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81. 发明申请

WO03027632A2 USE OF ISOGENIC HUMAN CANCER CELLS FOR HIGH-THROUGHPUT SCREENING AND DRUG DISCOVERY 审中-公开
标题翻译：用于高通量筛选和药物发现的ISOGENIC人类癌细胞的使用
公开(公告)号：WO03027632A2
公开(公告)日：2003-04-03
申请号：PCT/US0225951
申请日：2002-08-28
申请人： UNIV JOHNS HOPKINS , TORRANCE CHRISTOPHER J , VOGELSTEIN BERT , KINZLER KENNETH W
发明人： TORRANCE CHRISTOPHER J , VOGELSTEIN BERT , KINZLER KENNETH W
IPC分类号： A61K31/41 , A61K31/7068 , A61P35/00 , A61P43/00 , C07D257/04 , C07H19/06 , C07H19/16 , C12N5/10 , C12N15/09 , C12Q1/02 , G01N33/15 , G01N33/50 , G01N
CPC分类号： C07D257/04 , C07H19/16 , G01N33/5011 , G01N33/5023
摘要： A strategy for drug-screening is based on cells that are isogenic except for a gene of interest. Each cell can be tranfected with a vector that encodes a different fluorescent protein that can be differentially detected to monitor cell growth. Co-culture of both cells allows facile screening for compounds with selective toxicity towards a gene of interest. The drug screening is broadly applicable for mining therapeutic agents targeted to specific genetic alterations responsible for cancer development.
摘要翻译：药物筛选的策略是基于除目标基因之外的同基因细胞。每个细胞可以用编码不同荧光蛋白的载体转染，可以差异检测以监测细胞生长。两种细胞的共培养允许容易地筛选对目标基因具有选择性毒性的化合物。药物筛选广泛适用于针对负责癌症发展的特定遗传改变的采矿治疗剂。

82. 发明申请

WO0127324A3 CONVERTING DIPLOIDY TO HAPLOIDY FOR GENETIC DIAGNOSIS 审中-公开
标题翻译：将皮质转化为用于遗传性诊断的皮肤
公开(公告)号：WO0127324A3
公开(公告)日：2002-04-18
申请号：PCT/US0027508
申请日：2000-10-06
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , KINZLER KENNETH W , YAN HAI , PAPADOPOULOS NICHOLAS
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , YAN HAI , PAPADOPOULOS NICHOLAS
IPC分类号： G01N33/483 , C12N5/10 , C12N5/16 , C12N5/26 , C12N15/06 , C12N15/09 , C12Q1/02 , C12Q1/68 , C12R1/91 , G01N27/447 , G01N33/53 , G01N33/566 , G01N37/00
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.
摘要翻译：与遗传性疾病相关的突变的检测由于哺乳动物细胞的二倍体性质而复杂化。存在于一个等位基因中的突变通常被其他等位基因的野生型序列掩蔽。可以从单个融合体产生的体细胞杂交体内的每个染色体分离个体等位基因。来自杂种的核酸可以以明确的方式分析突变。这种方法被用于检测先前不符合遗传诊断的两种致癌突变。研究的家庭之一，Warthin Family G，是生物医学文献中描述的第一个遗传性结肠癌综合症患者。

83. 发明申请

WO0002910A9 HUMAN FAST-1 GENE 审中-公开
标题翻译：人类FAST-1基因
公开(公告)号：WO0002910A9
公开(公告)日：2000-05-18
申请号：PCT/US9913764
申请日：1999-06-18
申请人： UNIV JOHNS HOPKINS , ZHOU SHIBIN , ZAWEL LEIGH , VOGELSTEIN BERT , KINZLER KENNETH W
发明人： ZHOU SHIBIN , ZAWEL LEIGH , VOGELSTEIN BERT , KINZLER KENNETH W
IPC分类号： C07K14/47 , C12N15/12 , C07K16/18 , C12N15/62 , C12N15/81 , C12Q1/68
CPC分类号： G01N33/6872 , C07K14/4705 , G01N2333/495 , G01N2500/00
摘要： hFAST-1 is a human forkhead activin signal transducer gene. The hFAST-1 protein has the ability to bind to human Smad2 and activate an activin response element (ARE). The hFAST-1-dependent activation of ARE is dependent on endogenous Smad4 and stimulation of the TGF- beta receptor. The hFAST-1 protein binds to a novel DNA motif, TGT(G/T)(T/G)ATT, which is present within the ARE. This motif is important for the activation of genes responsive to ligands of the TGF- beta family. The invention includes tools for investigating the TGF- beta signaling pathway and screening for compounds which modulate the action of TGF- beta .
摘要翻译： hFAST-1是人类forkhead激活信号转导基因。 hFAST-1蛋白具有与人Smad2结合并激活激活素反应元件（ARE）的能力。 ARE的hFAST-1依赖性激活依赖于内源Smad4和TGF-β受体的刺激。 hFAST-1蛋白结合ARE中存在的新型DNA基序TGT（G / T）（T / G）ATT。该基序对于对TGF-β家族的配体起反应的基因的活化是重要的。本发明包括用于研究TGF-β信号通路和筛选调节TGF-β的作用的化合物的工具。

