 210000004027 cell Anatomy 0.000 claims description 62
- 201000011510 cancer Diseases 0.000 claims description 47
- 210000001519 tissue Anatomy 0.000 claims description 47
- 108090000623 proteins and genes Proteins 0.000 claims description 43
- 210000004072 lung Anatomy 0.000 claims description 29
- 238000013518 transcription Methods 0.000 claims description 26
- 230000035897 transcription Effects 0.000 claims description 26
- 239000000427 antigen Substances 0.000 claims description 21
- 108091007433 antigens Proteins 0.000 claims description 21
- 102000036639 antigens Human genes 0.000 claims description 21
- 239000012634 fragment Substances 0.000 claims description 21
- 210000002966 serum Anatomy 0.000 claims description 21
- 210000004369 blood Anatomy 0.000 claims description 17
- 239000008280 blood Substances 0.000 claims description 17
- 238000012360 testing method Methods 0.000 claims description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- 102000004169 proteins and genes Human genes 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 239000000090 biomarker Substances 0.000 claims description 11
- 125000000539 amino acid group Chemical group 0.000 claims description 10
- 108050007237 Glypican-3 Proteins 0.000 claims description 9
- 230000027455 binding Effects 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 239000003550 marker Substances 0.000 claims description 9
- 102000010956 Glypican Human genes 0.000 claims description 8
- 108050001154 Glypican Proteins 0.000 claims description 8
- 239000005557 antagonist Substances 0.000 claims description 8
- 201000005296 lung carcinoma Diseases 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 229940124597 therapeutic agent Drugs 0.000 claims description 7
- 239000007790 solid phase Substances 0.000 claims description 6
- 210000001124 body fluid Anatomy 0.000 claims description 5
- 239000010839 body fluid Substances 0.000 claims description 5
- 230000006872 improvement Effects 0.000 claims description 5
- 230000000630 rising effect Effects 0.000 claims description 5
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 230000005875 antibody response Effects 0.000 claims description 3
- 230000002708 enhancing effect Effects 0.000 claims description 3
- 230000012010 growth Effects 0.000 claims description 3
- 230000008348 humoral response Effects 0.000 claims description 3
- 238000003018 immunoassay Methods 0.000 claims description 3
- 238000005259 measurement Methods 0.000 claims description 3
- 238000012545 processing Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 108700022034 Opsonin Proteins Proteins 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims description 2
- 239000012530 fluid Substances 0.000 claims description 2
- 230000001900 immune effect Effects 0.000 claims description 2
- 238000011275 oncology therapy Methods 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 239000000104 diagnostic biomarker Substances 0.000 claims 1
- 239000002955 immunomodulating agent Substances 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 66
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 27
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 27
- 102100032530 Glypican-3 Human genes 0.000 description 20
- 241000282414 Homo sapiens Species 0.000 description 16
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 15
- 230000008859 change Effects 0.000 description 15
- 108090000765 processed proteins & peptides Proteins 0.000 description 13
- 108700020978 Proto-Oncogene Proteins 0.000 description 10
- 102000052575 Proto-Oncogene Human genes 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 8
- 238000003745 diagnosis Methods 0.000 description 8
- 238000012216 screening Methods 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 230000007541 cellular toxicity Effects 0.000 description 7
- 108700020796 Oncogene Proteins 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 230000003321 amplification Effects 0.000 description 6
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 6
- 210000004698 lymphocyte Anatomy 0.000 description 6
- 238000003199 nucleic acid amplification method Methods 0.000 description 6
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 5
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 108010034529 leucyl-lysine Proteins 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 4
- 206010070834 Sensitisation Diseases 0.000 description 4
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 4
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 4
- OGNMURQZFMHFFD-NHCYSSNCSA-N Val-Asn-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N OGNMURQZFMHFFD-NHCYSSNCSA-N 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 108010047495 alanylglycine Proteins 0.000 description 4
- 238000004043 dyeing Methods 0.000 description 4
- 230000002068 genetic effect Effects 0.000 description 4
- 108010087823 glycyltyrosine Proteins 0.000 description 4
- 210000002443 helper t lymphocyte Anatomy 0.000 description 4
- 108010025306 histidylleucine Proteins 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000010354 integration Effects 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 230000000527 lymphocytic effect Effects 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 230000002285 radioactive effect Effects 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 230000008313 sensitization Effects 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- VNXQRBXEQXLERQ-CIUDSAMLSA-N Asp-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N VNXQRBXEQXLERQ-CIUDSAMLSA-N 0.000 description 3
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 3
- 102000048850 Neoplasm Genes Human genes 0.000 description 3
- 108700019961 Neoplasm Genes Proteins 0.000 description 3
- MFQMZDPAZRZAPV-NAKRPEOUSA-N Ser-Val-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CO)N MFQMZDPAZRZAPV-NAKRPEOUSA-N 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 210000000612 antigen-presenting cell Anatomy 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 238000012790 confirmation Methods 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 108010037850 glycylvaline Proteins 0.000 description 3
- 238000011532 immunohistochemical staining Methods 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 108010054155 lysyllysine Proteins 0.000 description 3
- 230000004962 physiological condition Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 208000023958 prostate neoplasm Diseases 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 238000011144 upstream manufacturing Methods 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- JNTMAZFVYNDPLB-PEDHHIEDSA-N (2S,3S)-2-[[[(2S)-1-[(2S,3S)-2-amino-3-methyl-1-oxopentyl]-2-pyrrolidinyl]-oxomethyl]amino]-3-methylpentanoic acid Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JNTMAZFVYNDPLB-PEDHHIEDSA-N 0.000 description 2
- WEZDRVHTDXTVLT-GJZGRUSLSA-N 2-[[(2s)-2-[[(2s)-2-[(2-aminoacetyl)amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 WEZDRVHTDXTVLT-GJZGRUSLSA-N 0.000 description 2
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 2
- GSCLWXDNIMNIJE-ZLUOBGJFSA-N Ala-Asp-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GSCLWXDNIMNIJE-ZLUOBGJFSA-N 0.000 description 2
- HMRWQTHUDVXMGH-GUBZILKMSA-N Ala-Glu-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN HMRWQTHUDVXMGH-GUBZILKMSA-N 0.000 description 2
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 2
- OYJCVIGKMXUVKB-GARJFASQSA-N Ala-Leu-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N OYJCVIGKMXUVKB-GARJFASQSA-N 0.000 description 2
- IAUSCRHURCZUJP-CIUDSAMLSA-N Ala-Lys-Cys Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CS)C(O)=O IAUSCRHURCZUJP-CIUDSAMLSA-N 0.000 description 2
- OINVDEKBKBCPLX-JXUBOQSCSA-N Ala-Lys-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OINVDEKBKBCPLX-JXUBOQSCSA-N 0.000 description 2
- KUFVXLQLDHJVOG-SHGPDSBTSA-N Ala-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](C)N)O KUFVXLQLDHJVOG-SHGPDSBTSA-N 0.000 description 2
- REWSWYIDQIELBE-FXQIFTODSA-N Ala-Val-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O REWSWYIDQIELBE-FXQIFTODSA-N 0.000 description 2
- VBFJESQBIWCWRL-DCAQKATOSA-N Arg-Ala-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCNC(N)=N VBFJESQBIWCWRL-DCAQKATOSA-N 0.000 description 2
- HQIZDMIGUJOSNI-IUCAKERBSA-N Arg-Gly-Arg Chemical compound N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O HQIZDMIGUJOSNI-IUCAKERBSA-N 0.000 description 2
- FFEUXEAKYRCACT-PEDHHIEDSA-N Arg-Ile-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)CC)C(O)=O FFEUXEAKYRCACT-PEDHHIEDSA-N 0.000 description 2
- XUGATJVGQUGQKY-ULQDDVLXSA-N Arg-Lys-Phe Chemical compound NC(=N)NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 XUGATJVGQUGQKY-ULQDDVLXSA-N 0.000 description 2
- PRLPSDIHSRITSF-UNQGMJICSA-N Arg-Phe-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PRLPSDIHSRITSF-UNQGMJICSA-N 0.000 description 2
- CPTXATAOUQJQRO-GUBZILKMSA-N Arg-Val-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O CPTXATAOUQJQRO-GUBZILKMSA-N 0.000 description 2
- IARGXWMWRFOQPG-GCJQMDKQSA-N Asn-Ala-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IARGXWMWRFOQPG-GCJQMDKQSA-N 0.000 description 2
- DAPLJWATMAXPPZ-CIUDSAMLSA-N Asn-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(N)=O DAPLJWATMAXPPZ-CIUDSAMLSA-N 0.000 description 2
- KXEGPPNPXOKKHK-ZLUOBGJFSA-N Asn-Asp-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O KXEGPPNPXOKKHK-ZLUOBGJFSA-N 0.000 description 2
- UGXVKHRDGLYFKR-CIUDSAMLSA-N Asn-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(N)=O UGXVKHRDGLYFKR-CIUDSAMLSA-N 0.000 description 2
- DMLSCRJBWUEALP-LAEOZQHASA-N Asn-Glu-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O DMLSCRJBWUEALP-LAEOZQHASA-N 0.000 description 2
- SEKBHZJLARBNPB-GHCJXIJMSA-N Asn-Ile-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O SEKBHZJLARBNPB-GHCJXIJMSA-N 0.000 description 2
- IBLAOXSULLECQZ-IUKAMOBKSA-N Asn-Ile-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC(N)=O IBLAOXSULLECQZ-IUKAMOBKSA-N 0.000 description 2
- KHCNTVRVAYCPQE-CIUDSAMLSA-N Asn-Lys-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O KHCNTVRVAYCPQE-CIUDSAMLSA-N 0.000 description 2
- BSBNNPICFPXDNH-SRVKXCTJSA-N Asn-Phe-Cys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)N)N BSBNNPICFPXDNH-SRVKXCTJSA-N 0.000 description 2
- YXVAESUIQFDBHN-SRVKXCTJSA-N Asn-Phe-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O YXVAESUIQFDBHN-SRVKXCTJSA-N 0.000 description 2
- GMUOCGCDOYYWPD-FXQIFTODSA-N Asn-Pro-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O GMUOCGCDOYYWPD-FXQIFTODSA-N 0.000 description 2
- AMGQTNHANMRPOE-LKXGYXEUSA-N Asn-Thr-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O AMGQTNHANMRPOE-LKXGYXEUSA-N 0.000 description 2
- ZRAOLTNMSCSCLN-ZLUOBGJFSA-N Asp-Cys-Asn Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)C(=O)O ZRAOLTNMSCSCLN-ZLUOBGJFSA-N 0.000 description 2
- KYQNAIMCTRZLNP-QSFUFRPTSA-N Asp-Ile-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O KYQNAIMCTRZLNP-QSFUFRPTSA-N 0.000 description 2
- RPUYTJJZXQBWDT-SRVKXCTJSA-N Asp-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC(=O)O)N RPUYTJJZXQBWDT-SRVKXCTJSA-N 0.000 description 2
- DEVDFMRWZASYOF-ZLUOBGJFSA-N Cys-Asn-Asp Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O DEVDFMRWZASYOF-ZLUOBGJFSA-N 0.000 description 2
- YRKJQKATZOTUEN-ACZMJKKPSA-N Cys-Gln-Cys Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CS)N YRKJQKATZOTUEN-ACZMJKKPSA-N 0.000 description 2
- RRJOQIBQVZDVCW-SRVKXCTJSA-N Cys-His-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CS)N RRJOQIBQVZDVCW-SRVKXCTJSA-N 0.000 description 2
- BLGNLNRBABWDST-CIUDSAMLSA-N Cys-Leu-Asp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CS)N BLGNLNRBABWDST-CIUDSAMLSA-N 0.000 description 2
- TXCCRYAZQBUCOV-CIUDSAMLSA-N Cys-Pro-Gln Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O TXCCRYAZQBUCOV-CIUDSAMLSA-N 0.000 description 2
- FTTZLFIEUQHLHH-BWBBJGPYSA-N Cys-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CS)N)O FTTZLFIEUQHLHH-BWBBJGPYSA-N 0.000 description 2
- UGPCUUWZXRMCIJ-KKUMJFAQSA-N Cys-Tyr-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CS)N UGPCUUWZXRMCIJ-KKUMJFAQSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 108700024394 Exon Proteins 0.000 description 2
- 206010064571 Gene mutation Diseases 0.000 description 2
- AAOBFSKXAVIORT-GUBZILKMSA-N Gln-Asn-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O AAOBFSKXAVIORT-GUBZILKMSA-N 0.000 description 2
- VGTDBGYFVWOQTI-RYUDHWBXSA-N Gln-Gly-Phe Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 VGTDBGYFVWOQTI-RYUDHWBXSA-N 0.000 description 2
- XFAUJGNLHIGXET-AVGNSLFASA-N Gln-Leu-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O XFAUJGNLHIGXET-AVGNSLFASA-N 0.000 description 2
- SFAFZYYMAWOCIC-KKUMJFAQSA-N Gln-Phe-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N SFAFZYYMAWOCIC-KKUMJFAQSA-N 0.000 description 2
- ICRKQMRFXYDYMK-LAEOZQHASA-N Gln-Val-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O ICRKQMRFXYDYMK-LAEOZQHASA-N 0.000 description 2
- HNAUFGBKJLTWQE-IFFSRLJSSA-N Gln-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCC(=O)N)N)O HNAUFGBKJLTWQE-IFFSRLJSSA-N 0.000 description 2
- SRZLHYPAOXBBSB-HJGDQZAQSA-N Glu-Arg-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SRZLHYPAOXBBSB-HJGDQZAQSA-N 0.000 description 2
- JRCUFCXYZLPSDZ-ACZMJKKPSA-N Glu-Asp-Ser Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O JRCUFCXYZLPSDZ-ACZMJKKPSA-N 0.000 description 2
- WATXSTJXNBOHKD-LAEOZQHASA-N Glu-Asp-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O WATXSTJXNBOHKD-LAEOZQHASA-N 0.000 description 2
- MUSGDMDGNGXULI-DCAQKATOSA-N Glu-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O MUSGDMDGNGXULI-DCAQKATOSA-N 0.000 description 2
- ZPASCJBSSCRWMC-GVXVVHGQSA-N Glu-His-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CCC(=O)O)N ZPASCJBSSCRWMC-GVXVVHGQSA-N 0.000 description 2
- VGBSZQSKQRMLHD-MNXVOIDGSA-N Glu-Leu-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VGBSZQSKQRMLHD-MNXVOIDGSA-N 0.000 description 2
- SJJHXJDSNQJMMW-SRVKXCTJSA-N Glu-Lys-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O SJJHXJDSNQJMMW-SRVKXCTJSA-N 0.000 description 2
- AQNYKMCFCCZEEL-JYJNAYRXSA-N Glu-Lys-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AQNYKMCFCCZEEL-JYJNAYRXSA-N 0.000 description 2
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 2
- MWTGQXBHVRTCOR-GLLZPBPUSA-N Glu-Thr-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O MWTGQXBHVRTCOR-GLLZPBPUSA-N 0.000 description 2
- RGJKYNUINKGPJN-RWRJDSDZSA-N Glu-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(=O)O)N RGJKYNUINKGPJN-RWRJDSDZSA-N 0.000 description 2
- BKMOHWJHXQLFEX-IRIUXVKKSA-N Glu-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CCC(=O)O)N)O BKMOHWJHXQLFEX-IRIUXVKKSA-N 0.000 description 2
- UXJHNZODTMHWRD-WHFBIAKZSA-N Gly-Asn-Ala Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O UXJHNZODTMHWRD-WHFBIAKZSA-N 0.000 description 2
- JVWPPCWUDRJGAE-YUMQZZPRSA-N Gly-Asn-Leu Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O JVWPPCWUDRJGAE-YUMQZZPRSA-N 0.000 description 2
- YYQGVXNKAXUTJU-YUMQZZPRSA-N Gly-Cys-His Chemical compound NCC(=O)N[C@@H](CS)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O YYQGVXNKAXUTJU-YUMQZZPRSA-N 0.000 description 2
- ADZGCWWDPFDHCY-ZETCQYMHSA-N Gly-His-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CN=CN1 ADZGCWWDPFDHCY-ZETCQYMHSA-N 0.000 description 2
- HKSNHPVETYYJBK-LAEOZQHASA-N Gly-Ile-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)CN HKSNHPVETYYJBK-LAEOZQHASA-N 0.000 description 2
- ITZOBNKQDZEOCE-NHCYSSNCSA-N Gly-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)CN ITZOBNKQDZEOCE-NHCYSSNCSA-N 0.000 description 2
- BHPQOIPBLYJNAW-NGZCFLSTSA-N Gly-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN BHPQOIPBLYJNAW-NGZCFLSTSA-N 0.000 description 2
- LRQXRHGQEVWGPV-NHCYSSNCSA-N Gly-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)CN LRQXRHGQEVWGPV-NHCYSSNCSA-N 0.000 description 2
- 108010009504 Gly-Phe-Leu-Gly Proteins 0.000 description 2
- BMWFDYIYBAFROD-WPRPVWTQSA-N Gly-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN BMWFDYIYBAFROD-WPRPVWTQSA-N 0.000 description 2
- VNNRLUNBJSWZPF-ZKWXMUAHSA-N Gly-Ser-Ile Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VNNRLUNBJSWZPF-ZKWXMUAHSA-N 0.000 description 2
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 2
- LLWQVJNHMYBLLK-CDMKHQONSA-N Gly-Thr-Phe Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LLWQVJNHMYBLLK-CDMKHQONSA-N 0.000 description 2
