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71. 发明公开

EP3246416A1 SAFE SEQUENCING SYSTEM 有权
标题翻译：安全测序系统
公开(公告)号：EP3246416A1
公开(公告)日：2017-11-22
申请号：EP17154750.8
申请日：2012-04-12
申请人： The Johns Hopkins University
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth , PAPADOPOULOS, Nickolas , KINDE, Isaac
IPC分类号： C12Q1/68 , C12N15/11
CPC分类号： C12Q1/6874 , C12Q1/6806 , C12Q1/6869 , C12Q1/6876 , C12Q2563/179 , C12Q2600/158 , C12Q2535/122 , C12Q2565/514
摘要： The identification of mutations that are present in a small fraction of DNA templates is essential for progress in several areas of biomedical research. Though massively parallel sequencing instruments are in principle well-suited to this task, the error rates in such instruments are generally too high to allow confident identification of rare variants. We here describe an approach that can substantially increase the sensitivity of massively parallel sequencing instruments for this purpose. One example of this approach, called "Safe-SeqS" for (Safe-Sequencing System) includes (i) assignment of a unique identifier (UID) to each template molecule; (ii) amplification of each uniquely tagged template molecule to create UID-families; and (iii) redundant sequencing of the amplification products. PCR fragments with the same UID are truly mutant ("super-mutants") if =95% of them contain the identical mutation. We illustrate the utility of this approach for determining the fidelity of a polymerase, the accuracy of oligonucleotides synthesized in vitro, and the prevalence of mutations in the nuclear and mitochondrial genomes of normal cells.
摘要翻译：存在于一小部分DNA模板中的突变的鉴定对于生物医学研究的若干领域的进展是必不可少的。尽管大规模并行测序仪器原则上非常适合于此任务，但这些仪器的错误率通常太高，以至于无法确定罕见变体。我们在这里描述了一种可以大幅度提高大规模并行测序仪器的灵敏度的方法。这种方法的一个例子叫做安全测序系统（Safe-Sequencing System）的“Safe-SeqS”，包括（i）为每个模板分子分配一个唯一标识符（UID）（ii）扩增每个独特标记的模板分子以产生UID家族; 和（iii）扩增产物的冗余测序。具有相同UID的PCR片段确实是突变体（“超级突变体”），如果其中95％含有相同的突变。我们说明了这种方法用于确定聚合酶保真度的效用，体外合成的寡核苷酸的准确性以及正常细胞核和线粒体基因组突变的发生率。

72. 发明公开

EP3218004A1 CHECKPOINT BLOCKADE AND MICROSATELLITE INSTABILITY 无效
标题翻译：检查点堵塞和微粒不稳定性
公开(公告)号：EP3218004A1
公开(公告)日：2017-09-20
申请号：EP15858277.5
申请日：2015-11-12
申请人： The Johns Hopkins University
发明人： DIAZ, Luis , VOGELSTEIN, Bert , KINZLER, Kenneth W. , PAPADOPOULOS, Nickolas , LE, Dung
IPC分类号： A61K39/395 , A61P35/00
CPC分类号： C07K16/2803 , A61K2039/505 , A61K2039/55 , C07K16/2818 , C07K16/2827 , C07K16/30 , C07K16/40 , C07K2317/00 , C07K2317/24 , C07K2317/76 , C12Q1/6886 , C12Q2600/106 , C12Q2600/156 , C12Y113/11052
摘要： Blockade of immune checkpoints such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) shows promise in patients with cancer. Inhibitory antibodies directed at these receptors have been shown to break immune tolerance and promote anti-tumor immunity. These agents work particularly well in patients with a certain category of tumor. Such tumors may be particularly susceptible to treatment because of the multitude of neoantigens which they produce.
摘要翻译：免疫检查点如细胞毒性T淋巴细胞抗原-4（CTLA-4）和程序性死亡-1（PD-1）的阻断在癌症患者中显示出希望。已经显示针对这些受体的抑制性抗体会破坏免疫耐受性并促进抗肿瘤免疫力。这些药物在某类肿瘤患者中效果特别好。由于它们产生大量的新抗原，这些肿瘤可能特别容易受到治疗。