84. 发明申请

WO0002910A2 HUMAN FAST-1 GENE 审中-公开
标题翻译：人类快速1基因
公开(公告)号：WO0002910A2
公开(公告)日：2000-01-20
申请号：PCT/US9913764
申请日：1999-06-18
申请人： UNIV JOHNS HOPKINS , ZHOU SHIBIN , ZAWEL LEIGH , VOGELSTEIN BERT , KINZLER KENNETH W
发明人： ZHOU SHIBIN , ZAWEL LEIGH , VOGELSTEIN BERT , KINZLER KENNETH W
IPC分类号： C07K14/47 , C12N15/12 , C07K14/00
CPC分类号： G01N33/6872 , C07K14/4705 , G01N2333/495 , G01N2500/00
摘要： hFAST-1 is a human forkhead activin signal transducer gene. The hFAST-1 protein has the ability to bind to human Smad2 and activate an activin response element (ARE). The hFAST-1-dependent activation of ARE is dependent on endogenous Smad4 and stimulation of the TGF- beta receptor. The hFAST-1 protein binds to a novel DNA motif, TGT(G/T)(T/G)ATT, which is present within the ARE. This motif is important for the activation of genes responsive to ligands of the TGF- beta family. The invention includes tools for investigating the TGF- beta signaling pathway and screening for compounds which modulate the action of TGF- beta .
摘要翻译： hFAST-1是人类forkhead激活素信号转导基因。 hFAST-1蛋白具有结合人Smad2并激活激活素应答元件（ARE）的能力。 ARE的hFAST-1依赖性激活依赖于内源性Smad4和TGF-β受体的刺激。 hFAST-1蛋白与ARE内存在的新型DNA基序TGT（G / T）（T / G）ATT结合。该基序对于激活对TGF-β家族的配体有响应的基因是重要的。本发明包括用于研究TGF-β信号传导途径和筛选调节TGF-β作用的化合物的工具。

85. 发明申请

WO9853319A3 GENE EXPRESSION PROFILES IN NORMAL AND CANCER CELLS 审中-公开
标题翻译：基因表达谱在正常和癌细胞中
公开(公告)号：WO9853319A3
公开(公告)日：1999-07-08
申请号：PCT/US9810277
申请日：1998-05-20
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , KINZLER KENNETH W
发明人： VOGELSTEIN BERT , KINZLER KENNETH W
IPC分类号： C12Q1/68 , G01N33/574
CPC分类号： C12Q1/6809 , C12Q1/6886 , C12Q2600/118 , C12Q2600/136 , C12Q2600/158 , G01N33/574
摘要： As a step towards understanding the complex differences between normal and cancer cells, gene expression patterns were examined in gastrointestinal tumors. More than 300,000 transcripts derived from at least 45,000 different genes were analyzed. Although extensive similarity was noted between the expression profiles, more than 500 transcripts that were expressed at significantly different levels in normal and neoplastic cells were identified. These data provide insights into the extent of expression differences underlying malignancy and reveal genes that are useful as diagnostic or prognostic markers.
摘要翻译：作为理解正常和癌细胞之间复杂差异的一步，在胃肠道肿瘤中检查基因表达模式。分析来自至少45,000个不同基因的超过30万个转录物。虽然在表达谱之间注意到广泛的相似性，但是鉴定了在正常和肿瘤细胞中以显着不同水平表达的500多个转录物。这些数据提供了对恶性肿瘤的表达差异程度的了解，并揭示了可用作诊断或预后标志物的基因。