- BAYQNCWLXIDLHX-ONGXEEELSA-N Gly-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN BAYQNCWLXIDLHX-ONGXEEELSA-N 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- UROVZOUMHNXPLZ-AVGNSLFASA-N His-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CN=CN1 UROVZOUMHNXPLZ-AVGNSLFASA-N 0.000 description 2
- BRQKGRLDDDQWQJ-MBLNEYKQSA-N His-Thr-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O BRQKGRLDDDQWQJ-MBLNEYKQSA-N 0.000 description 2
- TZCGZYWNIDZZMR-UHFFFAOYSA-N Ile-Arg-Ala Natural products CCC(C)C(N)C(=O)NC(C(=O)NC(C)C(O)=O)CCCN=C(N)N TZCGZYWNIDZZMR-UHFFFAOYSA-N 0.000 description 2
- ASCFJMSGKUIRDU-ZPFDUUQYSA-N Ile-Arg-Gln Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O ASCFJMSGKUIRDU-ZPFDUUQYSA-N 0.000 description 2
- FVEWRQXNISSYFO-ZPFDUUQYSA-N Ile-Arg-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N FVEWRQXNISSYFO-ZPFDUUQYSA-N 0.000 description 2
- REJKOQYVFDEZHA-SLBDDTMCSA-N Ile-Asp-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N REJKOQYVFDEZHA-SLBDDTMCSA-N 0.000 description 2
- KUHFPGIVBOCRMV-MNXVOIDGSA-N Ile-Gln-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(C)C)C(=O)O)N KUHFPGIVBOCRMV-MNXVOIDGSA-N 0.000 description 2
- SPQWWEZBHXHUJN-KBIXCLLPSA-N Ile-Glu-Ser Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O SPQWWEZBHXHUJN-KBIXCLLPSA-N 0.000 description 2
- TWYOYAKMLHWMOJ-ZPFDUUQYSA-N Ile-Leu-Asn Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O TWYOYAKMLHWMOJ-ZPFDUUQYSA-N 0.000 description 2
- PMMMQRVUMVURGJ-XUXIUFHCSA-N Ile-Leu-Pro Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(O)=O PMMMQRVUMVURGJ-XUXIUFHCSA-N 0.000 description 2
- WVUDHMBJNBWZBU-XUXIUFHCSA-N Ile-Lys-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)O)N WVUDHMBJNBWZBU-XUXIUFHCSA-N 0.000 description 2
- AGGIYSLVUKVOPT-HTFCKZLJSA-N Ile-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N AGGIYSLVUKVOPT-HTFCKZLJSA-N 0.000 description 2
- RQJUKVXWAKJDBW-SVSWQMSJSA-N Ile-Ser-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N RQJUKVXWAKJDBW-SVSWQMSJSA-N 0.000 description 2
- ZGKVPOSSTGHJAF-HJPIBITLSA-N Ile-Tyr-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CO)C(=O)O)N ZGKVPOSSTGHJAF-HJPIBITLSA-N 0.000 description 2
- KXUKTDGKLAOCQK-LSJOCFKGSA-N Ile-Val-Gly Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O KXUKTDGKLAOCQK-LSJOCFKGSA-N 0.000 description 2
- WIYDLTIBHZSPKY-HJWJTTGWSA-N Ile-Val-Phe Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 WIYDLTIBHZSPKY-HJWJTTGWSA-N 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- 102100034343 Integrase Human genes 0.000 description 2
- 108010061833 Integrases Proteins 0.000 description 2
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 2
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 2
- 241000880493 Leptailurus serval Species 0.000 description 2
- HASRFYOMVPJRPU-SRVKXCTJSA-N Leu-Arg-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O HASRFYOMVPJRPU-SRVKXCTJSA-N 0.000 description 2
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 2
- OGCQGUIWMSBHRZ-CIUDSAMLSA-N Leu-Asn-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O OGCQGUIWMSBHRZ-CIUDSAMLSA-N 0.000 description 2
- QDSKNVXKLPQNOJ-GVXVVHGQSA-N Leu-Gln-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O QDSKNVXKLPQNOJ-GVXVVHGQSA-N 0.000 description 2
- HFBCHNRFRYLZNV-GUBZILKMSA-N Leu-Glu-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HFBCHNRFRYLZNV-GUBZILKMSA-N 0.000 description 2
- FMEICTQWUKNAGC-YUMQZZPRSA-N Leu-Gly-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O FMEICTQWUKNAGC-YUMQZZPRSA-N 0.000 description 2
- YFBBUHJJUXXZOF-UWVGGRQHSA-N Leu-Gly-Pro Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N1CCC[C@H]1C(O)=O YFBBUHJJUXXZOF-UWVGGRQHSA-N 0.000 description 2
- QJXHMYMRGDOHRU-NHCYSSNCSA-N Leu-Ile-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O QJXHMYMRGDOHRU-NHCYSSNCSA-N 0.000 description 2
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 2
- UHNQRAFSEBGZFZ-YESZJQIVSA-N Leu-Phe-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N UHNQRAFSEBGZFZ-YESZJQIVSA-N 0.000 description 2
- HGUUMQWGYCVPKG-DCAQKATOSA-N Leu-Pro-Cys Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N HGUUMQWGYCVPKG-DCAQKATOSA-N 0.000 description 2
- KWLWZYMNUZJKMZ-IHRRRGAJSA-N Leu-Pro-Leu Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O KWLWZYMNUZJKMZ-IHRRRGAJSA-N 0.000 description 2
- AKVBOOKXVAMKSS-GUBZILKMSA-N Leu-Ser-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O AKVBOOKXVAMKSS-GUBZILKMSA-N 0.000 description 2
- XZNJZXJZBMBGGS-NHCYSSNCSA-N Leu-Val-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O XZNJZXJZBMBGGS-NHCYSSNCSA-N 0.000 description 2
- JCFYLFOCALSNLQ-GUBZILKMSA-N Lys-Ala-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O JCFYLFOCALSNLQ-GUBZILKMSA-N 0.000 description 2
- GAOJCVKPIGHTGO-UWVGGRQHSA-N Lys-Arg-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O GAOJCVKPIGHTGO-UWVGGRQHSA-N 0.000 description 2
- 108010062166 Lys-Asn-Asp Proteins 0.000 description 2
- BYPMOIFBQPEWOH-CIUDSAMLSA-N Lys-Asn-Asp Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N BYPMOIFBQPEWOH-CIUDSAMLSA-N 0.000 description 2
- QUYCUALODHJQLK-CIUDSAMLSA-N Lys-Asp-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O QUYCUALODHJQLK-CIUDSAMLSA-N 0.000 description 2
- GFWLIJDQILOEPP-HSCHXYMDSA-N Lys-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CCCCN)N GFWLIJDQILOEPP-HSCHXYMDSA-N 0.000 description 2
- XOQMURBBIXRRCR-SRVKXCTJSA-N Lys-Lys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN XOQMURBBIXRRCR-SRVKXCTJSA-N 0.000 description 2
- JQSIGLHQNSZZRL-KKUMJFAQSA-N Lys-Lys-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)N JQSIGLHQNSZZRL-KKUMJFAQSA-N 0.000 description 2
- ZJSXCIMWLPSTMG-HSCHXYMDSA-N Lys-Trp-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZJSXCIMWLPSTMG-HSCHXYMDSA-N 0.000 description 2
- 206010027336 Menstruation delayed Diseases 0.000 description 2
- WTHGNAAQXISJHP-AVGNSLFASA-N Met-Lys-Val Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O WTHGNAAQXISJHP-AVGNSLFASA-N 0.000 description 2
- PHURAEXVWLDIGT-LPEHRKFASA-N Met-Ser-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N PHURAEXVWLDIGT-LPEHRKFASA-N 0.000 description 2
- AJHCSUXXECOXOY-UHFFFAOYSA-N N-glycyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)CN)C(O)=O)=CNC2=C1 AJHCSUXXECOXOY-UHFFFAOYSA-N 0.000 description 2
- BQVUABVGYYSDCJ-UHFFFAOYSA-N Nalpha-L-Leucyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)CC(C)C)C(O)=O)=CNC2=C1 BQVUABVGYYSDCJ-UHFFFAOYSA-N 0.000 description 2
- KOUUGTKGEQZRHV-KKUMJFAQSA-N Phe-Gln-Arg Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O KOUUGTKGEQZRHV-KKUMJFAQSA-N 0.000 description 2
- BIYWZVCPZIFGPY-QWRGUYRKSA-N Phe-Gly-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CO)C(O)=O BIYWZVCPZIFGPY-QWRGUYRKSA-N 0.000 description 2
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 2
- IPFXYNKCXYGSSV-KKUMJFAQSA-N Phe-Ser-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N IPFXYNKCXYGSSV-KKUMJFAQSA-N 0.000 description 2
- GKRCCTYAGQPMMP-IHRRRGAJSA-N Phe-Ser-Met Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(O)=O GKRCCTYAGQPMMP-IHRRRGAJSA-N 0.000 description 2
- ODPIUQVTULPQEP-CIUDSAMLSA-N Pro-Gln-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@@H]1CCCN1 ODPIUQVTULPQEP-CIUDSAMLSA-N 0.000 description 2
- DTQIXTOJHKVEOH-DCAQKATOSA-N Pro-His-Cys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC2=CN=CN2)C(=O)N[C@@H](CS)C(=O)O DTQIXTOJHKVEOH-DCAQKATOSA-N 0.000 description 2
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 2
- KIDXAAQVMNLJFQ-KZVJFYERSA-N Pro-Thr-Ala Chemical compound C[C@@H](O)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](C)C(O)=O KIDXAAQVMNLJFQ-KZVJFYERSA-N 0.000 description 2
- FHJQROWZEJFZPO-SRVKXCTJSA-N Pro-Val-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 FHJQROWZEJFZPO-SRVKXCTJSA-N 0.000 description 2
- WTWGOQRNRFHFQD-JBDRJPRFSA-N Ser-Ala-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WTWGOQRNRFHFQD-JBDRJPRFSA-N 0.000 description 2
- YMEXHZTVKDAKIY-GHCJXIJMSA-N Ser-Asn-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO)C(O)=O YMEXHZTVKDAKIY-GHCJXIJMSA-N 0.000 description 2
- VAIZFHMTBFYJIA-ACZMJKKPSA-N Ser-Asp-Gln Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCC(N)=O VAIZFHMTBFYJIA-ACZMJKKPSA-N 0.000 description 2
- WTPKKLMBNBCCNL-ACZMJKKPSA-N Ser-Cys-Glu Chemical compound C(CC(=O)O)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N WTPKKLMBNBCCNL-ACZMJKKPSA-N 0.000 description 2
- OJPHFSOMBZKQKQ-GUBZILKMSA-N Ser-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CO OJPHFSOMBZKQKQ-GUBZILKMSA-N 0.000 description 2
- FMDHKPRACUXATF-ACZMJKKPSA-N Ser-Gln-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O FMDHKPRACUXATF-ACZMJKKPSA-N 0.000 description 2
- LALNXSXEYFUUDD-GUBZILKMSA-N Ser-Glu-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O LALNXSXEYFUUDD-GUBZILKMSA-N 0.000 description 2
- MOQDPPUMFSMYOM-KKUMJFAQSA-N Ser-His-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CO)N MOQDPPUMFSMYOM-KKUMJFAQSA-N 0.000 description 2
- RIAKPZVSNBBNRE-BJDJZHNGSA-N Ser-Ile-Leu Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O RIAKPZVSNBBNRE-BJDJZHNGSA-N 0.000 description 2
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 2
- KCGIREHVWRXNDH-GARJFASQSA-N Ser-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N KCGIREHVWRXNDH-GARJFASQSA-N 0.000 description 2
- MUJQWSAWLLRJCE-KATARQTJSA-N Ser-Leu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MUJQWSAWLLRJCE-KATARQTJSA-N 0.000 description 2
- UGGWCAFQPKANMW-FXQIFTODSA-N Ser-Met-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O UGGWCAFQPKANMW-FXQIFTODSA-N 0.000 description 2
- RRVFEDGUXSYWOW-BZSNNMDCSA-N Ser-Phe-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O RRVFEDGUXSYWOW-BZSNNMDCSA-N 0.000 description 2
- QMCDMHWAKMUGJE-IHRRRGAJSA-N Ser-Phe-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O QMCDMHWAKMUGJE-IHRRRGAJSA-N 0.000 description 2
- KQNDIKOYWZTZIX-FXQIFTODSA-N Ser-Ser-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCNC(N)=N KQNDIKOYWZTZIX-FXQIFTODSA-N 0.000 description 2
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 2
- UYLKOSODXYSWMQ-XGEHTFHBSA-N Ser-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CO)N)O UYLKOSODXYSWMQ-XGEHTFHBSA-N 0.000 description 2
- VBPDMBAFBRDZSK-HOUAVDHOSA-N Thr-Asn-Trp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N)O VBPDMBAFBRDZSK-HOUAVDHOSA-N 0.000 description 2
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 2
- AYCQVUUPIJHJTA-IXOXFDKPSA-N Thr-His-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(O)=O AYCQVUUPIJHJTA-IXOXFDKPSA-N 0.000 description 2
- UYTYTDMCDBPDSC-URLPEUOOSA-N Thr-Ile-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N UYTYTDMCDBPDSC-URLPEUOOSA-N 0.000 description 2
- VTVVYQOXJCZVEB-WDCWCFNPSA-N Thr-Leu-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O VTVVYQOXJCZVEB-WDCWCFNPSA-N 0.000 description 2
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 2
- MGJLBZFUXUGMML-VOAKCMCISA-N Thr-Lys-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MGJLBZFUXUGMML-VOAKCMCISA-N 0.000 description 2
- MXNAOGFNFNKUPD-JHYOHUSXSA-N Thr-Phe-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MXNAOGFNFNKUPD-JHYOHUSXSA-N 0.000 description 2
- WKGAAMOJPMBBMC-IXOXFDKPSA-N Thr-Ser-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O WKGAAMOJPMBBMC-IXOXFDKPSA-N 0.000 description 2
- LECUEEHKUFYOOV-ZJDVBMNYSA-N Thr-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](N)[C@@H](C)O LECUEEHKUFYOOV-ZJDVBMNYSA-N 0.000 description 2
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 2
- BKVICMPZWRNWOC-RHYQMDGZSA-N Thr-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)[C@@H](C)O BKVICMPZWRNWOC-RHYQMDGZSA-N 0.000 description 2
- JLTQXEOXIJMCLZ-ZVZYQTTQSA-N Trp-Gln-Val Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O)=CNC2=C1 JLTQXEOXIJMCLZ-ZVZYQTTQSA-N 0.000 description 2
- WKCFCVBOFKEVKY-HSCHXYMDSA-N Trp-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N WKCFCVBOFKEVKY-HSCHXYMDSA-N 0.000 description 2
- JONPRIHUYSPIMA-UWJYBYFXSA-N Tyr-Ala-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JONPRIHUYSPIMA-UWJYBYFXSA-N 0.000 description 2
- AKXBNSZMYAOGLS-STQMWFEESA-N Tyr-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 AKXBNSZMYAOGLS-STQMWFEESA-N 0.000 description 2
- XQYHLZNPOTXRMQ-KKUMJFAQSA-N Tyr-Glu-Arg Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O XQYHLZNPOTXRMQ-KKUMJFAQSA-N 0.000 description 2
- UNUZEBFXGWVAOP-DZKIICNBSA-N Tyr-Glu-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UNUZEBFXGWVAOP-DZKIICNBSA-N 0.000 description 2
- QPOUERMDWKKZEG-HJPIBITLSA-N Tyr-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 QPOUERMDWKKZEG-HJPIBITLSA-N 0.000 description 2
- MDXLPNRXCFOBTL-BZSNNMDCSA-N Tyr-Ser-Tyr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MDXLPNRXCFOBTL-BZSNNMDCSA-N 0.000 description 2
- AKKYBQGHUAWPJR-MNSWYVGCSA-N Tyr-Thr-Trp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N)O AKKYBQGHUAWPJR-MNSWYVGCSA-N 0.000 description 2
- ASQFIHTXXMFENG-XPUUQOCRSA-N Val-Ala-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O ASQFIHTXXMFENG-XPUUQOCRSA-N 0.000 description 2
- SZTTYWIUCGSURQ-AUTRQRHGSA-N Val-Glu-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SZTTYWIUCGSURQ-AUTRQRHGSA-N 0.000 description 2
- LAYSXAOGWHKNED-XPUUQOCRSA-N Val-Gly-Ser Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O LAYSXAOGWHKNED-XPUUQOCRSA-N 0.000 description 2
- WNZSAUMKZQXHNC-UKJIMTQDSA-N Val-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N WNZSAUMKZQXHNC-UKJIMTQDSA-N 0.000 description 2
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 2
- CKTMJBPRVQWPHU-JSGCOSHPSA-N Val-Phe-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)O)N CKTMJBPRVQWPHU-JSGCOSHPSA-N 0.000 description 2
- JMCOXFSCTGKLLB-FKBYEOEOSA-N Val-Phe-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JMCOXFSCTGKLLB-FKBYEOEOSA-N 0.000 description 2
- SSYBNWFXCFNRFN-GUBZILKMSA-N Val-Pro-Ser Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SSYBNWFXCFNRFN-GUBZILKMSA-N 0.000 description 2
- PGQUDQYHWICSAB-NAKRPEOUSA-N Val-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N PGQUDQYHWICSAB-NAKRPEOUSA-N 0.000 description 2
- QTPQHINADBYBNA-DCAQKATOSA-N Val-Ser-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCCN QTPQHINADBYBNA-DCAQKATOSA-N 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 241000269370 Xenopus <genus> Species 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 108010044940 alanylglutamine Proteins 0.000 description 2
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 108010093581 aspartyl-proline Proteins 0.000 description 2
- 108010038633 aspartylglutamate Proteins 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000002759 chromosomal effect Effects 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 238000002405 diagnostic procedure Methods 0.000 description 2
- 108010054812 diprotin A Proteins 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 2
- 108010042598 glutamyl-aspartyl-glycine Proteins 0.000 description 2
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 2
- 108010073628 glutamyl-valyl-phenylalanine Proteins 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 108010033719 glycyl-histidyl-glycine Proteins 0.000 description 2
- 108010077435 glycyl-phenylalanyl-glycine Proteins 0.000 description 2
- 108010015792 glycyllysine Proteins 0.000 description 2
- 108010084389 glycyltryptophan Proteins 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 108010009298 lysylglutamic acid Proteins 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000002752 melanocyte Anatomy 0.000 description 2
- 108010056582 methionylglutamic acid Proteins 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 2
- 239000002159 nanocrystal Substances 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 108010030237 phenylalanyl-arginyl-valyl-phenylalanine Proteins 0.000 description 2
- 108010018625 phenylalanylarginine Proteins 0.000 description 2
- 108010012581 phenylalanylglutamate Proteins 0.000 description 2
- 108010051242 phenylalanylserine Proteins 0.000 description 2
- 108010090894 prolylleucine Proteins 0.000 description 2
- 108010053725 prolylvaline Proteins 0.000 description 2
- 239000002096 quantum dot Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 108010048818 seryl-histidine Proteins 0.000 description 2
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 230000017105 transposition Effects 0.000 description 2
- 108010038745 tryptophylglycine Proteins 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 108010073969 valyllysine Proteins 0.000 description 2
