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1. 发明申请

WO2003065870A2 DIGITAL AMPLIFICATION FOR DETECTION OF MISMATCH REPAIR DEFICIENT TUMOR CELLS 审中-公开
标题翻译：用于检测缺陷修复缺血性肿瘤细胞的数字放大
公开(公告)号：WO2003065870A2
公开(公告)日：2003-08-14
申请号：PCT/US2003/001062
申请日：2003-01-29
申请人： THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE , VOGELSTEIN, Bert , TRAVERSO, Giovanni, C. , KINZLER, Kenneth, W.
发明人： VOGELSTEIN, Bert , TRAVERSO, Giovanni, C. , KINZLER, Kenneth, W.
IPC分类号： A61B
CPC分类号： C12Q1/6886 , C12Q1/6851 , C12Q1/686 , C12Q2600/156 , C12Q2549/119 , C12Q2527/143
摘要： The detection of mutations in fecal DNA represents a promising, non-invasive approach for detecting colorectal cancers in average risk populations. One of the first practical applications of this technology involves the examination of microsatellite markers to sporadic cancers with mismatch repair deficiencies. As such cancers nearly always occur in the proximal colon, this test is useful as an adjunct to sigmoidoscopy, which detects only distal colorectal lesions.
摘要翻译：检测粪便DNA中的突变代表了一种有希望的非侵入性方法，用于检测平均危险人群中的结肠直肠癌。该技术的第一个实际应用之一涉及将微卫星标记物检查到具有错配修复缺陷的散发性癌症。因为这样的癌症几乎总是发生在近端结肠，这个测试是有用的乙状结肠镜检查的附件，只检测远端结肠直肠病变。

2. 发明申请

WO2003065870A3 DIGITAL AMPLIFICATION FOR DETECTION OF MISMATCH REPAIR DEFICIENT TUMOR CELLS 审中-公开
公开(公告)号：WO2003065870A3
公开(公告)日：2003-08-14
申请号：PCT/US2003/001062
申请日：2003-01-29
申请人： THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE , VOGELSTEIN, Bert , TRAVERSO, Giovanni, C. , KINZLER, Kenneth, W.
发明人： VOGELSTEIN, Bert , TRAVERSO, Giovanni, C. , KINZLER, Kenneth, W.
IPC分类号： C12Q1/68
摘要： The detection of mutations in fecal DNA represents a promising, non-invasive approach for detecting colorectal cancers in average risk populations. One of the first practical applications of this technology involves the examination of microsatellite markers to sporadic cancers with mismatch repair deficiencies. As such cancers nearly always occur in the proximal colon, this test is useful as an adjunct to sigmoidoscopy, which detects only distal colorectal lesions.

3. 发明申请

WO2003022863A1 SECRETED AND CELL SURFACE GENES EXPRESSED IN BENIGN AND MALIGNANT COLORECTAL TUMORS 审中-公开
标题翻译：分泌和细胞表面基因表达于胆管和恶性色素性肿瘤
公开(公告)号：WO2003022863A1
公开(公告)日：2003-03-20
申请号：PCT/US2002/028518
申请日：2002-09-09
申请人： THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE , BUCKHAULTS, Phillip , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： BUCKHAULTS, Phillip , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C07H21/04
CPC分类号： C07K14/495 , C07K14/47 , C07K14/705
摘要： Serial analysis of gene expression (SAGE) was used to identify transcripts encoding secreted or cell-surface proteins that were expressed in benign and malignant tumors of the colorectum. A total of 290,394 tags were analyzed from normal, adenomatous and cancerous colonic epithelium. Of the 21,343 different transcripts observed, 957 were found to be differentially expressed between normal and adenoma or between normal and cancer. Forty-nine transcripts were elevated ≥ 20-fold in adenomas, 40 transcripts were elevated ≥ 20-fold in cancers, and nine transcripts were elevated ≥ 20-fold in both. Product of six these nine transcripts (TGFBI, LYS, RDP, MIC-1, REGA, and DEHL) were predicted to be secreted or to reside on the cell surface and these were analyzed in more detail. The abnormal expression levels predicted by SAGE were confirmed by quantitative PCR analyses of each of these six genes. Moreover, the cell types responsible for the elevated expression were identified by in situ hybridization and by PCR analyses of epithelial cells immunoaffinity purified from primary tumors.
摘要翻译：基因表达（SAGE）的序列分析用于鉴定在结肠直肠癌和恶性肿瘤中表达的编码分泌的或细胞表面蛋白的转录物。从正常，腺瘤和癌性结肠上皮分析总共290,394个标签。在观察到的21,343种不同的转录物中，957被发现在正常和腺瘤之间或在正常和癌症之间差异表达。在腺瘤中，49个转录本升高了20倍，40个转录物在癌症中升高了20倍，而9个转录物在两者中升高了20倍。预计这六种转录本（TGFBI，LYS，RDP，MIC-1，REGA和DEHL）的六种产物被分泌或驻留在细胞表面上，并且更详细地分析这些转录物的产物。通过对这6种基因中的每一种进行定量PCR分析证实SAGE预测的异常表达水平。此外，通过原位杂交和通过从原发性肿瘤纯化的上皮细胞免疫亲和素的PCR分析来鉴定负责升高的表达的细胞类型。

