公开(公告)号：EP0972037B1

公开(公告)日：2006-08-16

申请号：EP98912994.5

申请日：1998-03-20

申请人： THE JOHNS HOPKINS UNIVERSITY ,  Kylix B.V.

发明人： BARKER, Nick ,  CLEVERS, Hans ,  KINZLER, Kenneth, W. ,  KORINEK, Vladimir ,  MORIN, Patrice, J. ,  SPARKS, Andrew, B. ,  VOGELSTEIN, Bert

IPC分类号： C12N15/12 ,  C07K14/47 ,  C12Q1/68 ,  G01N33/50 ,  A61K38/17 ,  A61K48/00

CPC分类号： C07K14/47 ,  A61K38/00 ,  A61K48/00 ,  C07K14/4705 ,  C12Q1/6897

摘要： The APC tumor suppressor protein binds to beta -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 beta -catenin. Nuclei of APC colon carcinoma cells were found to contain a stable beta -catenin-hTCF-4 complex that was constitutively active, as measured by transcription of a Tcf reporter gene. Reintroduction of APC removed beta -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 beta -catenin/Tcf-4 transcriptional activation. Furthermore, colorectal tumors with intact APC genes were shown to contain subtle activating mutations of beta -catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of beta -catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or beta -catenin.

公开(公告)号：EP1255856B1

公开(公告)日：2005-03-09

申请号：EP00952304.4

申请日：2000-07-31

申请人： THE JOHNS HOPKINS UNIVERSITY

发明人： KINZLER, Kenneth, W. ,  VOGELSTEIN, Bert

IPC分类号： C12Q1/68

CPC分类号： C12Q1/6886 ,  C12Q1/6818 ,  C12Q1/6851 ,  C12Q1/686 ,  C12Q1/6874 ,  C12Q2600/156 ,  C12Q2600/158

摘要： The identification of pre-defined mutations expected to be present in a minor fraction of a cell population is important for a variety of basic research and clinical applications. The exponential, analog nature of the polymerase chain reaction is transformed into a linear, digital signal suitable for this purpose. Single molecules can be isolated by dilution and individually amplified; each product is then separately analyzed for the presence of mutations. The process provides a reliable and quantitative measure of the proportion of variant sequences within a DNA sample.

公开(公告)号：EP1446012A1

公开(公告)日：2004-08-18

申请号：EP02786766.2

申请日：2002-11-21

申请人： The Johns Hopkins University School of Medicine

发明人： DANG, Long ,  KINZLER, Kenneth, W. ,  VOGELSTEIN, BERT

IPC分类号： A01N63/00 ,  A01N65/00 ,  A61K48/00 ,  C12N1/12 ,  C12N1/20 ,  G01N33/53

CPC分类号： C12R1/145 ,  A61K31/475 ,  A61K35/742 ,  A61K38/193 ,  A61K41/00 ,  A61K45/06 ,  C12N1/36 ,  A61K2300/00

摘要： Current chemotherapeutic approaches for cancer are in part limited by the inability of drugs to destroy neoplastic cells within poorly vascularized compartments of tumors. We have here systematically assessed anaerobic bacteria for their capacity to grow expansively within avascutar compartments of transplanted tumors. Among 26 different strains tested, one (Clostridium novyi) appeared particularly promising. We created a strain of C. novyi devoid of its lethal toxin (C. novyi-NT) and showed that intravenously injected C. novyi-NT spores germinated within the avascular regions of tumors in mice and destroyed surrounding viable tumor cells. When C. novyi-NT spores were administered together with conventional chemotherapeutic drugs, extensive hemorrhagic necrosis of tumors often developed within 24 hours, resulting in significant and prolonged anti-tumor effects. This strategy, called combination bacteriolytic therapy (COBALT), has the potential to add a valuablle dimension to the treatment of cancer.

公开(公告)号：EP1104475B1

公开(公告)日：2004-05-26

申请号：EP99943741.1

申请日：1999-08-20

申请人： The Johns Hopkins University School of Medicine

发明人： HE, Tong-Chuan ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W.

IPC分类号： C12N15/63 ,  C12Q1/68 ,  C07K14/27

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.

公开(公告)号：EP1104492B1

公开(公告)日：2004-02-11

申请号：EP99943742.9

申请日：1999-08-20

申请人： THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE

发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth, W. ,  POLYAK, Kornelia

IPC分类号： C12Q1/68

CPC分类号： C12Q1/6809 ,  C12Q1/6886 ,  C12Q2600/156

摘要： The accumulation of homoplasmic somatic mutations has been observed in the mitochondrial DNA of certain tumor cells. The presence or a recurrence of a tumor can be detected by determining the presence of single basepair mutations in the mitochondrial genome from a cell sample of a patient.

公开(公告)号：EP0847450B1

公开(公告)日：2003-11-05

申请号：EP96930551.5

申请日：1996-08-23

申请人： THE JOHNS HOPKINS UNIVERSITY

发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth, W. ,  PAPADOPOULOS, Nickolas

IPC分类号： C12Q1/68 ,  C12P21/00 ,  G01N33/50 ,  G01N33/574 ,  G01N33/68

CPC分类号： G01N33/68 ,  C12Q1/6827 ,  G01N33/5005 ,  C12Q2561/107

摘要： A diagnostic strategy for detection of inherited diseases caused by germline mutations is based on somatic cell hybridization. Each allele of a human gene involved in the inherited disease is isolated in a somatic cell hybrid. The products of the isolated human allele are then observed in the absence of the other allele of the human.