- 108010036211 5-HT-moduline Proteins 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- SOBIAADAMRHGKH-CIUDSAMLSA-N Ala-Leu-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O SOBIAADAMRHGKH-CIUDSAMLSA-N 0.000 description 1
- YCRAFFCYWOUEOF-DLOVCJGASA-N Ala-Phe-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=CC=C1 YCRAFFCYWOUEOF-DLOVCJGASA-N 0.000 description 1
- IHMCQESUJVZTKW-UBHSHLNASA-N Ala-Phe-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CC1=CC=CC=C1 IHMCQESUJVZTKW-UBHSHLNASA-N 0.000 description 1
- DHONNEYAZPNGSG-UBHSHLNASA-N Ala-Val-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 DHONNEYAZPNGSG-UBHSHLNASA-N 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- IIFDPDVJAHQFSR-WHFBIAKZSA-N Asn-Glu Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(O)=O IIFDPDVJAHQFSR-WHFBIAKZSA-N 0.000 description 1
- LVHMEJJWEXBMKK-GMOBBJLQSA-N Asn-Ile-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC(=O)N)N LVHMEJJWEXBMKK-GMOBBJLQSA-N 0.000 description 1
- BYLSYQASFJJBCL-DCAQKATOSA-N Asn-Pro-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O BYLSYQASFJJBCL-DCAQKATOSA-N 0.000 description 1
- CELPEWWLSXMVPH-CIUDSAMLSA-N Asp-Asp-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(O)=O CELPEWWLSXMVPH-CIUDSAMLSA-N 0.000 description 1
- HKEZZWQWXWGASX-KKUMJFAQSA-N Asp-Leu-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 HKEZZWQWXWGASX-KKUMJFAQSA-N 0.000 description 1
- ZVGRHIRJLWBWGJ-ACZMJKKPSA-N Asp-Ser-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZVGRHIRJLWBWGJ-ACZMJKKPSA-N 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 102100024505 Bone morphogenetic protein 4 Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- HEPLXMBVMCXTBP-QWRGUYRKSA-N Cys-Phe-Gly Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O HEPLXMBVMCXTBP-QWRGUYRKSA-N 0.000 description 1
- NRVQLLDIJJEIIZ-VZFHVOOUSA-N Cys-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](CS)N)O NRVQLLDIJJEIIZ-VZFHVOOUSA-N 0.000 description 1
- MSWBLPLBSLQVME-XIRDDKMYSA-N Cys-Trp-Leu Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CS)=CNC2=C1 MSWBLPLBSLQVME-XIRDDKMYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 102100033047 G-protein coupled receptor 3 Human genes 0.000 description 1
- ODBLJLZVLAWVMS-GUBZILKMSA-N Gln-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)N)N ODBLJLZVLAWVMS-GUBZILKMSA-N 0.000 description 1
- RMOCFPBLHAOTDU-ACZMJKKPSA-N Gln-Asn-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O RMOCFPBLHAOTDU-ACZMJKKPSA-N 0.000 description 1
- IWUFOVSLWADEJC-AVGNSLFASA-N Gln-His-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(O)=O IWUFOVSLWADEJC-AVGNSLFASA-N 0.000 description 1
- DUGYCMAIAKAQPB-GLLZPBPUSA-N Gln-Thr-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O DUGYCMAIAKAQPB-GLLZPBPUSA-N 0.000 description 1
- PHONAZGUEGIOEM-GLLZPBPUSA-N Glu-Glu-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PHONAZGUEGIOEM-GLLZPBPUSA-N 0.000 description 1
- QSDKBRMVXSWAQE-BFHQHQDPSA-N Gly-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN QSDKBRMVXSWAQE-BFHQHQDPSA-N 0.000 description 1
- UEGIPZAXNBYCCP-NKWVEPMBSA-N Gly-Cys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CS)NC(=O)CN)C(=O)O UEGIPZAXNBYCCP-NKWVEPMBSA-N 0.000 description 1
- DHDOADIPGZTAHT-YUMQZZPRSA-N Gly-Glu-Arg Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DHDOADIPGZTAHT-YUMQZZPRSA-N 0.000 description 1
- YNIMVVJTPWCUJH-KBPBESRZSA-N Gly-His-Tyr Chemical compound [H]NCC(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O YNIMVVJTPWCUJH-KBPBESRZSA-N 0.000 description 1
- HMHRTKOWRUPPNU-RCOVLWMOSA-N Gly-Ile-Gly Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O HMHRTKOWRUPPNU-RCOVLWMOSA-N 0.000 description 1
- LHYJCVCQPWRMKZ-WEDXCCLWSA-N Gly-Leu-Thr Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LHYJCVCQPWRMKZ-WEDXCCLWSA-N 0.000 description 1
- POJJAZJHBGXEGM-YUMQZZPRSA-N Gly-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)CN POJJAZJHBGXEGM-YUMQZZPRSA-N 0.000 description 1
- 101150001754 Gusb gene Proteins 0.000 description 1
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical group OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 102100031000 Hepatoma-derived growth factor Human genes 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- MDOBWSFNSNPENN-PMVVWTBXSA-N His-Thr-Gly Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O MDOBWSFNSNPENN-PMVVWTBXSA-N 0.000 description 1
- SYPULFZAGBBIOM-GVXVVHGQSA-N His-Val-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N SYPULFZAGBBIOM-GVXVVHGQSA-N 0.000 description 1
- QLBXWYXMLHAREM-PYJNHQTQSA-N His-Val-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC1=CN=CN1)N QLBXWYXMLHAREM-PYJNHQTQSA-N 0.000 description 1
- 101000762379 Homo sapiens Bone morphogenetic protein 4 Proteins 0.000 description 1
- 101000871088 Homo sapiens G-protein coupled receptor 3 Proteins 0.000 description 1
- 101001083798 Homo sapiens Hepatoma-derived growth factor Proteins 0.000 description 1
- QSPLUJGYOPZINY-ZPFDUUQYSA-N Ile-Asp-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N QSPLUJGYOPZINY-ZPFDUUQYSA-N 0.000 description 1
- SJLVSMMIFYTSGY-GRLWGSQLSA-N Ile-Ile-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N SJLVSMMIFYTSGY-GRLWGSQLSA-N 0.000 description 1
- HPCFRQWLTRDGHT-AJNGGQMLSA-N Ile-Leu-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O HPCFRQWLTRDGHT-AJNGGQMLSA-N 0.000 description 1
- 108091026898 Leader sequence (mRNA) Proteins 0.000 description 1
- HXWALXSAVBLTPK-NUTKFTJISA-N Leu-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(C)C)N HXWALXSAVBLTPK-NUTKFTJISA-N 0.000 description 1
- GRZSCTXVCDUIPO-SRVKXCTJSA-N Leu-Arg-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O GRZSCTXVCDUIPO-SRVKXCTJSA-N 0.000 description 1
- WUFYAPWIHCUMLL-CIUDSAMLSA-N Leu-Asn-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O WUFYAPWIHCUMLL-CIUDSAMLSA-N 0.000 description 1
- PPBKJAQJAUHZKX-SRVKXCTJSA-N Leu-Cys-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CC(C)C PPBKJAQJAUHZKX-SRVKXCTJSA-N 0.000 description 1
- CCQLQKZTXZBXTN-NHCYSSNCSA-N Leu-Gly-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O CCQLQKZTXZBXTN-NHCYSSNCSA-N 0.000 description 1
- UCDHVOALNXENLC-KBPBESRZSA-N Leu-Gly-Tyr Chemical compound CC(C)C[C@H]([NH3+])C(=O)NCC(=O)N[C@H](C([O-])=O)CC1=CC=C(O)C=C1 UCDHVOALNXENLC-KBPBESRZSA-N 0.000 description 1
- SEMUSFOBZGKBGW-YTFOTSKYSA-N Leu-Ile-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O SEMUSFOBZGKBGW-YTFOTSKYSA-N 0.000 description 1
- BIZNDKMFQHDOIE-KKUMJFAQSA-N Leu-Phe-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=CC=C1 BIZNDKMFQHDOIE-KKUMJFAQSA-N 0.000 description 1
- MAXILRZVORNXBE-PMVMPFDFSA-N Leu-Phe-Trp Chemical compound C([C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=CC=C1 MAXILRZVORNXBE-PMVMPFDFSA-N 0.000 description 1
- IDGZVZJLYFTXSL-DCAQKATOSA-N Leu-Ser-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IDGZVZJLYFTXSL-DCAQKATOSA-N 0.000 description 1
- LCNASHSOFMRYFO-WDCWCFNPSA-N Leu-Thr-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O LCNASHSOFMRYFO-WDCWCFNPSA-N 0.000 description 1
- IDGRADDMTTWOQC-WDSOQIARSA-N Leu-Trp-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IDGRADDMTTWOQC-WDSOQIARSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- YVMQJGWLHRWMDF-MNXVOIDGSA-N Lys-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCCN)N YVMQJGWLHRWMDF-MNXVOIDGSA-N 0.000 description 1
- KYNNSEJZFVCDIV-ZPFDUUQYSA-N Lys-Ile-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O KYNNSEJZFVCDIV-ZPFDUUQYSA-N 0.000 description 1
- WRODMZBHNNPRLN-SRVKXCTJSA-N Lys-Leu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O WRODMZBHNNPRLN-SRVKXCTJSA-N 0.000 description 1
- DNWBUCHHMRQWCZ-GUBZILKMSA-N Lys-Ser-Gln Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(N)=O DNWBUCHHMRQWCZ-GUBZILKMSA-N 0.000 description 1
- VWPJQIHBBOJWDN-DCAQKATOSA-N Lys-Val-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O VWPJQIHBBOJWDN-DCAQKATOSA-N 0.000 description 1
- DRRXXZBXDMLGFC-IHRRRGAJSA-N Lys-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN DRRXXZBXDMLGFC-IHRRRGAJSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108700011259 MicroRNAs Proteins 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 241000714177 Murine leukemia virus Species 0.000 description 1
- 210000004460 N cell Anatomy 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- BBDSZDHUCPSYAC-QEJZJMRPSA-N Phe-Ala-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O BBDSZDHUCPSYAC-QEJZJMRPSA-N 0.000 description 1
- KNPVDQMEHSCAGX-UWVGGRQHSA-N Phe-Cys Chemical compound SC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 KNPVDQMEHSCAGX-UWVGGRQHSA-N 0.000 description 1
- LLGTYVHITPVGKR-RYUDHWBXSA-N Phe-Gln-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O LLGTYVHITPVGKR-RYUDHWBXSA-N 0.000 description 1
- DVOCGBNHAUHKHJ-DKIMLUQUSA-N Phe-Ile-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O DVOCGBNHAUHKHJ-DKIMLUQUSA-N 0.000 description 1
- RORUIHAWOLADSH-HJWJTTGWSA-N Phe-Ile-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC1=CC=CC=C1 RORUIHAWOLADSH-HJWJTTGWSA-N 0.000 description 1
- DSXPMZMSJHOKKK-HJOGWXRNSA-N Phe-Phe-Tyr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O DSXPMZMSJHOKKK-HJOGWXRNSA-N 0.000 description 1
- CXMSESHALPOLRE-MEYUZBJRSA-N Phe-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC2=CC=CC=C2)N)O CXMSESHALPOLRE-MEYUZBJRSA-N 0.000 description 1
- IEIFEYBAYFSRBQ-IHRRRGAJSA-N Phe-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N IEIFEYBAYFSRBQ-IHRRRGAJSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- XYSXOCIWCPFOCG-IHRRRGAJSA-N Pro-Leu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O XYSXOCIWCPFOCG-IHRRRGAJSA-N 0.000 description 1
- SMFQZMGHCODUPQ-ULQDDVLXSA-N Pro-Lys-Phe Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SMFQZMGHCODUPQ-ULQDDVLXSA-N 0.000 description 1
- BGWKULMLUIUPKY-BQBZGAKWSA-N Pro-Ser-Gly Chemical compound OC(=O)CNC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 BGWKULMLUIUPKY-BQBZGAKWSA-N 0.000 description 1
- CXGLFEOYCJFKPR-RCWTZXSCSA-N Pro-Thr-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O CXGLFEOYCJFKPR-RCWTZXSCSA-N 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 102000016611 Proteoglycans Human genes 0.000 description 1
- 108010067787 Proteoglycans Proteins 0.000 description 1
- 206010038997 Retroviral infections Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- WTUJZHKANPDPIN-CIUDSAMLSA-N Ser-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N WTUJZHKANPDPIN-CIUDSAMLSA-N 0.000 description 1
- UGJRQLURDVGULT-LKXGYXEUSA-N Ser-Asn-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UGJRQLURDVGULT-LKXGYXEUSA-N 0.000 description 1
- BGOWRLSWJCVYAQ-CIUDSAMLSA-N Ser-Asp-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O BGOWRLSWJCVYAQ-CIUDSAMLSA-N 0.000 description 1
- IFPBAGJBHSNYPR-ZKWXMUAHSA-N Ser-Ile-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O IFPBAGJBHSNYPR-ZKWXMUAHSA-N 0.000 description 1
- HEUVHBXOVZONPU-BJDJZHNGSA-N Ser-Leu-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HEUVHBXOVZONPU-BJDJZHNGSA-N 0.000 description 1
- PTWIYDNFWPXQSD-GARJFASQSA-N Ser-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)N)C(=O)O PTWIYDNFWPXQSD-GARJFASQSA-N 0.000 description 1
- PPCZVWHJWJFTFN-ZLUOBGJFSA-N Ser-Ser-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPCZVWHJWJFTFN-ZLUOBGJFSA-N 0.000 description 1
- XPVIVVLLLOFBRH-XIRDDKMYSA-N Ser-Trp-Lys Chemical compound NCCCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](N)CO)C(O)=O XPVIVVLLLOFBRH-XIRDDKMYSA-N 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- XYEXCEPTALHNEV-RCWTZXSCSA-N Thr-Arg-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O XYEXCEPTALHNEV-RCWTZXSCSA-N 0.000 description 1
- DIPIPFHFLPTCLK-LOKLDPHHSA-N Thr-Gln-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N)O DIPIPFHFLPTCLK-LOKLDPHHSA-N 0.000 description 1
- XOWKUMFHEZLKLT-CIQUZCHMSA-N Thr-Ile-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O XOWKUMFHEZLKLT-CIQUZCHMSA-N 0.000 description 1
- XYFISNXATOERFZ-OSUNSFLBSA-N Thr-Ile-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N XYFISNXATOERFZ-OSUNSFLBSA-N 0.000 description 1
- BCYUHPXBHCUYBA-CUJWVEQBSA-N Thr-Ser-His Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O BCYUHPXBHCUYBA-CUJWVEQBSA-N 0.000 description 1
- KVEWWQRTAVMOFT-KJEVXHAQSA-N Thr-Tyr-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O KVEWWQRTAVMOFT-KJEVXHAQSA-N 0.000 description 1
- BKIOKSLLAAZYTC-KKHAAJSZSA-N Thr-Val-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O BKIOKSLLAAZYTC-KKHAAJSZSA-N 0.000 description 1
- 108091036066 Three prime untranslated region Proteins 0.000 description 1
- NOFFAYIYPAUNRM-HKUYNNGSSA-N Trp-Gly-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC2=CNC3=CC=CC=C32)N NOFFAYIYPAUNRM-HKUYNNGSSA-N 0.000 description 1
- KBKTUNYBNJWFRL-UBHSHLNASA-N Trp-Ser-Asn Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O)=CNC2=C1 KBKTUNYBNJWFRL-UBHSHLNASA-N 0.000 description 1
- WOAQYWUEUYMVGK-ULQDDVLXSA-N Tyr-Lys-Arg Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WOAQYWUEUYMVGK-ULQDDVLXSA-N 0.000 description 1
- OVLIFGQSBSNGHY-KKHAAJSZSA-N Val-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C(C)C)N)O OVLIFGQSBSNGHY-KKHAAJSZSA-N 0.000 description 1
- UXODSMTVPWXHBT-ULQDDVLXSA-N Val-Phe-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N UXODSMTVPWXHBT-ULQDDVLXSA-N 0.000 description 1
- XBJKAZATRJBDCU-GUBZILKMSA-N Val-Pro-Ala Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O XBJKAZATRJBDCU-GUBZILKMSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 108010070944 alanylhistidine Proteins 0.000 description 1
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 108010060035 arginylproline Proteins 0.000 description 1
- 108010077245 asparaginyl-proline Proteins 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002962 chemical mutagen Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 238000002875 fluorescence polarization Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 108010049041 glutamylalanine Proteins 0.000 description 1
- 108010089804 glycyl-threonine Proteins 0.000 description 1
- 208000035392 hereditary 6 prostate cancer Diseases 0.000 description 1
- 208000032154 hereditary 8 prostate cancer Diseases 0.000 description 1
- 108010092114 histidylphenylalanine Proteins 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 108010076756 leucyl-alanyl-phenylalanine Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 108010064235 lysylglycine Proteins 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 108010085203 methionylmethionine Proteins 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940023041 peptide vaccine Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 1
- 229940067626 phosphatidylinositols Drugs 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108010031719 prolyl-serine Proteins 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 230000009991 second messenger activation Effects 0.000 description 1
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000012409 standard PCR amplification Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 108010001055 thymocartin Proteins 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 108010029384 tryptophyl-histidine Proteins 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57423—Specifically defined cancers of lung
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57434—Specifically defined cancers of prostate
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
-
- 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
- C12Q2600/156—Polymorphic or mutational 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
- C12Q2600/158—Expression markers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
- G01N2333/726—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Pathology (AREA)
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Oncology (AREA)
- General Physics & Mathematics (AREA)
- Food Science & Technology (AREA)
- Cell Biology (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
公开了检测和治疗前列腺癌和肺癌的方法。在实施该方法中,检测对象样品中的GPR110蛋白或其RNA转录物,观察到的GPR110或转录水平被用于确定个体是否有与前列腺癌或肺癌相关的GPR110水平的升高。依照本发明,有此种水平升高的病人可以用各种GPR110相关的免疫治疗剂治疗。
Description
技术领域
本发明涉及前列腺癌和肺癌相关的基因和编码的蛋白,以及检测和治疗前列腺癌和肺癌的方法和试剂。
参考文献
下列文献被下文引用,以支持本发明的背景技术或实施本发明所应用的方法。
1.Bjarnadottir TK,Geirardsdottir K,Ingemansson M,Mirza MA,Fredriksson R,Schioth HB.Identification of novel splice variants of Adhesion Gprotein-coupled receptors.Gene.2007 Jan 31;387(1-2):38-48.Epub 2006 Aug30.