86. 发明申请

WO2013003585A3 ENRICHMENT OF NUCLEIC ACIDS BY COMPLIMENTARY CAPTURE 审中-公开
标题翻译：通过完全捕获富集核酸
公开(公告)号：WO2013003585A3
公开(公告)日：2013-03-28
申请号：PCT/US2012044634
申请日：2012-06-28
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , KINZLER KENNETH W , PAPADOPOULOS NICKOLAS , WU JIAN
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , PAPADOPOULOS NICKOLAS , WU JIAN
IPC分类号： C12Q1/68 , C12N15/11
CPC分类号： C12Q1/6806 , C12Q2535/122 , C12Q2563/131 , C12Q2563/149 , C12Q2565/518
摘要： Assays can be used to detect mutations found in neoplasms of the pancreas, as well as for other neoplasms and other uses. Nucleic acids can be captured from body fluids such as cyst fluids. Thousands of oligonucleotides can be synthesized in parallel, amplified and ligated together. The ligated products can be further amplified. The amplified, ligated products are used to capture complementary DNA sequences, which can be analyzed, for example by massively parallel sequencing.
摘要翻译：分析可用于检测胰腺肿瘤中发现的突变，以及其他肿瘤和其他用途。核酸可以从体液如囊肿液中捕获。数千个寡核苷酸可以平行合成，扩增并连接在一起。连接产物可以进一步扩增。扩增的连接产物用于捕获互补DNA序列，其可以通过例如大规模平行测序进行分析。

87. 发明申请

WO2012099881A2 MUTANT PROTEINS AS CANCER-SPECIFIC BIOMARKERS 审中-公开
标题翻译：突变蛋白作为癌症特异性生物标志物
公开(公告)号：WO2012099881A2
公开(公告)日：2012-07-26
申请号：PCT/US2012021553
申请日：2012-01-17
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , WANG QING , PANDEY AKHILESH , KINZLER KENNETH W , PAPADOPOULOS NICKOLAS
发明人： VOGELSTEIN BERT , WANG QING , PANDEY AKHILESH , KINZLER KENNETH W , PAPADOPOULOS NICKOLAS
IPC分类号： G01N33/68 , G01N33/551 , G01N33/574
CPC分类号： G01N33/6893 , G01N33/574 , G01N33/6848
摘要： Altered protein products resulting from somatic mutations are directly identified and quantified by mass spectrometry. The peptides expressed from normal and mutant alleles are detected by Selected Reaction Monitoring (SRM) of their product ions using a triple quadrupole mass spectrometer. As a prototypical example of this approach, we quantify the number and fraction of mutant Ras protein present in cancer cell lines. There were an average of 1.3 million molecules of Ras protein per cell and the ratio of mutant to normal Ras proteins ranged from 0.49 to 5.6. Similarly, we detected and quantified mutant Ras proteins in clinical specimens such as colorectal and pancreatic tumor tissues as well as in pre-malignant pancreatic cyst fluids. These methods are useful for diagnostic applications.
摘要翻译：通过质谱法直接鉴定和定量由体细胞突变产生的改变的蛋白质产物。使用三重四极质谱仪通过其产物离子的选择性反应监测（SRM）来检测从正常和突变等位基因表达的肽。作为这种方法的原型实例，我们量化了存在于癌细胞系中的突变型Ras蛋白的数量和分数。每个细胞平均有130万个Ras蛋白分子，突变体与正常Ras蛋白的比例范围为0.49至5.6。同样，我们在临床标本如结直肠癌和胰腺肿瘤组织以及恶变前胰腺囊液中检测并定量了突变型Ras蛋白。这些方法对诊断应用程序很有用。