4. 发明申请

WO2000011195A1 C-MYC IS ACTIVATED BY BETA-CATENIN AND TCF-4 审中-公开
标题翻译： C-MYC是由卡培他滨和TCF-4激活的
公开(公告)号：WO2000011195A1
公开(公告)日：2000-03-02
申请号：PCT/US1999/018774
申请日：1999-08-20
申请人： THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE , HE, Tong-Chuan , VOGELSTEIN, Bert , KINZLER, Kenneth, W.
发明人： HE, Tong-Chuan , VOGELSTEIN, Bert , KINZLER, Kenneth, W.
IPC分类号： C12N15/63
CPC分类号： C07K14/47 , A61K38/00 , A61K48/00 , C07K14/4705 , C12Q1/6897
摘要： The APC tumor suppressor protein binds to β-catenin, a protein recently shown to interact with Tcf/Lef transcription factors. Here, the gene encoding a Tcf family member that is expressed in colonic epithelium ( hTcf-4 ) was cloned and characterized. hTcf-4 transactivates transcription only when associated with β-catenin. Nuclei of APC -/- colon carcinoma cells were found to contain a stable β-catenin-hTCF-4 complex that was constitutively active, as measured by transcription of a Tcf reporter gene. Reintroduction of APC removed β-catenin from hTcf4 and abrogated the transcriptional transactivation. Constitutive transcription of TCF target genes, caused by loss of APC function, may be a crucial event in the early transformation of colonic epithelium. It is also shown here that the products of mutant APC genes found in colorectal tumors are defective in regulating β-catenin/Tcf-4 transcriptional activation. Furthermore, colorectal tumors with intact APC genes were shown to contain subtle activating mutations of β-catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of β-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or β-catenin.
摘要翻译： APC肿瘤抑制蛋白结合β-连环蛋白，最近显示出与Tcf / Lef转录因子相互作用的蛋白质。这里，克隆并表征编码在结肠上皮（hTcf-4）中表达的Tcf家族成员的基因。 hTcf-4仅在与β-连环蛋白相关时才转录转录。发现APC < - / - >结肠癌细胞的核含有一个稳定的β-连环蛋白-hTCF-4复合物，其通过Tcf报告基因的转录测量而具有组成型活性。重新引入APC从hTcf4中除去β-连环蛋白，并废除转录反式激活。由APC功能丧失引起的TCF靶基因的组成转录可能是结肠上皮早期转化的关键事件。这里还显示，在结肠直肠肿瘤中发现的突变APC基因的产物在调节β-连环蛋白/ Tcf-4转录激活中是缺陷的。此外，具有完整APC基因的结肠直肠肿瘤显示含有改变功能显着磷酸化位点的β-连环蛋白的微妙活化突变。这些结果表明，β-连环蛋白的调节对于APC的肿瘤抑制作用至关重要，并且该调节可以通过APC或β-连环蛋白的突变来规避。

5. 发明申请

WO1993020235A1 METHODS OF DETECTING MAMMALIAN NUCLEIC ACIDS ISOLATED FROM STOOL SPECIMEN AND REAGENTS THEREFOR 审中-公开
标题翻译：检测从其样本和试剂中分离的MAMMALIAN核酸的方法
公开(公告)号：WO1993020235A1
公开(公告)日：1993-10-14
申请号：PCT/US1993002960
申请日：1993-03-31
申请人： THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE
发明人： THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE , VOGELSTEIN, Bert , KINZLER, Kenneth, W.
IPC分类号： C12Q01/68
CPC分类号： G01N33/50 , C12Q1/6806 , C12Q1/6886 , C12Q2600/156 , Y10S435/81 , Y10T436/143333 , C12Q2527/137
摘要： A method to isolate nucleic acids from stool specimen which is used to detect mutations associated with gastrointestinal neoplasia. An exemplary result obtained is shown in the Figure. Reagents used to carry out the isolation of nucleic acids are also disclosed.
摘要翻译：从粪便标本中分离核酸的方法，用于检测与胃肠道肿瘤相关的突变。获得的示例性结果示于图中。还公开了用于进行核酸分离的试剂。