73. 发明授权

EP2326735B1 GENETIC ALTERATIONS IN ISOCITRATE DEHYDROGENASE AND OTHER GENES IN MALIGNANT GLIOMA 有权
标题翻译：异柠檬酸脱氢酶基因变异并在恶性胶质瘤的其他基因
公开(公告)号：EP2326735B1
公开(公告)日：2016-11-16
申请号：EP09792198.5
申请日：2009-09-03
申请人： The Johns Hopkins University , Duke University
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth W. , PARSONS, D. Williams , ZHANG, Xiaosong , LIN, Jimmy Cheng-Ho , LEARY, Rebecca J. , ANGENENDT, Philipp , PAPADOPOULOS, Nickolas , VELCULESCU, Victor , PARMIGIANI, Giovanni , KARCHIN, Rachel , JONES, Sian , YAN, Hai , BIGNER, Darell , KUAN, Chien-Tsun , RIGGINS, Gregory J.
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6886 , C12Q2600/112 , C12Q2600/118 , C12Q2600/136 , C12Q2600/156

74. 发明公开

EP2780473A1 DIFFERENTIAL IDENTIFICATION OF PANCREATIC CYSTS 有权
标题翻译：孢囊区分性鉴定
公开(公告)号：EP2780473A1
公开(公告)日：2014-09-24
申请号：EP12849091.9
申请日：2012-11-12
申请人： The Johns Hopkins University
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth W. , PAPADOPOULOS, Nickolas , WU, Jian , HRUBAN, Ralph , MAITRA, Anirban , DAL MOLIN, Marco
IPC分类号： C12Q1/68 , C12N15/11
CPC分类号： C12Q1/6886 , C12Q1/6883 , C12Q2600/156
摘要： More than 2% of adults harbor a pancreatic cyst, a subset of which progress to invasive lesions with lethal consequences. To assess the genomic landscapes of neoplastic cysts of the pancreas, we determined the exomic sequences of DNA from the neoplastic epithelium of eight surgically resected cysts of each of the major neoplastic cyst types: serous cystadenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs) and solid pseudo-papillary neoplasms (SPNs). SPNs are low-grade malignancies, and IPMNs and MCNs, but not SCAs, have the capacity to progress to cancer. We found that SCAs, IPMNs, MCNs, and SPNs contained 10 = 4.6, 27 = 12, 16 = 7.6, and 2.9 = 2.1 somatic mutations per tumor, respectively. Among the mutations identified, E3 ubiquitin ligase components were of particular note. Four of the eight SCAs contained mutations of VHL, a key component of the VHL ubiquitin ligase complex that has previously been assoCiated both with renal cell carcinomas, SCAs, and other neoplasms. Six of the eight IPMNs and three of the eight MCNs harbored mutations of RNF43, a gene coding for a protein with intrinsic E3 ubiquitin ligase activity that has not previously been found to be genetically altered in any human cancer. The preponderance of inactivating mutations in RNF43 unequivoCally establish it as a suppressor of both IPMNs and MCNs. SPNs contained remarkably few genetic alterations, but always contained mutations of CTNNB1, previously demonstrated to inhibit degradation of the encoded protein (ß-catenin) by E3 ubiquitin ligases. These results highlight the essential role of ubiquitin ligases in these neoplasms and have important implications for the diagnosis and treatment of patients with cystic tumors.