2.Bjarnadottir TK,Fredriksson R,Hoglund PJ,Gloriam DE,LagerstromMC,Schioth HB.The human and mouse repertoire of the adhesion family of G-protein-coupled receptors.Genomics.2004Jul;84(1):23-33.
3.Fredriksson R,Lagerstrom MC,Hoglund PJ,Schioth HB.Novel humanG protein-coupled receptors with long N-terminals containing GPS domains andSer/Thr-rich regions.FEBS Lett.2002Nov 20;531(3):407-14.
4.Nusse,R.,van Ooyen,A.,Cox,D.,Fung,Y.K.&Varmus,H.Mode ofproviral activation of a putative mammary oncogene(int-1)on mousechromosome 15.Nature 307,131-6(1984).
5.Nusse,R.&Varmus,H.E.Many tumors induced by the mousemammary tumor virus contain a provirus integrated in the same region of thehost genome.Cell 31,99-109(1982).
6.Sorensen,A.B.,Duch,M.,Amtoft,H.W.,Jorgensen,P.&Pedersen,F.S.Sequence tags of provirus integration sites in DNAs of tumors induced bythe murine retrovirus SL3-3.J Virol 70,4063-70(1996).
7.Lund,A.H.et al.Genome-wide retroviral insertional tagging of genesinvolved in cancer in Cdkn2a-deficient mice.Nat Genet 32,160-5(2002).
8.Mikkers,H.et al.High-throughput retroviral tagging to identifycomponents of specific signaling pathways in cancer.Nat Genet 32,153-9(2002).
9.Collier,L.S.,Carlson,C.M.,Ravimohan,S.,Dupuy,A.J.&Largaespada,D.A.Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse.Nature 436,272-6(2005).
10.Dupuy,A.J.,Akagi,K.,Largaespada,D.A.,Copeland,N.G.&Jenkins,N.A.Mammalian mutagenesis using a highly mobile somatic SleepingBeauty transposon system.Nature 436,221-6(2005).
11.Wang,et al.,Nucleic Acids Research,(England)2005,Vol.33,p.21.
12.Oh da Y,Kim K,Kwon HB,Seong JY.Cellular and molecular biologyof orphan G protein-coupled receptors.Int Rev Cytol.2006;252:163-218.
13.Lundstrom K.Latest development in drug discovery on G protein-coupled receptors.Curr Protein Pept Sci.2006Oct;7(5):465-70.
14.Jacoby E,Bouhelal R,Gerspacher M,Seuwen K.The 7TM G-protein-coupled receptor target family.ChemMedChem.2006Aug;1(8):761-82.
背景技术
前列腺癌是北美男性中最普遍的恶性癌症。据估计在美国每年有大约200,000例新发病例和31,500例与前列腺癌相关的死亡发生。前列腺癌是目前男性癌症死亡中第二主要的病因,仅次于肺癌。其占所有男性癌症的29%和男性癌症相关死亡的11%。
目前,FDA已经批准血清PSA(前列腺-特异性抗原)用作前列腺癌筛查的实验室指标。与很多血清肿瘤标志一样,正常和癌变的腺体都产生PSA。患有前列腺癌的男性,局部的和晚期或播散的疾病都增加其血清水平。PSA水平一般与肿瘤体积成比例。由于癌症和良性前列腺增生测到的PSA水平之间有很大的重叠,获得低点的或临界升高值的连续水平是重要的。
游离PSA(fPSA)检测的引入导致了早期前列腺癌鉴定更高水平的特异性。1998年,FDA批准了fPSA检测作为总PSA值在4.0-10.0ng/mL间的男性的诊断辅助手段。此处经常是总PSA检测的诊断灰色地带,fPSA可以帮助分类。通常,在任意游离PSA水平,越为增大的前列腺,其癌变的可能越大。但是,这些检测至多是定性的,更可靠的检测类型和对癌症治疗分期的方法是必需的。
前列腺癌,与其它类型癌症一样,是由基因变异,即,突变导致的。在突变细胞中,促进和抑制生长的因子间的正常平衡被打破,结果,这些突变细胞持续增生——肿瘤细胞的标志。突变可以自发或由外部因素而引起,例如化学诱变剂,辐射,或病毒整合,其插入可能包含或不包含癌基因的外源基因组DNA。细胞基因可以由点突变,插入和移码(包括截短),(功能)缺失(包括沉默),或有时可以导致基因融合的易位修饰。这样,原癌基因可以变成癌基因,其促进增生,抑癌基因可以失活,也诱导肿瘤生长。上面提到的DNA变化的任意联合都能促使肿瘤形成。这些变化的结果可能会或不会被免疫系统的检查(免疫监视)所抑制。
在此之前,GPR110水平的变化和前列腺癌或肺癌之间不存在已被证明的关联。这样的关联可以有很多重要的诊断和治疗用途。依据本发明,现已发现(i)GPR110水平在前列腺癌和肺癌细胞中显著增加,和(ii)这种增加可以在病人血液或尿液中被检测。
发明概述
本发明包括,一方面,在人对象中筛查肺癌或前列腺癌的方法。该方法包括步骤:(a)检测对象样品中人GPR110的水平或其RNA转录物的水平,(b)确定人GPR110或其RNA转录物的检测水平是否分别比从大多数正常人样品确定的正常人个体内GPR110或其转录物水平高至少三倍。可选择地,该方法可以包括通过在人对象中分别独立检验肺癌或前列腺癌的方法筛查肺癌或前列腺癌的存在,条件是测定水平比正常水平高至少三倍,其中独立检验可以在步骤(a)和(b)之前,同时,或之后进行。
在对象样品是肺或前列腺的组织学组织样品情况下,步骤(a)可以包括,在对抗体结合到具有GPR110表位的细胞有效的条件下,将所述样品与特异性针对GPR110表位的抗-GRP110抗体接触,并检测结合于所述样品的抗体水平,和步骤(b)可以包括确定与对象肺或前列腺组织样品结合的抗体的检测水平是否分别比结合于从正常个体获得的人肺或前列腺组织样品的抗-GPR110抗体的检测水平高至少三倍。抗体可以特异性针对由SEQ ID NO:1内的氨基酸残基表示的GPR110表位。抗体可以是放射标记的GPR110抗体,步骤(a)可以包括通过闪烁扫描法检测所述组织内局部化的放射性标记的水平。
在对象样品是对象血液或血清样品的情况下,步骤(a)可以包括,在对抗体结合GPR110表位有效的条件下,将所述样品与特异性针对GPR110表位的抗-GPR110抗体接触,从未结合抗体分离结合于GPR110表位的抗体,并检测结合于GPR110表位的抗体的水平,和步骤(b)可以包括确定结合于GPR110表位的抗体的检测水平是否比结合于从正常个体获得的血液或血清样品中存在的GPR110表位的抗-GPR110抗体的检测水平高至少三倍。步骤(a)可以包括将血液或血清样品的体液施加于固相免疫检测装置,其中样品中GPR110水平由比色或荧光指标定性表示,确定步骤包括将该指标与已知标准比较。
在对象样品是肺或前列腺组织样品的情况下,步骤(a)可以包括处理样品以从中提取RNA转录物和检测编码GPR110蛋白至少一个片段的RNA转录物的水平,和步骤(b)可以包括确定RNA转录物的检测水平是否比从正常个体获得的肺或前列腺组织样品中编码GPR110蛋白至少一个片段的转录物的检测水平高至少三倍。
另一方面,本发明包括检查肺癌或前列腺癌存在的方法中的改进,其通过检测肺癌或前列腺癌的诊断性生物学指标水平的降低或升高来进行。这种改进包括步骤:(a)检测对象样品中人GPR110或其转录物的水平,和(b)确定人GPR110或其转录物的检测水平是否分别比从多数正常人样品确定的正常人个体中GPR110或其转录物的水平高至少三倍,作为肺癌或前列腺癌存在的另一个指标。上面提到的方法的多种优选实施方案也应用于本发明的这个方面。
例如,所述改进可以用于检查人男性对象中前列腺癌的方法中,所述方法包括将对象体液样品与特异性针对选自总前列腺特异性抗原(PSA),游离PSA,和磷脂酰肌醇聚糖3蛋白(GPC3)之一的至少一种标志蛋白的抗体反应,确定对象是否有增加水平的至少一种所述标志蛋白,做为前列腺癌的指标。
又另一方面,本发明涉及来自人对象的血液或血清样品中的GPR110的检测值和选自总前列腺特异性抗原(PSA),游离PSA和磷脂酰肌醇聚糖3蛋白(GPC3)的至少一种的标志抗原的检测值在筛查个体前列腺癌的存在中的用途。
本发明也公开了用于筛查人对象中的前列腺癌或肺癌,或对象前列腺癌或肺癌治疗分期的诊断装置,包括(a)接受对象体液样品的结构,(b)一种抗体,其特异性针对GPR110的选定结构域或表位,结合于所述结构,能够与所述结构接受的体液反应,并与其他结合于该结构的试剂一起产生可检测的反应,指示包含所述表位或结构域的GPR110样品蛋白的存在,和(c)已知标准指标,根据此指标,可检测反应所产生的水平可以被评定为与前列腺癌或肺癌有关的增加水平。此装置可以更普遍地用于筛查或分期以GPR110水平增加为特征的其它类型的人类癌症。
所述装置的结构可以包括多孔垫板,其中包埋有抗体,当液体样品加到垫板上时,用于与所述样品反应,可检测反应可以用比色或荧光指标指示,且已知的标准指标可以包括这样的指标,其代表包含相应于前列腺癌或肺癌相关的表位或结构域的表位或结构域的GPR110水平。
所述装置可以包括用于形成与产生的GPR110的水平有关的信号的分光光度计测量器,用于比较该信号与前列腺癌或肺癌相关的已知标准信号值的微处理器,和用于显示所述微处理器的输出结果的显示器。
所述装置中的抗-GPR110结合蛋白可以是特异性针对包含在SEQ IDNO:1或SEQ ID NO:2中的表位的抗体。
为了用于筛查人对象的前列腺癌,所述装置的元件(b)可以进一步包括一种抗体,其(i)特异性针对至少一种选自总前列腺特异性抗原(PSA),游离PSA,和磷脂酰肌醇聚糖3蛋白(GPC3)之一的标志蛋白,(ii)与所述结构结合和(iii)能够与所述结构接受的体液反应,与结合于该结构的其它试剂一起,产生指示样品中标志蛋白水平的可检测反应,和元件(c)可以进一步包括第二已知标准指标,根据该指标,产生的可检测的标志蛋白反应水平,与可检测的GPR110水平一起,被评定为前列腺癌的指标。两个标准指标可以被安排为,例如,配对值,每个配对代表个体前列腺癌预先确定的可能性。
本发明还公开了一种治疗个体前列腺癌或肺癌的方法,步骤为:(a)分别与同样组织的人细胞中GPR110蛋白或RNA转录物的正常范围比较,确定来自对象的癌症组织细胞是否有增加水平的GPR110蛋白或RNA转录物,作为前列腺癌或肺癌的指标,和(b)如果个体有如此增加的GPR110水平,施用治疗有效量的GPR110抗体,当其与前列腺癌或肺癌细胞免疫特异性反应时有效抑制该细胞的生长或生存。
GPR110抗体可以是特异性针对包含在SEQ ID NO:1中的表位的人或人源化的抗-GPR110抗体。当结合于前列腺癌或肺癌细胞表面的GPR110时,该抗体可以有效促进抗体依赖的细胞毒。该抗体可以偶联于一种治疗剂,当该治疗剂结合于或被掺入所述细胞,其有效杀伤或抑制癌症细胞。
进一步公开的是一种减轻患有前列腺癌或肺癌的个体肿瘤负荷的方法,步骤为:(a)将对象抗原呈递细胞暴露于人GPR110多肽或其抗原片段,和(b)通过暴露,刺激和引起CD4辅助性T细胞,CD8细胞毒性淋巴细胞Tc和CD8非细胞毒性T抑制性淋巴细胞的克隆性扩增,从而引起对象中GPR110抗原特异性CD4辅助性T细胞,GPR110抗原特异性CD8细胞毒性淋巴细胞Tc和GPR110抗原特异性CD8非细胞毒性T-抑制性淋巴细胞的扩增。
所述暴露步骤可以包括,有效激活细胞的条件下,体外暴露对象抗原呈递细胞于人GPR110多肽或其抗原片段,并将激活的细胞注射给对象。
可选择地,暴露步骤可以包括将合适佐剂中携带的人GPR110多肽或其片段注射给对象。
在一个相关的方面,本发明包括一种减轻患有前列腺癌或肺癌的对象肿瘤负荷的方法,其是通过将合适佐剂中携带的人GPR110多肽或其抗原片段注射给对象。
在另外的方面,本发明包括一种筛选可以有效治疗前列腺癌或肺癌的化合物的方法。该方法包括将每一系列待检化合物加入到其细胞表面表达GPR110蛋白的细胞中的步骤,在GPR110激动剂或拮抗剂结合到细胞表面蛋白的情况下,会有效导致细胞状态的可检测变化,加入每种待检化合物,确定是否发生了此种细胞状态的可检测变化。
在另外的方面,本发明包括分析物GPR110或其片段或变体的检测。试剂包括特异性针对GPR110或片段的抗GPR110抗体,和检测标签或标记,优选共价结合于该抗体,当结合于被测物GPR110,其能用于检测和/或定量出现的抗体量。
阅读了下面更充分描述的本发明内容的条件下,本发明的这些和其他方面,目的,优点,和特点对于本领域技术人员是显而易见的。
附图简介
图1显示了小鼠Gpr110基因座的基因组排列,为UCSC基因组网络站点浏览器的专门屏幕打印视图(February 2006版mm8基因汇编)。顶部,在17号染色体上的碱基位置。“PicoSL3”下面的绿色垂直柱代表逆转录病毒整合到从单一肿瘤(754S-2)鉴定的基因座。公共结构域整合位点(68SB865H07-1)在“RTCGD”下面被标明。
图2A-2C显示了人前列腺肿瘤(2A),良性前列腺增生(2B),和正常组织(2C)的免疫组化染色(棕色)。在正常组织或良性前列腺增生中通常观察到没有表达或低表达,而在肿瘤组织中观察到显著的过表达。多克隆兔抗体血清与人GPR110的1-590氨基酸残基(此处定义为SEQ ID NO:1)内发现的表位反应,。
图3A和3B显示了用抗-GPR110抗体(3A)和抗-PSA抗体染人良性前列腺增生组织的免疫组化染色(棕色)。箭头指向一小组癌症干细胞,其为GPR110阳性和PSA阴性。使用的GPR110肽血清与图2中描述的相同。
图4A和4B显示了人肺肿瘤(4A)和正常组织(4B)的免疫组化染色(棕色)。正常组织中观察到不表达或低表达,而肿瘤组织中观察到显著的过表达。使用的肽血清与图2中描述的相同。
图5A和5B显示了确定病人GPR110水平的固相诊断装置,在检测初始阶段(5A)和最终阶段(5B)。
图6显示了依照本发明构建的用于诊断前列腺癌或肺癌基因易感性的基因芯片的一部分。
图7A和7B显示了通过在两份不同的正常和肿瘤肺组织中定量PCR检测的GPR110RNA的表达。GUSB基因做为内对照被检测。相对于正常肺样品的平均表达,计算每份样品的表达。
发明详述
A定义
下列术语具有下面给出的定义,除非另在说明书中指明。
“筛查”癌症意味着诊断信息,单独,或者与其他诊断信息一起,可以用于确定癌症的存在或不存在,或者癌症可能性的增加,或者用于癌症分类,例如,肺癌以GPR110表达水平升高为特征。
“诊断肺癌或前列腺癌的其它指标”指诊断试验,而不是可以用于检测或特征化癌症的存在或程度或类型的生物学指标。典型的指标包括X-线,CT扫描,或MRI成像方法获得的成像资料,或活组织的组织学观察。
癌症的“分期”治疗,依照本发明,包括基于检测到的GPR110水平确定个体的癌症分期和制定该期的疗法。癌症有四个公认分期,其通过癌症细胞的定位和组织架构的程度定义。此外,癌症可以被定义为早期(此时癌症对很多基于激素的治疗有反应),和晚期(更严重的雄激素不依赖的阶段)。
“GPR110的检测水平”指野生型人GPR110,或者变体(例如,剪接变体或该蛋白突变形式),或GPR110片段的检测水平。
“人GPR110转录物的检测水平”指编码野生型人GPR110,或者变体(例如,剪接变体或该蛋白突变形式)或GPR110片段的RNA转录物的检测水平。
GPR110“增加”或“高于正常”的水平指例如通过免疫化学染色或检测确定的该蛋白或其片段或变体的水平比正常(非癌性的)个体群检测的该蛋白的可检测水平值高至少约百分之五十。优选地,GPR110的水平至少比来自正常人的相似样品的GPR110值高三倍。
GPR110RNA转录物“增加”或“高于正常”的水平指例如,通过PCR扩增和转录物分离确定的转录物量的水平比正常(非癌性的)个体群检测的该转录物的可检测水平值高至少约百分之五十。优选地,GPR110的水平至少比来自正常人的相似样品的GPR110值高三倍。