6. 发明申请

WO1997010363A1 METHOD FOR SERIAL ANALYSIS OF GENE EXPRESSION 审中-公开
标题翻译：基因表达序列分析方法
公开(公告)号：WO1997010363A1
公开(公告)日：1997-03-20
申请号：PCT/US1996014638
申请日：1996-09-12
申请人： THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE
发明人： THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE , KINZLER, Kenneth, W. , VOGELSTEIN, Bert , VELVULESCU, Victor, E. , ZHANG, Lin
IPC分类号： C12Q01/68
CPC分类号： C12N15/1096 , C12Q1/6809 , C12Q1/6869 , C12Q2539/103
摘要： Serial analysis of gene expression, SAGE, a method for the rapid quantitative and qualitative analysis of transcripts is provided. Short defined sequence tags corresponding to expressed genes are isolated and analysed. Sequencing of over 1,000 defined tags in a short period of time (e.g., hours) reveals a gene expression pattern characteristic of the function of a cell or tissue. Moreover, SAGE is useful as a gene discovery tool for the identification and isolation of novel sequence tags corresponding to novel transcripts and genes.
摘要翻译：提供基因表达的串行分析，SAGE，一种用于快速定量和定性分析转录本的方法。分离并分析与表达基因相对应的短定义序列标签。在短时间（例如，小时）内测定超过1,000个定义的标签显示了细胞或组织功能特征的基因表达模式。此外，SAGE可用作用于鉴定和分离对应于新转录物和基因的新序列标签的基因发现工具。

7. 发明申请

WO2005113824A2 PROTEIN TYROSINE PHOSPHATASE MUTATIONS IN CANCERS 审中-公开
标题翻译：蛋白质酪氨酸磷酸酶突变体
公开(公告)号：WO2005113824A2
公开(公告)日：2005-12-01
申请号：PCT/US2005/017105
申请日：2005-05-16
申请人： WANG, Zhenghe , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： WANG, Zhenghe , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6886 , C12N9/16 , C12Q2600/112 , C12Q2600/136 , C12Q2600/156 , C12Q2600/158 , C12Y301/03048 , G01N33/5011 , G01N2333/916
摘要： Tyrosine phosphorylation, regulated by protein tyrosine phosphatases (PTPs) and kinases (PTKs), is important in signaling pathways underlying tumorigenesis. A mutational analysis of the tyrosine phosphatase gene superfamily in human cancers identified 83 somatic mutations in six PTPs ( PTPRF, PTPRG, PTPRT, PTPN3, PTPN13, PTPN14 ) affecting 26 % of colorectal cancers and a smaller fraction of lung, breast and gastric cancers. Fifteen mutations were nonsense, frameshift or splice site alterations predicted to result in truncated proteins lacking phosphatase activity. Five missense mutations in the most commonly altered PTP ( PTPRP ) were biochemically examined and found to reduce phosphatase activity. Expression of wild-type but not a mutant PTPRT in human cancer cells inhibited cell growth. These observations suggest that the tyrosine phosphatase genes are tumor suppressor genes, regulating cellular pathways that may be amenable to therapeutic intervention.
摘要翻译：由蛋白酪氨酸磷酸酶（PTP）和激酶（PTK）调节的酪氨酸磷酸化在肿瘤发生的信号通路中是重要的。人类癌症中酪氨酸磷酸酶基因超家族的突变分析鉴定了影响26％结肠直肠癌和较小部分肺癌，乳腺癌和胃癌的6种PTPs（PTPRF，PTPRG，PTPRT，PTPN3，PTPN13，PTPN14）中的83个体细胞突变。十五个突变是无义，移位或剪接位点改变，预计会导致截短的蛋白质缺乏磷酸酶活性。在生物化学检查中发现最常改变的PTP（PTPRP）中的五个错义突变被发现可以降低磷酸酶活性。野生型但不是突变PTPRT在人类癌细胞中的表达抑制细胞生长。这些观察表明，酪氨酸磷酸酶基因是肿瘤抑制基因，调节可能适合于治疗性干预的细胞途径。