公开(公告)号：EP1320627A2

公开(公告)日：2003-06-25

申请号：EP01918690.7

申请日：2001-03-15

申请人： The Johns Hopkins University

发明人： FLISS, Makiko ,  SIDRANSKY, David ,  JEN, Jin ,  POLYAK, Komelia ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W.

IPC分类号： C12Q1/68

CPC分类号： C12Q1/6809 ,  C12Q1/6883 ,  C12Q1/6886 ,  C12Q2600/156 ,  C12Q2600/158

摘要： Mitochondrial mutations occur as a product of contact of a person with an environmental pollutant. Mitochondrial mutations are readily detectable in body fluids. Measurement of mitochondrial mutations in body fluids can be used as a dosimeter to monitor exposure to the environmental pollutant. Mitochondrial mutations can also be detected in cancer patients. Probes and primers containing mutant mitochondrial sequences can be used to monitor patient condition.

摘要翻译： 线粒体突变作为人与环境污染物接触的产物发生。 线粒体突变在体液中容易检测。 体液中线粒体突变的测量可用作剂量计来监测对环境污染物的暴露。 线粒体突变也可以在癌症患者中检测到。 含有突变线粒体序列的探针和引物可用于监测患者状况。

公开(公告)号：EP1307557A2

公开(公告)日：2003-05-07

申请号：EP01961827.1

申请日：2001-08-01

申请人： The Johns Hopkins University

发明人： ST. CROIX, Brad ,  KINZLER, Kenneth, W. ,  VOGELSTEIN, Bert

IPC分类号： C12N15/12 ,  C07K16/28 ,  C07K19/00 ,  A61K39/395 ,  A61P35/00 ,  C07K14/705 ,  C12N5/10 ,  A61K39/00 ,  G01N33/50 ,  G01N33/574 ,  A61K38/17 ,  A61K51/10 ,  A61P9/00 ,  C12Q1/68 ,  A61K48/00

CPC分类号： C07K16/30 ,  A61K2039/505

摘要： To gain a better understanding of tumor angiogenesis, new techniques for isolating endothelial cells (ECs) and evaluating gene expression patterns were developed. When transcripts from ECs derived from normal and malignant colorectal tissues were compared with transcripts from non-endothelial cells, over 170 genes predominantly expressed in the endothelium were identified. Comparison between normal- and tumor-derived endothelium revealed 79 differentially expressed genes, including 46 that were specifically elevated in tumor-associated endothelium. Experiments with representative genes from this group demonstrated that most were similarly expressed in the endothelium of primary lung, breast, brain, and pancreatic cancers as well as in metastatic lesions of the liver. These results demonstrate that neoplastic and normal endothelium in humans are distinct at the molecular level, and have significant implications for the development of anti-angiogenic therapies in the future.

摘要翻译： 为了更好地了解肿瘤血管生成，开发了分离内皮细胞（ECs）和评估基因表达模式的新技术。 将来自正常和恶性结肠直肠组织的ECs的转录物与来自非内皮细胞的转录物进行比较，鉴定出主要在内皮中表达的170多个基因。 正常和肿瘤衍生的内皮的比较显示79个差异表达的基因，其中46个在肿瘤相关内皮特异性升高。 来自该组的代表性基因的实验表明，大多数类似物在原发性肺癌，乳腺癌，脑癌和胰腺癌以及肝转移性损伤的内皮中均表达。 这些结果表明，人类的肿瘤和正常内皮在分子水平上是不同的，并且对未来抗血管生成疗法的发展具有重要意义。

公开(公告)号：EP1259628A1

公开(公告)日：2002-11-27

申请号：EP01911013.9

申请日：2001-02-21

申请人： The Johns Hopkins UNiversity School of Medicine ,  Nicolaides, Nicholas, C. ,  Sass, Philip, M. ,  Grasso, Luigi ,  Vogelstein, Bert ,  Kinzler, Kenneth

发明人： NICOLAIDES, Nicholas, C. ,  SASS, Philip, M. ,  GRASSO, Luigi ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W.

IPC分类号： C12N15/81 ,  C12N5/10 ,  C12N15/01

CPC分类号： C12N15/81

摘要： Yeast cells are mutagenized to obtain desirable mutants. Mutagenesis is mediated by a defective mismatch repair system which can be enhanced using conventional exogenously applied mutagens. Yeast cells with the defective mismatch repair system are hypermutable, but after selection of desired mutant yeast strains, they can be rendered genetically stable by restoring the mismatch repair system to proper functionality.

公开(公告)号：EP1220952A2

公开(公告)日：2002-07-10

申请号：EP00968746.8

申请日：2000-10-06

申请人： The Johns Hopkins University

发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth, W. ,  YAN, Hai ,  PAPADOPOULOS, Nicholas

IPC分类号： C12Q1/68 ,  C12N15/06 ,  C12N5/26

CPC分类号： C12N5/166 ,  C12Q1/6886 ,  C12Q2600/156

摘要： Detection of mutations associated with hereditary diseases is complicated by the diploid nature of mammalian cells. Mutations present in one allele are often masked by the wild-type sequence of the other allele. Individual alleles can be isolated from every chromosome within somatic cell hybrids generated from a single fusion. Nucleic acids from the hybrids can be analyzed for mutations in an unambiguous manner. This approach was used to detect two cancer-causing mutations that had previously defied genetic diagnosis. One of the families studied, Warthin Family G, was the first kindred with a hereditary colon cancer syndrome described in the biomedical literature.