“正常(非癌性的)个体群检测的GPR110蛋白或其RNA转录物的可检测水平值”可以指,例如,5个或更多,优选10个或更多正常个体群的该值的统计学均数或平均值,或者可以指正常个体群中个体的GPR110蛋白或转录物的最高记录值。该数值通过使用以下描述的检测方法检测来自所选样品源例如肺或前列腺组织或者血液或血清样品的GPR110或其转录物而迅速确定。应理解正常值是从与检测其中GPR110或其转录物水平增加的存在的组织或样品源相同类型的组织例如肺或前列腺组织或样品源例如血液或血清样品确定的。
“GPR110检测”指一种检测,其测定野生型或变体形式的GPR110蛋白或其表位的水平或存在,或测定编码GPR110蛋白或其片段的RNA转录物水平。
B.GPR110蛋白和表达
人GPR110基因编码一个推定的孤立“粘附类型”G蛋白-偶联受体,其生物学功能和天然配体是未知的(refs.1-3)。人GPR110基因有两种已知的同种型并被发现位于染色体区6p12.3。同种型1(NM_153840.2)编码一种推定的蛋白(NP_722582.2),具有910个氨基酸(AA),计算分子量(MW)101234Da。同种型2(NM_025048.2)编码一种推定蛋白(NP_079324.2),具有218个氨基酸,计算分子量24745Da,和与同种型1相比独特的C-末端。小鼠Gpr110基因(NM_133766.1)被发现位于染色体区17B3;编码的蛋白(NP_598537.1)具有908个氨基酸,计算分子量101338Da。人GPR110蛋白是一种推定的细胞表面7跨膜蛋白,包含G-蛋白-偶联受体蛋白水解位点(GPS)结构域和SEA结构域,以及几个可能的靠近N-端的N-连结糖基化位点。
C.鉴定GPR110为癌症基因
癌症基因(癌基因和肿瘤抑制基因)通过使用原病毒标记以高通量方式定义。尽管病毒还没有被提示为人类癌症的主要原因,利用肿瘤病毒的研究已经导致发现了很多癌基因和原癌基因。在病毒标记中,小鼠被不包含癌基因的逆转录病毒感染(例如,小鼠白血病病毒,MLV或小鼠乳腺瘤病毒,MMTV(4-8)。近来,通过使用转座子,这种方法的宿主范围已被拓宽(9,10)。
在逆转录病毒的感染过程中,病毒整合到细胞基因组,将其DNA插入基因附近或内部,其导致各种结果:(i)插入位点距离原癌基因太远,从而不能活化原癌基因。在此情况下,不选择该细胞。(ii)原病毒插入到一个原癌基因的200kb内,但不在该基因内(类型1)。在此,或者病毒启动子或者病毒增强子增加了该原癌基因的表达水平。(iii)原病毒插入一个基因内,破坏或改变其功能(类型2)。不选择在不是原癌基因或肿瘤抑制基因的基因中包含类型1或类型2插入事件的细胞。如果整合导致了肿瘤的形成,邻近整合位点的基因能够被鉴定,可分类为原癌基因或者肿瘤抑制基因。本方法用于鉴定许多新原癌基因和进一步证实通过与病毒癌基因的同源性特点发现的已知的原癌基因(7,8)。如果逆转录病毒落入到一个基因内并截短或破坏它,可以获得一个肿瘤抑制基因。在这些情况下,该抑制基因可以是单倍体不足的,或可选择地,小鼠同时提供其它等位基因上的突变。整合事件也能够导致更复杂的结果,例如截短的基因产物或反义或微RNA的转录的显性负面效应。
在用T淋巴细胞病毒SL3-3的筛选中,收获包含原病毒整合入Gpr110基因的内含子1中的小鼠肿瘤(图1)。该整合引起Gpr110基因的过表达。该基因的人类同源体是人GPR110基因。
D.人类肿瘤和正常组织中GPR110的表达和RNA转录物
GPR110抗体的抗原性表位在人前列腺肿瘤中过表达(图2A),而良性前列腺增生(BPH)细胞和前列腺肿瘤细胞的正常对应部分没有或只微弱表达GPR110蛋白(图2B,2C),说明该蛋白分布和/或局部量(密度)的增加可以诊断人前列腺癌。有时,一小亚类BPH细胞被GPR110抗体染色(图3A,箭头)。这些GPR110阳性细胞缺乏PSA表达(图3B,箭头),并且符合被分类为前列腺癌干细胞。
此外,GPR110抗体的抗原表位在人肺肿瘤内也是过表达的(图4A),而这些肿瘤细胞的正常对应部分没有或只微量表达GPR110蛋白(图4B),说明该蛋白分布和/或局部量(密度)的增加可以诊断人肺癌。
更为普遍地,本发明提供了一种检测通常只微弱表达或包含GPR110的组织或其他对象样品例如血液或血清以确定癌症存在和程度的方法。该方法尤其对检测前列腺和肺组织有用,例如确定病人前列腺癌和肺癌的亚型。在一种直接用于检测前列腺和肺组织的方法中,组织被标记的特异性针对GPR110的选择结构域或表位的抗体染色,例如,荧光标记抗体(见下面的E部分),以将标记连接到组织细胞。可选择地,组织用非标记的GPR110抗体染色,细胞结合抗体复合物用第二标记抗体标记,例如携带荧光、比色或金-颗粒报道子的第二抗体。根据相对于正常前列腺或肺细胞中标志的分布和范围的可检测标志增加的分布和/或范围(通常是两者)来确定组织中前列腺癌或肺癌的存在,程度和分期。给结合于组织学的组织样品的抗体的程度和范围评分的计分法众所周知(例如,“Loda系统”)。在本方法中,强度评分2+或3+和a%细胞染色评分2或3见于35%-40%的用抗GPR110抗体标记的肺肿瘤。对于前列腺肿瘤,20%的肿瘤具有强度评分1和%细胞染色评分2。对于良性前列腺增生样品,当用抗GPR110抗体标记时,70%的强度评分和%细胞染色评分都为0;30%具有强度评分“痕量”或1,a%细胞评分1。
为确证GPR110在肺癌中的作用,检测两种不同系列的正常和肿瘤肺组织中的GPR110RNA转录物水平(使用外显子连接(ExJ2-3)Taqman探针)。在第一系列组织中,被检测的15份肺腺癌肿瘤中的4份(2,3,6和13)显示了比正常肺样品高8倍到超过100倍的GPR110RNA水平(图7A)。在第二系列组织中,与正常肺样品相比,40份肺癌样品中的6份具有从5倍到35倍GPR110的过表达(图7B)。此6份升高的样品(27,33,34,和39)中的4份来自肺腺癌,剩下的2份(26和40)是鳞状细胞癌。从两个表达实验总的来说,升高的GPR110表达可见于约20%的被检测肺肿瘤。
E.制备抗-GPR110抗体
该部分描述了抗-GPR110抗体的产生,像在下面部分进一步描述的那样,用于诊断和治疗目的。本发明使用的抗-GPR110抗体能够通过各种生产单克隆,多克隆,和/或重组抗体的常规方法获得。一种优选的抗体,尤其用于诊断用途,是小鼠单克隆抗体,根据众所周知的杂交瘤方法制备。简要地,可以首先获得人GPR110,例如,通过表达GPR110基因。纯化的GPR110蛋白用作免疫原。可选择地,GPR110的一部分肽可以用做致敏抗原。特别地,为了产生特异性针对选择的GPR110表位或结构域的抗体,定义该结构域或表位的肽可以用做免疫原。示例性的免疫原包括SEQ ID NO:1内的氨基酸残基代表的GPR110表位。
在诊断应用中有用的抗-GPR110抗体可以用多种可检测标签标记,包括可检测的报道子,例如用于酶联免疫吸附试验(ELISA)的酶,可检测的颗粒,例如金颗粒和携带报道子的脂质体,比色或荧光报道子,标记例如量子点纳米晶体颗粒(quantum dot nanocrystal particle),放射性标记,和标记例如生物素标记,其可以连接第二可检测标记,例如可连接报道子标记的抗生蛋白链菌素标记。在一些检测形式中,未标记的抗GPR110抗体,例如,小鼠IgG抗体,通过与标记的抗体如标记的抗-小鼠IgG抗体反应而被检测。
对于治疗用途,具有GPR110结合活性的人单克隆抗体能够通过用GPR110体外致敏人淋巴细胞,和使致敏的淋巴细胞与具有永久分裂潜能的人源骨髓瘤细胞融合而产生。可选择地,做为抗原的GPR110可以被施用给具有所有人类抗体基因库的转基因动物,以获得抗-GPR110抗体产生细胞,于是GPR110的人类抗体可以从永生化的抗-GPR110抗体产生细胞获得。
同样用于治疗用途,抗体可以偶联于(用其衍生化)一种治疗剂,例如毒素,锚定于螯合形式的放射性标记的金属,或装载抗肿瘤剂的载体例如脂质体,其中抗体载体定位于细胞表面,有效引起细胞膜的破坏(例如,通过载体与细胞膜的融合),并释放治疗剂到细胞内。
在另外的方法中,特异性针对GPR110抗原的人或人源化抗体可以用重组技术制备,例如已被报道过的那些(见,例如,美国专利6,090,382和6,258,562)。
F.诊断方法和试剂
在一个方面,本发明包括筛查人对象前列腺癌或肺癌的方法,所述方法通过以下步骤进行:(a)检测对象样品中人GPR110或其RNA转录物水平,和(b)确定人GPR110或其RNA转录物的检测水平是否分别比从多数正常人样品确定的正常人个体的GPR110或其转录物水平至少高三倍。如果检测水平比正常水平至少高三倍,该方法可以进一步包括通过在对象中分别独立检验肺癌或前列腺癌的方法检测肺癌或前列腺癌的存在,其中独立检验可以在步骤(a)和(b)之前,同时或以后进行。
例如,当独立检验先于GPR110检测,该独立检验可以表明肺癌或前列腺肿瘤的存在,并且GPR110检测随后被用于确证癌症的存在和/或指明癌症是以GPR110或其转录物水平增加为特征的类型。当独立检验与GPR110检测同时进行,该方法提供检测结果,其中两个或更多的癌症标志包括GPR110或其转录物被用于检测个体中的肺癌或前列腺癌。在第三种实施方案中,独立检验可以在GPR110检测之后进行,以证明肺癌或前列腺癌的诊断,和/或表明癌症是以GPR110或其变体的增加的水平的存在为特征的类型。
所述方法的一种实施方案中,对象样品是肺或前列腺组织学的组织样品,已经在上面描述。在该实施方案中,样品被制备用于组织学检测,在抗体结合具有GPR110表位的细胞的有效条件下,用特异性针对GPR110表位的抗GPR110抗体染色。与样品相关的抗体水平可以使用标准组织学方法确定,例如总体染色或荧光的检测,或在抗-GPR110抗体被放射性标志标记的情况下通过放射性水平的检测。
该方法的一种实施方案中,对象样品是血液或血清样品,在下面详述。该实施方案包括在抗体结合GPR110表位的有效条件下,使样品与特异性针对GPR110表位的抗GPR110抗体接触,和分离未结合抗体和结合于GPR110表位的抗体,检测结合于GPR110表位的抗体的水平。具有固定的抗-GPR测定的固相-条带检测装置用于捕获样品中的GPR110,在下面讨论。优选的体液样品是血液,尿液和唾液。尿液被检测的情况下,指示前列腺癌或肺癌的GPR110的检测水平典型地处于大于约1ng/ml样品液体的范围。
第三种普遍实施方案中,对象样品是肺或前列腺组织,用于检测GPR110转录物,参照图7A和7B在上面详述。在此实施方案中,组织样品被处理,从中提取RNA转录物,依照公知的方法,编码GPR110蛋白至少一个片段的RNA转录物水平由标准方法确定,例如通过PCR序列特异性扩增,或其它方法,包括序列特异性探针。
更普遍地,GPR110或其转录物的检测,做为诊断前列腺癌或肺癌的存在、程度、或分期的一种辅助,可以单独或与前列腺癌或肺癌相关的另外的标志蛋白的检测和筛查联合使用。生物标记或标志蛋白指任何可检测的生物分子,其中改变的表达,分布或该生物标记的特定形式与生理条件例如疾病状态的存在、程度或分期相关。如本领域技术人员的理解,不需要生物标记和生理条件之间有严格的关联,在生物标记和生理条件之间只存在统计学显著性关联。另外的生物标记可以选自,但不限于,前列腺特异性抗原(PSA),包括总的PSA或游离的PSA或两者,磷脂酰肌醇聚糖3蛋白(GPC3)和其组合。
在另外的生物标记是PSA的情形下,根据本领域的方法,对于总PSA、游离PSA或其组合可以如上述确定PSA的水平或分布。在一些例子中,总PSA和fPSA的水平,在本领域通常表示为fPSA对总PSA的比例,可以与GPR110的检测联合使用。PSA检测可以在与检测GPR110所使用的相同或不同的生物学样品上进行。例如,为了筛查男性人对象前列腺癌,上面描述的本方法中的步骤(a)可包括使样品与特异性针对前列腺特异性抗原(PSA)的抗体反应,以产生与样品中PSA水平相关的反应产物,步骤(b)可以包括与非癌性人群样品中的PSA的正常范围比较,确定PSA的水平。
另外的生物标记GPC3的特点在于硫酸肝素蛋白多糖,其通过糖基化磷脂酰肌醇锚定在细胞膜上。该蛋白分子量65.6kDa,多肽链有580个氨基酸残基。该蛋白多糖的硫酸肝素链与肝素结合生长因子相互作用,从而作为细胞信号的共受体,尽管GPC3也可以其它方式结合。在胚胎发育中,GPC3调节肾脏分支形态发生过程中BMP和EGF-介导效应。它也控制肢体成型和骨骼发育中对BMP4的细胞反应。GPC3蛋白的水平在前列腺癌组织中增加。其做为前列腺癌的特异生物标记的用途和其检测方法,例如通过特异结合于GPC3的抗体的检测,在系列号为11/325,847的美国共同申请中描述。检测GPC3的方法可以使用特异性结合于GPC3的抗体,例如多克隆,单克隆,或重组抗体。一种示例性抗体,尤其用于诊断用途,包括小鼠单克隆抗体,其根据公知的杂交瘤方法制备。简要地,可以首先获得人GPC3,例如,通过表达GPC3(MXR7)基因,如Lage,H.等(Gene 188(1997),151-156)公开的那样。纯化的GPC3蛋白被用做免疫原。可选择地,GPC3的一部分肽可以被用做致敏抗原。部分肽可以通过从人GPC3氨基酸序列化学合成获得。例如可以应用的示例GPC3序列包括但不限于,DLFIDKKVLKVAHVEHEET,SEQ ID NO:3(氨基酸残基365到383,由外显子4编码)和LAYDLDVDDAPGNSQQ,SEQID NO:4(氨基酸残基526到541,由外显子8编码)等。考虑到GPR3的序列已知,用于产生直接针对GPC3的抗体的其它肽对于本领域技术人员是显而易见的。
检测可以通过多种用于检测体液抗原的测定方法中的任一种实现,包括ELISA技术,均相法,例如,包括荧光淬灭,和多种固相夹心检测,其中GPR110抗原被固相支持物上携带的抗-GPR110抗体捕获,固定的抗原-抗体复合物被第二抗-GPR110抗体标记,例如,携带比色或金-颗粒报道子的第二抗体。
图5A和5B说明了依照本发明的一个实施方案构建的固相检测条,其适于进行刚才提到夹心免疫测定,并且分别显示了开始和最终的检测状态。检测条,总体显示在10处,包括多孔支持物或垫12,其具有在支持物上游区的加样区14和在下游区的样品检测区16。加样区包括可检测的抗-GPRS10抗体试剂,例如,标记金颗粒的抗GPR110抗体,以非结合,即,非固定形式携带在该区内。该试剂由实心圆标示,例如在18处。与标记的抗体试剂中的抗体相同或不同的抗GPR110抗体被固定于固体支持物的检测区内,由“Y”形标示,例如在20处。
还显示了参照区22,其定位邻近于检测区,具有一个或多个有颜色的或阴影区,对应体液标本中GPR110的不同检测水平。在实施方案中显示,区22包括三个区域22a,22b,和22c,分别对应GPR110的以下检测水平:(a)低于癌症相关的水平,(b)对应较低的癌症相关阈值水平,和(c)比22b区的阈层值明显高的水平,如,2-3倍。这三个区域提供了一种已知的标准指示,照此指示,产生的可检测反应水平可以被评估作为与前列腺癌或肺癌相关的水平。检测条和参考区一起组成了检测装置,用于在人对象内筛查前列腺癌或肺癌,或用于人对象前列腺癌或肺癌的分期治疗。
在实施中,已知量的待检体液样品被加入到检测条的加样区,其弥散入该区,使得抗体试剂与样品中的GPR110抗原反应以形成抗原-抗体复合物。然后该复合物和未结合抗体试剂借毛细作用移往下游检测区,在该处抗原-抗体复合物由固定的抗体捕获,未结合试剂被带到支持物的末端,如24处所示。正如所能理解的,体液中的抗原浓度越高,检测区捕获的试剂浓度越高,该区内的颜色或强度越大。所述检测区产生的颜色或强度与参照区的标准比较,以确定与前列腺癌或肺癌存在或不存在相关的GPR110的定性水平。如果在检测中观察到高于阈值水平的GPR110,该对象可以归类于存在可能性更高的癌症类型,并且该对象可以被推荐进行另外的检查和/或更经常的检查。
在另外一个实施方案中,检测装置包括如同上述的检测条,但其已知的参照指示是由检测条阅读仪器提供的,阅读器具有(i)接受检测条的阅读槽,(ii)光源和光学检测,例如,分光光度计测量器,用于在检测条的检测区测量与检测相关的光学情况,(iii)电子的或处理器单元,其记录和处理来自光学检测器的信号,并转换该信号为GPR110的检测水平,和(iv)用户显示屏或窗。该仪器可以报告检测的体液样品实际的GPR110,允许操作者比较显示值与检测条或仪器提供的已知标准指示水平,以评估是否该个体有与前列腺癌或肺癌相关联的GPR110水平的增加,或为了治疗设计,评估癌症的可能阶段。可选择地,仪器自身可以包含储存的已知标准指示水平,其可以在内部与检测的水平比较,以产生指明是否检测到了与前列腺癌或肺癌相关联的GPR110的增加水平的输出信号,或指明癌症的阶段。
为了检测多种标志蛋白,刚才描述的检测装置可以怎样被改变,是能够被理解的,特别地,为了筛查或检测前列腺癌,GPR110蛋白与总PSA,游离PSA和/或GPC3组合。每个标记可以在限定了标记-特异性抗体的单独检测条中检测,装置可以进一步包括多种参照区,每个区提供已知标准指示,并由此可检测的标记蛋白反应产生的水平可以被评估,与可检测的GPR110水平一起,做为前列腺癌的指标。
可选择地,在电子检测装置中,多种标志的参照值可以被存储或用元组值代表,例如,配对值,其中元组中的每个值代表给定标志的癌症指示值,所以通过对照储存的元组值,分析多个值检测结果,基于与多种标志的相关性,该装置可以确定癌症风险。
G.鉴定与癌症相关的基因突变