8. 发明申请

WO2005076984A2 THYMIDYLATE SYNTHASE GENE AND METASTASIS 审中-公开
标题翻译：甲基合成酶基因和METASTASIS
公开(公告)号：WO2005076984A2
公开(公告)日：2005-08-25
申请号：PCT/US2005/003776
申请日：2005-02-07
申请人： THE JOHN HOPKINS UNIVERSITY , WANG, Tian-LI , DIAZ, Luis , LENGAUER, Christoph , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： WANG, Tian-LI , DIAZ, Luis , LENGAUER, Christoph , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C12Q1/68 , G01N33/48 , G01N33/50 , G06F19/00
CPC分类号： C12Q1/6886 , C12Q2600/106 , C12Q2600/136
摘要： Thymidylate synthase (TYMS) gene amplification was observed in 23% of 31 5-FU resistant liver metastases, while no amplification was observed in metastases of patients that had not been treated with 5-FU. Patients with metastases containing TYMS amplification had a substantially shorter median survival (329 days) than those without amplification (1021 days, p
摘要翻译：在31例5-FU耐药性肝转移患者中，23例患者观察到胸苷酸合成酶（TYMS）基因扩增，而未用5-FU治疗的患者转移灶未观察到扩增。含有TYMS扩增的转移患者的中位生存期（329天）比没有扩增的患者显着更短（1021天，p <0.01）。 TYMS的遗传扩增对复发性结肠直肠癌患者的治疗具有重要意义。

9. 发明申请

WO2005062812A3 A rAAV-BASED SYSTEM FOR SOMATIC CELL GENE DISRUPTION 审中-公开
公开(公告)号：WO2005062812A3
公开(公告)日：2005-07-14
申请号：PCT/US2004/042597
申请日：2004-12-21
申请人： THE JOHNS HOPKINS UNIVERSITY , VOGELSTEIN, Bert , KINZLER, Kenneth, W. , KOHLI, Manu , RAGO, Carlo
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth, W. , KOHLI, Manu , RAGO, Carlo
IPC分类号： C12N15/63
摘要： Emerging evidence suggests that recombinant adeno-associated viral (rAAV) vectors can be used for specific gene targeting in human somatic cells. We have developed an rAAV vector construction procedure employing fusion PCR and a single cloning step that considerably simplifies the knockout process. We demonstrate its utility by disrupting genes at specific positions within human colon cancer cells as well as within immortalized normal epithelial cells. This technology should be broadly applicable to in vitro studies that require the manipulation of the human genome.

10. 发明申请

WO2005039491A2 CERTAIN IMPROVED COMBINATION BACTERIOLYTIC THERAPY FOR THE TREATMENT OF TUMORS 审中-公开
标题翻译：某些改进的联合用于治疗肿瘤的细菌疗法治疗
公开(公告)号：WO2005039491A2
公开(公告)日：2005-05-06
申请号：PCT/US2004/034624
申请日：2004-10-21
申请人： THE JOHN HOPKINS UNIVERSITY , DANG, Long , BETTEGOWDA, Chetan , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： DANG, Long , BETTEGOWDA, Chetan , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： A61K
CPC分类号： A61K35/742 , A61K31/195 , A61K31/4045 , A61K38/06 , A61K2300/00
摘要： Current approaches for treating cancer are limited, in part, by the inability of drugs to affect the poorly vascularized regions of tumors. We have found that spores of anaerobic bacteria in combination with agents which interact with microtubules can cause the destruction of both the vascular and avascular compartments of tumors. Two classes of microtubule inhibitors were found to exert markedly different effects. Some agents that inhibited microtubule synthesis such as HTI-286 and vinorelbine, caused rapid, massive hemorrhagic necrosis when used in combination with spores. In contrast, agents that stabilized microtubules, such as the taxanes docetaxel and MAC-321, resulted in slow tumor regressions that killed most neoplastic cells. Remaining cells in the poorly perfused regions of tumors could be eradicated by sporulated bacteria Mechanistic studies showed that the microtubule destabilizers, but not the microtubule stabilizers, radically reduced blood flow to tumors, thereby enlarging the hypoxic niche in which spores could germinate. A single intravenous injection of spores plus selected microtubule-interacting agents was able to cause regressions of several tumors in the absence of excessive toxicity.
摘要翻译：目前用于治疗癌症的方法部分地由于药物不能影响肿瘤血管化程度差的区域而受到限制。我们发现厌氧菌的孢子与微管相互作用的药物联合使用会导致肿瘤血管和血管腔的破坏。发现两类微管抑制剂发挥显着不同的作用。一些抑制微管合成的药物如HTI-286和长春瑞滨，当与孢子结合使用时会引起快速，大量的出血性坏死。相反，稳定微管的药物，如紫杉类多西他赛和MAC-321，导致缓慢的肿瘤消退，从而杀死大多数肿瘤细胞。机体研究表明，微管去稳定剂，但不是微管稳定剂，从根本上减少了血液流向肿瘤，从而扩大了孢子可能发芽的低氧生态位。单次静脉注射孢子加选定的微管相互作用剂能够在没有过量毒性的情况下引起几种肿瘤的消退。

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