88. 发明申请

WO2008103135A3 THE MICRORNAOME 审中-公开
标题翻译：微笑
公开(公告)号：WO2008103135A3
公开(公告)日：2008-12-24
申请号：PCT/US2007004518
申请日：2007-02-16
申请人： UNIV JOHNS HOPKINS , CUMMINS JORDAN , VELCULESCU VICTOR , KINZLER KENNETH W , VOGELSTEIN BERT
发明人： CUMMINS JORDAN , VELCULESCU VICTOR , KINZLER KENNETH W , VOGELSTEIN BERT
IPC分类号： C07H21/02 , A01N43/04 , A61K31/70 , C07H21/04 , C12N15/113
CPC分类号： C12N15/113 , C12N2310/141 , C12N2320/11 , C12N2330/10 , C12N2510/00 , C12Q1/6886
摘要： MicroRNAs (miRNAs) are a class of small noncoding RNAs that have important regulatory roles in multicellular organisms. The public miRNA database contains 321 human miRNA sequences, 234 of which have been experimentally verified. To explore the possibility that additional miRNAs are present in the human genome, we have developed an experimental approach called miRNA serial analysis of gene expression (miRAGE) and used it to perform the largest experimental analysis of human miRNAs to date. Sequence analysis of 273,966 small RNA tags from human colorectal cells allowed us to identify 200 known mature miRNAs, 133 novel miRNA candidates, and 112 previously uncharacterized miRNA* forms. To aid in the evaluation of candidate miRNAs, we disrupted the Dicer locus in three human colorectal cancer cell lines and examined known and novel miRNAs in these cells. The miRNAs are useful to diagnose and treat cancers.
摘要翻译：微小RNA（miRNA）是一类在多细胞生物体中具有重要调节作用的小型非编码RNA。公共miRNA数据库包含321个人类miRNA序列，其中234个已经通过实验验证。为了探讨其他miRNA存在于人类基因组中的可能性，我们开发了一种称为miRNA序列分析基因表达（miRAGE）的实验方法，并将其用于迄今为止对人类miRNA进行最大的实验分析。来自人结肠直肠细胞的273,966个小RNA标签的序列分析允许我们鉴定200个已知的成熟miRNA，133个新型miRNA候选物和112个先前未表征的miRNA *形式。为了帮助评估候选miRNA，我们破坏了三种人结肠直肠癌细胞系中Dicer基因座，并检测了这些细胞中已知和新型的miRNA。这些miRNA可用于诊断和治疗癌症。

89. 发明申请

WO2005039492A3 IMPROVED COMBINATION BACTERIOLYTIC THERAPY FOR THE TREATMENT OF TUMORS 审中-公开
公开(公告)号：WO2005039492A3
公开(公告)日：2005-06-30
申请号：PCT/US2004034625
申请日：2004-10-21
申请人： UNIV JOHNS HOPKINS , 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： A01N63/00 , A61K20060101
CPC分类号： A61K35/742 , A61K31/337 , A61K31/427 , A61K45/06 , Y10S435/842 , 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 vinorelbine, caused rapid, massive hemorrhagic necrosis when used in combination with spores. In contrast, agents that stabilized microtubules, such as the taxane docetaxel, resulted in slow tumor regressions that killed most neoplastic cells. Remaining cells in the poorly perfused regions of tumors could be eradicated by sponzlated 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.

90. 发明申请

WO2004082458A2 TYROSINE KINOME 审中-公开
公开(公告)号：WO2004082458A2
公开(公告)日：2004-09-30
申请号：PCT/US2004004452
申请日：2004-02-18
申请人： UNIV JOHNS HOPKINS , BARDELLI ALBERTO , PARSONS WILL , VELCULESCU VICTOR , KINZLER KENNETH W , VOGELSTEIN BERT
发明人： BARDELLI ALBERTO , PARSONS WILL , VELCULESCU VICTOR , KINZLER KENNETH W , VOGELSTEIN BERT
IPC分类号： A61B20060101 , C12N9/12 , C12Q1/68 , A61B
CPC分类号： C12Q1/6886 , A61K31/506 , C12N9/1205 , C12Q1/025 , C12Q1/485 , C12Q1/6809 , C12Q1/6827 , C12Q2600/136 , C12Q2600/156 , G01N33/574
摘要： Protein kinases are important signaling molecules involved in tumorigenesis. Mutational analysis of the human tyrosine kinase gene family (98 genes) identified somatic alterations in -20% of colorectal cancers, with the majority of mutations occurring in NTRK3, FES, GUCY2F and a previously uncharacterized tyrosine kinase gene called MCCK/MLK4. Most alterations were in conserved residues affecting key regions of the kinase domain. These data represent a paradigm for the unbiased analysis of signal transducing genes in cancer and provide useful targets for therapeutic intervention.
摘要翻译：蛋白激酶是参与肿瘤发生的重要信号分子。人类酪氨酸激酶基因家族（98个基因）的突变分析鉴定了-20％的结肠直肠癌的体细胞变化，大部分突变发生在NTRK3，FES，GUCY2F和以前称为MCCK / MLK4的未表征的酪氨酸激酶基因。大多数改变是保守的残基影响激酶结构域的关键区域。这些数据代表了对癌症中信号转导基因的无偏见分析的范例，并为治疗干预提供了有用的目标。

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