在另一个方面,本发明提供了一种鉴定与人对象体内癌症风险增加相关的突变,所述癌症例如前列腺癌或肺癌。以下部分描述与前列腺癌或肺癌有关;但是,应理解该方法可以实施加于其它导致GPR110表达增加的癌症。实施该方法时,从患有前列腺癌或肺癌的病人中提取基因组DNA,所述病人优选包括选自代表不同种族和年龄组的男性或女性的病人。DNA序列或被检测区,特别地,是(i)人GPR110基因的启动子或15kB内的或不超过外显子1的5’UTR区,(ii)同一个基因5kB内的或不超过外显子15的3’UTR区,和(iii)同一个基因外显子1-15之内。
位于上述区域的一个或多个位点的突变,包括基因扩增,通过比较每个序列和来自正常(野生型)前列腺或肺组织的同一个区域的序列被鉴定。优选地,确定来自许多野生型个体的序列以保证真实的野生型序列。对于每份提取的DNA,比较病人序列和野生型序列,以鉴定病人序列中的突变,从而鉴定可能与前列腺癌或肺癌风险增加有关的突变。
一旦大量的这些突变例如至少50-200或更多被鉴定,其可以被用于构建基因筛查装置,例如,基因芯片,其对筛查个体对前列腺癌或肺癌的基因易感性有用。在一种实施方案中,所述装置包括基因芯片,其如图6中30所示,具有阵列区,如区34,36,各自包含结合的已知序列片段,如区34内的片段37。片段或探针长度优选25-27个碱基,各自包括上文鉴定的GPR110基因上游与前列腺癌或肺癌相关的突变之一。基因芯片构建和用这样的芯片检测突变序列是公知的。
在一种有代表性的基因筛查方法中,获得病人细胞,提取基因组DNA,使用荧光素化探针通过标准PCR扩增感兴趣的序列区。扩增的物质于随后在适于杂交的条件下与芯片阵列的序列反应,清洗阵列表面以去除未结合物质,接着用合适的芯片阅读器扫描以鉴定与前列腺癌或肺癌相关的任何突变序列。附图显示了将标记的基因组DNA片段(标明为42处)结合到具有结合的探针分子40的阵列区38。测定该阵列区的荧光信号可诊断临界上游GPR110区中的已知基因突变,能够诊断对前列腺癌或肺癌的基因易感性。
在另一可选实施方案中,如上面被鉴定的突变用于构建一系列分子倒位探针(MIPs),其能够鉴定基因突变的存在。构建和使用MIPs用于鉴定基因突变已经描述过(见,例如,参考文献11)。
H.治疗方法和药物制剂
该发明也包括治疗以癌症细胞中GPR110表达增加为特征的癌症的方法,例如,减轻人对象的肿瘤负荷。下面部分的描述与前列腺癌或肺癌相关;但是,应理解该方法可以用于以GPR110表达增加为特征的其它癌症。
在一种方法中,GPR110抗原,例如,全长GPR110或一个抗原肽,如,上面公开的GPR110肽中的一个,如包含来自SEQ ID NO:1之一的氨基序列被用于激活参与诱导特异性针对前列腺癌或肺癌细胞的细胞毒性T细胞的免疫细胞。在一种实施方案中,在有效激活细胞的条件下例如存在GM-CSF的条件下,其可以通过离体暴露将从病人获得的抗原呈递细胞给GPR110抗原实现。一旦被离体激活,该细胞再返回到病人体内,在那里激活的细胞有效刺激抗肿瘤的细胞毒性T细胞的克隆性扩增。该免疫治疗方法在例如美国专利号6,080,409和其中引用的相关文献中描述。
可选择地,GPR110抗原可以作为疫苗施用给病人,通常其存在于合适的佐剂中,例如包含GM-CSF的佐剂。该肽疫苗有效地刺激和引起CD4辅助性T细胞,CD8Tc细胞毒性淋巴细胞和CD8非细胞毒性T-抑制性淋巴细胞的克隆性扩增,引起个体内GPR110抗原特异性CD4辅助性T细胞,GPR110抗原特异性CD8Tc细胞毒性淋巴细胞和GPR110抗原特异性CD8非细胞毒性T-抑制性淋巴细胞的扩增。
制备适于注射的包含抗原的组合物,和免疫刺激细胞毒性T细胞合适的抗原剂量已经在很多关于免疫治疗诱导T细胞的专利和发表文献中描述。那些方法在涉及治疗前列腺癌或肺癌的GPR110抗原的本方法中是可应用的。治疗之后,监测病人癌症状态的变化,特别是通过联合肿瘤可视化方法,例如MRI或CAT扫描,和监测包括GPR110自身的前列腺癌或肺癌相关抗原的水平。
在另外一种常用的免疫治疗方法中,依照上述的检测方法,诊断患有前列腺癌或肺癌的病人首先被确证具有GPR110水平的升高。如果该检测中所述对象检验呈阳性,他或她通过施用抗-GPR110抗体被治疗。优选地,该抗体是人的或人源化抗体,如上面描述的那样制备,并通过在合适的生理学载体中静脉注射或皮下注射而施用。抗体量优选1到10mg/针剂,病人以每14天左右的间隔进行治疗。在治疗过程中,监视病人癌症状态的变化(通常通过联合肿瘤可视化方法)和前列腺癌或肺癌相关抗原的水平,如上所述。该疗法可以与其他前列腺癌或肺癌的治疗方法包括药物或放射性同位素疗法联合进行,并且可以持续直至观察到肿瘤体积理想的缩小。GPR110抗体可以是人或人源化抗体,当结合于前列腺癌或肺癌细胞表面的GPR110时,有效地促进抗体-依赖的细胞毒作用。该抗体可以用治疗剂例如毒素衍生,当偶联物结合于该细胞或被细胞吸收,有效地杀伤或抑制癌症细胞。
I基于细胞的化合物筛选
通常,多种表达系统和分析被用于评价G蛋白-偶联受体(GPCR)的功能和鉴定做为激动剂和拮抗剂的化合物。参考文献12-14综述了目前普遍针对GPCR的药物化合物筛选的高通量方法。在大规模筛选方案中,GPCR通常使用基于细胞的重组表达系统表达,包括酵母,昆虫(杆状病毒),非洲爪蟾属卵母细胞,和哺乳动物细胞系。尽管确定GPCR的药理学活性传统上是通过进行放射示踪标记的配体结合实验处理的,简单受体结合使用非放射活性的方法,如荧光偏振和荧光共振能量转移技术,也可以被检测。
GPRC与下游信号通路的功能性偶联可以通过测定下游事件如细胞内钙动员的标准实验评估。使用这些基于细胞的实验,目的GPCR例如在哺乳动物细胞内连同泛宿主性的自然存在的G蛋白如Gq15/16(或其联合体)或泛宿主性的改造的嵌合G-蛋白一起表达,后二者都可以与多个GPCR偶联并转导信号;细胞内钙的增多可以利用标准钙-敏感荧光染料检测。为了检测更多的即时第二信使信号分子,如cAMP和花生四烯酸,可以使用基因报告载体,其中cAMP结合位点例如与萤光素酶融合基因偶联。可选择地,基于荧光的系统可以用于检测与GPCR脱敏作用有关的蛋白例如B-抑制蛋白2的易位。其他类型的表达系统包括在非洲爪蟾属黑素细胞中表达GPCR,其中GPCR活性通过检测黑素细胞中存在的内源色素的色散或凝结来测定。
尽管本发明就特定实施方案和应用作了阐述,仍可以在不脱离要求保护的本发明情况下,进行多种变化和修改,这是可以理解的。
序列表
SEQ ID NO:1人GPR110蛋白的N-末端细胞外结构域(同种型1)(残基1-590)
MKVGVLWLISFFTFTDGHGGFLGKNDGIKTKKELIVNKKKHLGPVEEYQLLLQVT
YRDSKEKRDLRNFLK
LLKPPLLWSHGLIRIIRAKATTDCNSLNGVLQCTCEDSYTWFPPSCLDPQNCYL
HTAGALPSCECHLNNL
SQSVNFCERTKIWGTFKINERFTNDLLNSSSAIYSKYANGIEIQLKKAYERIQGFE
SVQVTQFRNGSIVA
GYEVVGSSSASELLSAIEHVAEKAKTALHKLFPLEDGSFRVFGKAQCNDIVFGF
GSKDDEYTLPCSSGYR
GNITAKCESSGWQVIRETCVLSLLEELNKNFSMIVGNATEAAVSSFVQNLSVIIR
QNPSTTVGNLASVVS
ILSNISSLSLASHFRVSNSTMEDVISIADNILNSASVTNWTVLLREEKYASSRLLET
LENISTLVPPTAL
PLNFSRKFIDWKGIPVNKSQLKRGYSYQIKMCPQNTSIPIRGRVLIGSDQFQRSL
PETIISMASLTLGNI
LPVSKNGNAQVNGPVISTVIQNYSINEVFLFFSKIESNLSQPHCVFWDFSHLQW
NDAGCHLVNETQDIVT
CQCTHLTSFSILMSPFVPSTIFPVVKWITY
SEQ ID NO:2人GPR110蛋白(同种型1)(残基1-910)
MKVGVLWLISFFTFTDGHGGFLGKNDGIKTKKELIVNKKKHLGPVEEYQLLLQVT
YRDSKEKRDLRNFLK
LLKPPLLWSHG LIRIIRAKATTDCNSLNGVLQCTCEDSYTWFPPSCLDPQNCYL
HTAGALPSCECHLNNL
SQSVNFCERTKIWGTFKINERFTNDLLNSSSAIYSKYANGIEIQLKKAYERIQGFE
SVQVTQFRNGSIVA
GYEVVGSSSASELLSAIEHVAEKAKTALHKLFPLEDGSFRVFGKAQCNDIVFGF
GSKDDEYTLPCSSGYR
GNITAKCESSGWQVIRETCVLSLLEELNKNFSMIVGNATEAAVSSFVQNLSVIIR
QNPSTTVGNLASVVS
ILSNISSLSLASHFRVSNSTMEDVISIADNILNSASVTNWTVLLREEKYASSRLLET
LENISTLVPPTAL
PLNFSRKFIDWKGIPVNKSQLKRGYSYQIKMCPQNTSIPIRGRVLIGSDQFQRSL
PETIISMASLTLGNI
LPVSKNGNAQVNGPVISTVIQNYSINEVFLFFSKIESNLSQPHCVFWDFSHLQW
NDAGCHLVNETQDIVT
CQCTHLTSFSILMSPFVPSTIFPVVKWITYVGLGISIGSLILCLIIEALFWKQIKKSQ
TSHTRRICMVNI
ALSLLIADVWFIVGATVDTTVNPSGVCTAAVFFTHFFYLSLFFWMLMLGILLAYRII
LVFHHMAQHLMMA
VGFCLGYGCPLIISVITIAVTQPSNTYKRKDVCWLNWSNGSKPLLAFVVPALAIV
AVNFVVVLLVLTKLW
RPTVGERLSRDDKATIIRVGKSLLILTPLLGLTWGFGIGTIVDSQNLAWHVIFALL
NAFQGFFILCFGIL
LDSKLRQLLFNKLSALSSWKQTEKQNSSDLSAKPKFSKPFNPLQNKGHYAFSH
TGDSSDNIMLTQFVSNE
SEQ ID NO:3(365至383氨基酸残基,由外显子4编码)
DLFIDKKVLKVAHVEHEET
SEQ ID NO:4(526至541氨基酸残基,由外显子8编码)
LAYDLDVDDAPGNSQQ
序列表
<110>皮可贝拉有限责任公司
<120>诊断和治疗前列腺癌和肺癌的方法
<130>598498015WO0
<140>To be Assigned
<141>Herewith
<150>US 60/916,719
<151>2007-05-08
<160>4
<170>FastSEQ for Windows Version 4.0
<210>1
<211>590
<212>PRT
<213>Homo sapiens
<400>1
Met Lys Val Gly Val Leu Trp Leu Ile Ser Phe Phe Thr Phe Thr Asp
1 5 10 15
Gly His Gly Gly Phe Leu Gly Lys Asn Asp Gly Ile Lys Thr Lys Lys
20 25 30
Glu Leu Ile Val Asn Lys Lys Lys His Leu Gly Pro Val Glu Glu Tyr
35 40 45
Gln Leu Leu Leu Gln Val Thr Tyr Arg Asp Ser Lys Glu Lys Arg Asp
50 55 60
Leu Arg Asn Phe Leu Lys Leu Leu Lys Pro Pro Leu Leu Trp Ser His
65 70 75 80
Gly Leu Ile Arg Ile Ile Arg Ala Lys Ala Thr Thr Asp Cys Asn Ser
85 90 95
Leu Asn Gly Val Leu Gln Cys Thr Cys Glu Asp Ser Tyr Thr Trp Phe
100 105 110
Pro Pro Ser Cys Leu Asp Pro Gln Asn Cys Tyr Leu His Thr Ala Gly
115 120 125
Ala Leu Pro Ser Cys Glu Cys His Leu Asn Asn Leu Ser Gln Ser Val
130 135 140
Asn Phe Cys Glu Arg Thr Lys Ile Trp Gly Thr Phe Lys Ile Asn Glu
145 150 155 160
Arg Phe Thr Asn Asp Leu Leu Asn Ser Ser Ser Ala Ile Tyr Ser Lys
165 170 175
Tyr Ala Asn Gly Ile Glu Ile Gln Leu Lys Lys Ala Tyr Glu Arg Ile
180 185 190
Gln Gly Phe Glu Ser Val Gln Val Thr Gln Phe Arg Asn Gly Ser Ile
195 200 205
Val Ala Gly Tyr Glu Val Val Gly Ser Ser Ser Ala Ser Glu Leu Leu
210 215 220
Ser Ala Ile Glu His Val Ala Glu Lys Ala Lys Thr Ala Leu His Lys
225 230 235 240
Leu Phe Pro Leu Glu Asp Gly Ser Phe Arg Val Phe Gly Lys Ala Gln
245 250 255
Cys Asn Asp Ile Val Phe Gly Phe Gly Ser Lys Asp Asp Glu Tyr Thr
260 265 270
Leu Pro Cys Ser Ser Gly Tyr Arg Gly Asn Ile Thr Ala Lys Cys Glu
275 280 285
Ser Ser Gly Trp Gln Val Ile Arg Glu Thr Cys Val Leu Ser Leu Leu
290 295 300
Glu Glu Leu Asn Lys Asn Phe Ser Met Ile Val Gly Asn Ala Thr Glu
305 310 315 320
Ala Ala Val Ser Ser Phe Val Gln Asn Leu Ser Val Ile Ile Arg Gln
325 330 335
Asn Pro Ser Thr Thr Val Gly Asn Leu Ala Ser Val Val Ser Ile Leu
340 345 350
Ser Asn Ile Ser Ser Leu Ser Leu Ala Ser His Phe Arg Val Ser Asn
355 360 365
Ser Thr Met Glu Asp Val Ile Ser Ile Ala Asp Asn Ile Leu Asn Ser
370 375 380
Ala Ser Val Thr Asn Trp Thr Val Leu Leu Arg Glu Glu Lys Tyr Ala
385 390 395 400
Ser Ser Arg Leu Leu Glu Thr Leu Glu Asn Ile Ser Thr Leu Val Pro
405 410 415
Pro Thr Ala Leu Pro Leu Asn Phe Ser Arg Lys Phe Ile Asp Trp Lys
420 425 430
Gly Ile Pro Val Asn Lys Ser Gln Leu Lys Arg Gly Tyr Ser Tyr Gln
435 440 445
Ile Lys Met Cys Pro Gln Asn Thr Ser Ile Pro Ile Arg Gly Arg Val
450 455 460
Leu Ile Gly Ser Asp Gln Phe Gln Arg Ser Leu Pro Glu Thr Ile Ile
465 470 475 480
Ser Met Ala Ser Leu Thr Leu Gly Asn Ile Leu Pro Val Ser Lys Asn
485 490 495
Gly Asn Ala Gln Val Asn Gly Pro Val Ile Ser Thr Val Ile Gln Asn
500 505 510
Tyr Ser Ile Asn Glu Val Phe Leu Phe Phe Ser Lys Ile Glu Ser Asn
515 520 525
Leu Ser Gln Pro His Cys Val Phe Trp Asp Phe Ser His Leu Gln Trp
530 535 540
Asn Asp Ala Gly Cys His Leu Val Asn Glu Thr Gln Asp Ile Val Thr
545 550 555 560
Cys Gln Cys Thr His Leu Thr Ser Phe Ser Ile Leu Met Ser Pro Phe
565 570 575
Val Pro Ser Thr Ile Phe Pro Val Val Lys Trp Ile Thr Tyr
580 585 590
<210>2
<211>910
<212>PRT
<213>Homo sapiens
<400>2
Met Lys Val Gly Val Leu Trp Leu Ile Ser Phe Phe Thr Phe Thr Asp
1 5 10 15
Gly His Gly Gly Phe Leu Gly Lys Asn Asp Gly Ile Lys Thr Lys Lys
20 25 30
Glu Leu Ile Val Asn Lys Lys Lys His Leu Gly Pro Val Glu Glu Tyr
35 40 45
Gln Leu Leu Leu Gln Val Thr Tyr Arg Asp Ser Lys Glu Lys Arg Asp
50 55 60
Leu Arg Asn Phe Leu Lys Leu Leu Lys Pro Pro Leu Leu Trp Ser His
65 70 75 80
Gly Leu Ile Arg Ile Ile Arg Ala Lys Ala Thr Thr Asp Cys Asn Ser
85 90 95
Leu Asn Gly Val Leu Gln Cys Thr Cys Glu Asp Ser Tyr Thr Trp Phe
100 105 110
Pro Pro Ser Cys Leu Asp Pro Gln Asn Cys Tyr Leu His Thr Ala Gly
115 120 125
Ala Leu Pro Ser Cys Glu Cys His Leu Asn Asn Leu Ser Gln Ser Val
130 135 140
Asn Phe Cys Glu Arg Thr Lys Ile Trp Gly Thr Phe Lys Tle Asn Glu
145 150 155 160
Arg Phe Thr Asn Asp Leu Leu Asn Ser Ser Ser Ala Ile Tyr Ser Lys
165 170 175
Tyr Ala Asn Gly Ile Glu Ile Gln Leu Lys Lys Ala Tyr Glu Arg Ile
180 185 190
Gln Gly Phe Glu Ser Val Gln Val Thr Gln Phe Arg Asn Gly Ser Ile
195 200 205
Val Ala Gly Tyr Glu Val Val Gly Ser Ser Ser Ala Ser Glu Leu Leu
210 215 220
Ser Ala Ile Glu His Val Ala Glu Lys Ala Lys Thr Ala Leu His Lys
225 230 235 240
Leu Phe Pro Leu Glu Asp Gly Ser Phe Arg Val Phe Gly Lys Ala Gln
245 250 255
Cys Asn Asp Ile Val Phe Gly Phe Gly Ser Lys Asp Asp Glu Tyr Thr
260 265 270
Leu Pro Cys Ser Ser Gly Tyr Arg Gly Asn Ile Thr Ala Lys Cys Glu
275 280 285
Ser Ser Gly Trp Gln Val Ile Arg Glu Thr Cys Val Leu Ser Leu Leu
290 295 300
Glu Glu Leu Asn Lys Asn Phe Ser Met Ile Val Gly Asn Ala Thr Glu
305 310 315 320
Ala Ala Val Ser Ser Phe Val Gln Asn Leu Ser Val Ile Ile Arg Gln
325 330 335
Asn Pro Ser Thr Thr Val Gly Asn Leu Ala Ser Val Val Ser Ile Leu
340 345 350
Ser Asn Ile Ser Ser Leu Ser Leu Ala Ser His Phe Arg Val Ser Asn
355 360 365
Ser Thr Met Glu Asp Val Ile Ser Ile Ala Asp Asn Ile Leu Asn Ser
370 375 380
Ala Ser Val Thr Asn Trp Thr Val Leu Leu Arg Glu Glu Lys Tyr Ala
385 390 395 400
Ser Ser Arg Leu Leu Glu Thr Leu Glu Asn Ile Ser Thr Leu Val Pro
405 410 415
Pro Thr Ala Leu Pro Leu Asn Phe Ser Arg Lys Phe Ile Asp Trp Lys
420 425 430
Gly Ile Pro Val Asn Lys Ser Gln Leu Lys Arg Gly Tyr Ser Tyr Gln
435 440 445
Ile Lys Met Cys Pro Gln Asn Thr Ser Ile Pro Ile Arg Gly Arg Val
450 455 460
Leu Ile Gly Ser Asp Gln Phe Gln Arg Ser Leu Pro Glu Thr Ile Ile
465 470 475 480
Ser Met Ala Ser Leu Thr Leu Gly Asn Ile Leu Pro Val Ser Lys Asn
485 490 495
Gly Asn Ala Gln Val Asn Gly Pro Val Ile Ser Thr Val Ile Gln Asn
500 505 510Tyr Ser Ile Asn Glu Val Phe Leu Phe Phe Ser Lys Ile Glu Ser Asn
515 520 525
Leu Ser Gln Pro His Cys Val Phe Trp Asp Phe Ser His Leu Gln Trp
530 535 540
Asn Asp Ala Gly Cys His Leu Val Asn Glu Thr Gln Asp Ile Val Thr
545 550 555 560
Cys Gln Cys Thr His Leu Thr Ser Phe Ser Ile Leu Met Ser Pro Phe
565 570 575
Val Pro Ser Thr Ile Phe Pro Val Val Lys Trp Ile Thr Tyr Val Gly
580 585 590
Leu Gly Ile Ser Ile Gly Ser Leu Ile Leu Cys Leu Ile Ile Glu Ala
595 600 605
Leu Phe Trp Lys Gln Ile Lys Lys Ser Gln Thr Ser His Thr Arg Arg
610 615 620
Ile Cys Met Val Asn Ile Ala Leu Ser Leu Leu Ile Ala Asp Val Trp
625 630 635 640
Phe Ile Val Gly Ala Thr Val Asp Thr Thr Val Asn Pro Ser Gly Val
645 650 655
Cys Thr Ala Ala Val Phe Phe Thr His Phe Phe Tyr Leu Ser Leu Phe
660 665 670
Phe Trp Met Leu Met Leu Gly Ile Leu Leu Ala Tyr Arg Ile Ile Leu
675 680 685
Val Phe His His Met Al a Gln His Leu Met Met Al a Val Gl y Phe Cys
690 695 700
Leu Gly Tyr Gly Cys Pro Leu Ile Ile Ser Val Ile Thr Ile Ala Val
705 710 715 720
Thr Gln Pro Ser Asn Thr Tyr Lys Arg Lys Asp Val Cys Trp Leu Asn
725 730 735
Trp Ser Asn Gly Ser Lys Pro Leu Leu Ala Phe Val Val Pro Ala Leu
740 745 750
Ala Ile Val Ala Val Asn Phe Val Val Val Leu Leu Val Leu Thr Lys
755 760 765
Leu Trp Arg Pro Thr Val Gly Glu Arg Leu Ser Arg Asp Asp Lys Ala
770 775 780
Thr Ile Ile Arg Val Gly Lys Ser Leu Leu Ile Leu Thr Pro Leu Leu
785 790 795 800
Gly Leu Thr Trp Gly Phe Gly Ile Gly Thr Ile Val Asp Ser Gln Asn
805 810 815
Leu Ala Trp His Val Ile Phe Ala Leu Leu Asn Ala Phe Gln Gly Phe
820 825 830
Phe Ile Leu Cys Phe Gly Ile Leu Leu Asp Ser Lys Leu Arg Gln Leu
835 840 845
Leu Phe Asn Lys Leu Ser Ala Leu Ser Ser Trp Lys Gln Thr Glu Lys
850 855 860
Gln Asn Ser Ser Asp Leu Ser Ala Lys Pro Lys Phe Ser Lys Pro Phe
865 870 875 880
Asn Pro Leu Gln Asn Lys Gly His Tyr Ala Phe Ser His Thr Gly Asp
885 890 895
Ser Ser Asp Asn Ile Met Leu Thr Gln Phe Val Ser Asn Glu
900 905 910
<210>3
<211>19
<212>PRT
<213>Homo sapiens
<400>3
Asp Leu Phe Ile Asp Lys Lys Val Leu Lys Val Ala His Val Glu His
1 5 10 15
Glu Glu Thr
<210>4
<211>16
<212>PRT
<213>Homo sapiens
<400>4
Leu Ala Tyr Asp Leu Asp Val Asp Asp Ala Pro Gly Asn Ser Gln Gln
1 5 10 15
Claims (24)
1.GPR110或其RNA转录物在制备一种用于通过如下方法在人对象中筛查肺癌或前列腺癌的试剂盒中的用途,所述方法包括
(a)检测对象样品中的人GPR110或其RNA转录物的水平
(b)确定人GPR110或其RNA转录物的检测水平是否分别比从大多数正常人样品确定的正常人对象内GPR110或其转录物水平高至少三倍。
2.权利要求1所述的用途,其中对象样品是肺或前列腺的组织学组织样品,且使用特异性针对GPR110表位的抗-GRP110抗体检测人GPR110的水平,其中步骤(a)包括,在对抗体结合到具有GPR110表位的细胞有效的条件下将所述样品与特异性针对GPR110表位的抗-GRP110抗体接触,并检测结合于所述样品的抗体水平,和步骤(b)包括确定与对象肺或前列腺组织样品结合的抗体的检测水平是否分别比结合于从正常个体获得的人肺或前列腺组织样品的抗-GPR110抗体的检测水平高至少三倍。
3.权利要求2所述的用途,其中所述抗体特异性针对SEQ ID NO:1中氨基酸残基代表的GPR110表位。
4.权利要求2所述的用途,其中步骤(a)中的抗-GPR110抗体是放射性标记的GPR110抗体,步骤(a)包括通过闪烁扫描法检测所述组织内局部化的放射性标记的水平。
5.权利要求1所述的用途,其中对象样品是对象血液或血清样品,且使用特异性针对GPR110表位的抗-GRP110抗体检测人GPR110的水平,其中步骤(a)包括在对抗体结合GPR110表位有效的条件下将所述样品与特异性针对GPR110表位的抗-GPR110抗体接触,从未结合抗体分离结合于GPR110表位的抗体,并检测结合于GPR110表位的抗体的水平,和步骤(b)包括确定结合于GPR110表位的抗体的检测水平是否比结合于从正常个体获得的血液或血清样品中存在的GPR110表位的抗-GPR110抗体的检测水平高至少三倍。
6.权利要求5所述的用途,其中步骤(a)包括将血液或血清样品体液施加于固相免疫分析装置,其中样品中的GPR110水平由比色或荧光指标定性表示,确定步骤包括将该指标与已知标准比较。
7.权利要求1所述的用途,其中对象样品是肺或前列腺组织样品,步骤(a)包括处理样品以从中提取RNA转录物并检测编码GPR110蛋白至少一个片段的RNA转录物的水平,和步骤(b)包括确定RNA转录物的检测水平是否比从正常个体获得的肺或前列腺组织样品中编码GPR110蛋白至少一个片段的转录物的检测水平高至少三倍。
8.GPR110或其RNA转录物作为肺癌或前列腺癌的诊断性生物学标志在制备用于通过检测所述生物学标志的降低或升高的水平来筛查肺癌或前列腺癌存在的试剂盒中的用途,改进包括
(a)检测对象样品中人GPR110或其转录物的水平,和
(b)确定人GPR110或其转录物的检测水平是否分别比从多数正常人样品确定的正常人个体中GPR110或其转录物的水平高至少三倍,作为肺癌或前列腺癌存在的另一个指标。
9.权利要求8所述的用途,其中对象样品是对象肺或前列腺组织学组织样品,步骤(a)包括在对抗体结合具有GPR110表位的细胞有效的条件下将所述样品与特异性针对GPR110表位的抗-GPR110抗体接触,检测结合于所述样品的抗体水平,和步骤(b)包括确定结合对象肺或前列腺组织样品的抗体的检测水平是否分别比结合于从正常个体获得的人肺或前列腺组织样品的抗GPR110抗体的检测水平高至少三倍。
10.权利要求9所述的用途,其中所述抗体是特异性针对SEQ IDNO:1中氨基酸残基代表的GPR110表位。
11.权利要求9所述的用途,其中步骤(a)中的抗-GPR110抗体是放射性标记的GPR110抗体,步骤(a)包括通过闪烁扫描检测所述组织中局部化的放射性标记的水平。
12.权利要求9所述的用途,其中对象样品是对象血液或血清样品,步骤(a)包括在对抗体结合GPR110表位有效的条件下将所述样品与特异性针对GPR110表位的抗GPR110抗体接触,从未结合抗体分离结合于GPR110表位的抗体,并检测结合于GPR110表位的抗体的水平,和步骤(b)包括确定结合于GPR110表位的抗体检测水平是否比结合于从正常个体获得的血液或血清样品中存在的GPR110表位的抗-GPR110抗体的检测水平高至少三倍。
13.权利要求12所述的用途,其中步骤(a)包括将血液或血清样品体液施加于固相免疫分析装置,其中样品中的GPR110水平由比色或荧光指标定性表示,确定步骤包括将该指标与已知标准比较。
14.权利要求8所述的用途,其中对象样品是肺或前列腺组织样品,步骤(a)包括处理样品以从中提取RNA转录物和检测编码GPR110蛋白至少一个片段的RNA转录物的水平,和步骤(b)包括确定RNA转录物的检测水平是否比从正常个体获得的肺或前列腺组织样品中的编码GPR110蛋白至少一个片段的转录物的检测水平高至少三倍。
15.权利要求8所述的用途,所述改进是在检测男性对象中的前列腺癌方法中,其通过将对象体液样品与特异性针对选自总前列腺特异性抗原(PSA)、游离PSA和磷脂酰肌醇蛋白聚糖3(GPC3)之一的至少一种标志蛋白的抗体反应,并确定该对象是否具有增加水平的至少一种所述标志蛋白,作为前列腺癌的指标。
16.用于测定来自人对象的血液或血清样品中GPR110值的试剂和用于测定选自总前列腺特异性抗原(PSA)、游离PSA和磷脂酰肌醇蛋白聚糖3(GPC3)的至少一种标志抗原的值的试剂在制备用于筛查对象前列腺癌存在的试剂盒中的用途。
17.用于筛查人对象中前列腺癌或肺癌或给对象前列腺癌或肺癌治疗分期的一种诊断装置,包括:
(a)接受来自对象的体液样品的结构
(b)一种抗体,其特异性针对GPR110的选定结构域或表位,结合于所述结构,能够与所述结构接受的体液反应,并与其他结合于该结构的试剂一起产生可检测的反应,指示包含所述表位或结构域的GPR110样品蛋白的存在,
(c)第一已知标准指标,根据此指标,可检测反应所产生的水平可以被评定为与前列腺癌或肺癌有关的水平增加。
18.权利要求17所述的装置,其中该装置内的结构包括多孔垫板,其中包埋抗体,当液体样品加到垫板上时用于与样品反应,可检测反应用比色或荧光指标指示,且已知的标准指标包括这样的标记,其代表包含相应于与前列腺癌或肺癌相关的表位或结构域的表位或结构域的GPR110的水平。
19.权利要求18所述的装置,进一步包括用于产生与产生的GPR110水平相关的信号的分光光度计测量器,用于比较该信号与前列腺癌或肺癌相关的已知标准信号值的微处理器,和用于显示该微处理器的输出结果的显示器。
20.权利要求18所述的装置,其中装置内的抗-GPR110结合蛋白是特异性针对包含在SEQ ID NO:1或SEQ ID NO:2中的表位的抗体。
21.GPR110抗体在制备一种用于通过如下方法治疗对象前列腺癌或肺癌的药物中的用途,所述方法包含:
(a)与同样组织的人细胞中的GPR110或其转录物的正常范围比较,确定是否来自对象的癌症组织细胞有增加水平的GPR110蛋白或RNA转录物,作为前列腺癌或肺癌的指标,和
(b)如果该对象有如此增加的GPR110或转录物水平,施用治疗有效量的GPR110抗体,当其与前列腺癌或肺癌细胞发生免疫特异性反应时有效抑制该细胞的生长或生存。
22.权利要求21所述的用途,其中GPR110抗体是特异性针对包含在SEQ ID NO:1中的表位的人或人源化的抗-GPR110抗体。
23.权利要求21所述的用途,其中当结合于前列腺癌或肺癌细胞表面的GPR110时,该抗体有效促进抗体依赖性细胞毒。
24.权利要求21所述的用途,其中该抗体偶联于治疗剂,当该治疗剂结合或掺入癌症细胞时能有效杀伤或抑制所述细胞。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US91671907P | 2007-05-08 | 2007-05-08 | |
US60/916,719 | 2007-05-08 | ||
PCT/US2008/005983 WO2008140774A2 (en) | 2007-05-08 | 2008-05-08 | Methods for diagnosing and treating prostate and lung cancer |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101918836A CN101918836A (zh) | 2010-12-15 |
CN101918836B true CN101918836B (zh) | 2014-04-30 |
Family
ID=40002842
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200880023852.5A Expired - Fee Related CN101918836B (zh) | 2007-05-08 | 2008-05-08 | 诊断和治疗前列腺癌和肺癌的方法 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20130224209A1 (zh) |
EP (1) | EP2156184B1 (zh) |
JP (1) | JP2010528261A (zh) |
CN (1) | CN101918836B (zh) |
AU (1) | AU2008251877A1 (zh) |
CA (1) | CA2686954A1 (zh) |
WO (1) | WO2008140774A2 (zh) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101754812B (zh) | 2007-05-04 | 2013-06-26 | 克拉洛诊断仪器公司 | 流体连接器和微流体系统 |
EP2427575B1 (en) | 2009-05-07 | 2018-01-24 | Veracyte, Inc. | Methods for diagnosis of thyroid conditions |
CA2805270C (en) * | 2010-06-04 | 2021-03-09 | The Brigham And Women's Hospital, Inc. | Treatment of inflammatory disorders |
JP5909070B2 (ja) * | 2010-10-28 | 2016-04-26 | 国立大学法人 東京大学 | Gs共役受容体に対する医薬品候補化合物をスクリーニングする方法 |
CN108108590A (zh) | 2012-03-05 | 2018-06-01 | 阿克蒂克合伙公司 | 分析系统和方法 |
CN102914658A (zh) * | 2012-10-24 | 2013-02-06 | 高维强 | Crisp3蛋白在前列腺癌诊断和治疗中的应用 |
US11976329B2 (en) | 2013-03-15 | 2024-05-07 | Veracyte, Inc. | Methods and systems for detecting usual interstitial pneumonia |
US10151754B2 (en) | 2014-01-17 | 2018-12-11 | Minomic International Ltd. | Cell surface prostate cancer antigen for diagnosis |
CN104090103B (zh) * | 2014-03-24 | 2016-08-31 | 福州市传染病医院 | 基于抗体修饰ZnSe纳米晶检测肝癌标志物GPC3的试剂盒 |
FI3123381T3 (fi) | 2014-03-28 | 2023-11-27 | Opko Diagnostics Llc | Eturauhassyövän diagnosointiin liittyviä koostumuksia ja menetelmiä |
EP2944652A1 (en) * | 2014-05-13 | 2015-11-18 | Technische Universität München | Glypican-3-specific T-cell receptors and their uses for immunotherapy of hepatocellular carcinoma |
US20160130656A1 (en) * | 2014-07-14 | 2016-05-12 | Allegro Diagnostics Corp. | Methods for evaluating lung cancer status |
US20170335396A1 (en) | 2014-11-05 | 2017-11-23 | Veracyte, Inc. | Systems and methods of diagnosing idiopathic pulmonary fibrosis on transbronchial biopsies using machine learning and high dimensional transcriptional data |
WO2016100301A1 (en) | 2014-12-15 | 2016-06-23 | The Brigham And Women's Hospital, Inc. | Use of cadherin-11 antagonists to treat obesity-associated conditions and other metabolic disorders |
CN107406510B (zh) | 2015-03-27 | 2022-02-18 | 欧普科诊断有限责任公司 | 前列腺抗原标准品及其用途 |
CN112034185A (zh) * | 2020-09-11 | 2020-12-04 | 上海市胸科医院 | Gpr110、vegfr、cd34在鉴别肺腺癌亚型中的用途 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2795403B2 (ja) * | 1986-07-30 | 1998-09-10 | 株式会社 シノテスト | 免疫的測定方法及び装置 |
JP4282906B2 (ja) * | 1998-08-10 | 2009-06-24 | アジェンシス,インコーポレイテッド | Bpc−1:前立腺および膀胱の癌細胞によって発現および分泌がなされる分泌型の脳特異的蛋白質 |
EP1364012A2 (en) | 2000-11-08 | 2003-11-26 | Millennium Pharmaceuticals, Inc. | 38650, 28472, 5495, 65507, 81588 and 14354 methods and compositions of human proteins and uses thereof |
EP1463928A2 (en) | 2001-04-18 | 2004-10-06 | Protein Design Labs | Methods of diagnosis of lung cancer, compositions and methods of screening for modulators of lung cancer |
AU2002337657A1 (en) * | 2001-07-25 | 2003-02-17 | Millennium Pharmaceuticals, Inc. | Novel genes, compositions, kits, and methods for identification, assessment, prevention, and therapy of prostate cancer |
WO2004023145A1 (ja) * | 2002-09-04 | 2004-03-18 | Perseus Proteomics Inc. | Gpc3の検出による癌の診断方法 |
WO2006086578A1 (en) * | 2002-10-02 | 2006-08-17 | Alfred E. Mann Institute For Biomedical Engineering At The University Of Southern California | Internal biochemical sensing device |
JP2004279157A (ja) * | 2003-03-14 | 2004-10-07 | Rohto Pharmaceut Co Ltd | 癌病巣判定のためのキット並びに方法 |
US20060094046A1 (en) * | 2004-02-11 | 2006-05-04 | Arie Abo | Compositions and methods relating to angiogenesis and tumorigenesis |
EP1723430A2 (fr) * | 2004-03-03 | 2006-11-22 | Biomerieux | Procede de detection de la forme libre activable du psa et son utilisation pour le diagnostic des pathologies benignes de la prostate et de l adenocarcinome de la prostate |
WO2006060653A2 (en) * | 2004-11-30 | 2006-06-08 | Veridex Llc | Lung cancer prognostics |
US20060211059A1 (en) * | 2005-03-18 | 2006-09-21 | Taneja Samir S | Methods of improving screening, diagnosis and staging of prostate cancer using serum testosterone |
JP2007075072A (ja) * | 2005-09-16 | 2007-03-29 | Satoshi Takahashi | プロサイモシンαの機能抑制用組成物を含む抗癌剤、およびプロサイモシンα遺伝子の発現抑制用組成物に含有される核酸 |
US20070099251A1 (en) * | 2005-10-17 | 2007-05-03 | Institute For Systems Biology | Tissue-and serum-derived glycoproteins and methods of their use |
-
2008
- 2008-05-08 AU AU2008251877A patent/AU2008251877A1/en not_active Abandoned
- 2008-05-08 WO PCT/US2008/005983 patent/WO2008140774A2/en active Application Filing
- 2008-05-08 CA CA 2686954 patent/CA2686954A1/en not_active Abandoned
- 2008-05-08 JP JP2010507474A patent/JP2010528261A/ja active Pending
- 2008-05-08 EP EP20080754314 patent/EP2156184B1/en not_active Not-in-force
- 2008-05-08 CN CN200880023852.5A patent/CN101918836B/zh not_active Expired - Fee Related
-
2013
- 2013-01-21 US US13/746,180 patent/US20130224209A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
WO2008140774A2 (en) | 2008-11-20 |
JP2010528261A (ja) | 2010-08-19 |
AU2008251877A2 (en) | 2010-02-04 |
AU2008251877A9 (en) | 2010-01-21 |
AU2008251877A1 (en) | 2008-11-20 |
CA2686954A1 (en) | 2008-11-20 |
EP2156184A2 (en) | 2010-02-24 |
EP2156184A4 (en) | 2010-07-21 |
WO2008140774A3 (en) | 2009-01-15 |
US20130224209A1 (en) | 2013-08-29 |
EP2156184B1 (en) | 2013-11-27 |
CN101918836A (zh) | 2010-12-15 |
WO2008140774A9 (en) | 2010-02-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101918836B (zh) | 诊断和治疗前列腺癌和肺癌的方法 | |
US8071324B2 (en) | Methods for diagnosing and treating kidney cancer | |
US7488584B2 (en) | Methods for diagnosing and treating kidney and colorectal cancer | |
US7723043B2 (en) | Methods for screening for prostate cancer | |
KR20110084995A (ko) | 전립선암에서의 반복적 유전자 융합체 | |
US7910316B2 (en) | Kit and method for detecting urothelial cancer | |
CN106662543A (zh) | 肺癌患者中的非侵入性基因突变检测 | |
AU2007271232A1 (en) | Prostate specific transcripts and the use thereof for prostate cancer therapeutics and diagnostics | |
KR100819395B1 (ko) | 포유류에서의 전-종양 및/또는 종양 상태의 확인법 | |
CN101341256B (zh) | 前列腺癌中的复发基因融合 | |
CN101322031B (zh) | 表达PDGFRα的非小细胞肺癌(NSCLC)肿瘤的鉴定 | |
KR101777259B1 (ko) | En2 단백질을 특이적으로 인식하는 단클론 항체 또는 이를 함유하는 전립선암 진단용 조성물 | |
CN103429617A (zh) | 包含抗-ck8/18复合物自身抗体的标记物及其诊断癌症的用途 | |
AU773297B2 (en) | Bladder nuclear matrix proteins, polynucleotide sequences encoding them, and their use | |
US20130109107A1 (en) | Diagnosis and treatment of autoimmune disease | |
JP3524536B2 (ja) | 癌の診断、モニタリング、ステージング、イメージングおよび処置のための新規方法 | |
JP4474551B2 (ja) | 神経膠腫細胞株u251の増殖能抑制剤及び浸潤能抑制剤 | |
US8313917B2 (en) | Methods of diagnosing latent and active malignancies | |
JP2008263840A (ja) | 胃ガンの診断又は検出のための組成物及び方法 | |
AU2004201412A1 (en) | Bladder nuclear matrix proteins, polynucleotide sequences encoding them, and their use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140430 Termination date: 20150508 |
|
EXPY | Termination of patent right or utility model |