75. 发明公开

EP2697397A2 SAFE SEQUENCING SYSTEM 有权
标题翻译：安全测序系统
公开(公告)号：EP2697397A2
公开(公告)日：2014-02-19
申请号：EP12772013.4
申请日：2012-04-12
申请人： The Johns Hopkins University
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth W. , PAPADOPOULOS, Nickolas , KINDE, Isaac
IPC分类号： C12Q1/68 , C12N15/11
CPC分类号： C12Q1/6874 , C12Q1/6806 , C12Q1/6869 , C12Q1/6876 , C12Q2563/179 , C12Q2600/158 , C12Q2535/122 , C12Q2565/514
摘要： The identification of mutations that are present in a small fraction of DNA templates is essential for progress in several areas of biomedical research. Though massively parallel sequencing instruments are in principle well-suited to this task, the error rates in such instruments are generally too high to allow confident identification of rare variants. We here describe an approach that can substantially increase the sensitivity of massively parallel sequencing instruments for this purpose. One example of this approach, called "Safe-SeqS" for (Safe-Sequencing System) includes (i) assignment of a unique identifier (UID) to each template molecule; (ii) amplification of each uniquely tagged template molecule to create UID-families; and (iii) redundant sequencing of the amplification products. PCR fragments with the same UID are truly mutant ("super-mutants") if ≥95% of them contain the identical mutation. We illustrate the utility of this approach for determining the fidelity of a polymerase, the accuracy of oligonucleotides synthesized
in vitro , and the prevalence of mutations in the nuclear and mitochondrial genomes of normal cells.
摘要翻译：存在于一小部分DNA模板中的突变的鉴定对于生物医学研究的若干领域的进展是必不可少的。尽管大规模并行测序仪器原则上非常适合于此任务，但这些仪器的错误率通常太高，以至于无法确定罕见变体。我们在这里描述了一种可以大幅度提高大规模并行测序仪器的灵敏度的方法。这种方法的一个例子叫做安全测序系统（Safe-Sequencing System）的“Safe-SeqS”，包括（i）为每个模板分子分配一个唯一标识符（UID）（ii）扩增每个独特标记的模板分子以产生UID家族; 和（iii）扩增产物的冗余测序。具有相同UID的PCR片段如果≥95％含有相同的突变，则是真正的突变体（“超级突变体”）。我们说明了这种方法用于确定聚合酶保真度的效用，体外合成的寡核苷酸的准确性以及正常细胞核和线粒体基因组突变的发生率。

76. 发明公开

EP2326734A2 PATHWAYS UNDERLYING PANCREATIC TUMORIGENESIS AND AN HEREDITARY PANCREATIC CANCER GENE 有权
标题翻译：胰腺肿瘤的发生和遗传PANKREASKREBSGEN信号通路
公开(公告)号：EP2326734A2
公开(公告)日：2011-06-01
申请号：EP09812193.2
申请日：2009-09-03
申请人： The Johns Hopkins University
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth, W. , PARSONS, D., Williams , JONES, Sian , ZHANG, Xiaosong , LIN, Jimmy Chang-Ho , LEARY, Rebecca J. , ANGENENDT, Philipp , PAPADOPOULOS, Nickolas , VELCULESCU, Victor , PARMIGIANI, Giovanni , KARCHIN, Rachel , KERN, Scott , HRUBAN, Ralph , ESHLEMAN, James R. , GOGGINS, Michael , KLEIN, Alison
IPC分类号： C12Q1/68
CPC分类号： G01N33/57438 , C12Q1/6886 , C12Q2600/156 , G01N2800/50
摘要： There are currently few therapeutic options for patients with pancreatic cancers and new insights into the pathogenesis of this lethal disease are urgently needed. To this end, we performed a comprehensive analysis of the genes altered in 24 pancreatic tumors. First, we determined the sequences of 23,781 transcripts, representing 20,583 protein-encoding genes, in DNA from these tumors. Second, we searched for homozygous deletions and amplifications using microarrays querying ~one million single nucleotide polymorphisms in each sample. Third, we analyzed the transcriptomes of the same samples using SAGE and next-generation sequencing-by-synthesis technologies. We found that pancreatic cancers contain an average of 63 genetic alterations, of which 49 are point mutations, 8 are homozygous deletions, and 6 are amplifications. Further analyses revealed a core set of 12 regulatory processes or pathways that were each genetically altered in 70 % to 100 % of the samples. The data suggest that dysregulation of this core set of pathways is responsible for the major features of pancreatic tumorigenesis.

77. 发明公开

EP0847450A1 MONO-ALLELIC MUTATION ANALYSIS FOR IDENTIFYING GERMLINE MUTATIONS 失效
标题翻译： MONO-等位基因突变分析及KEIMBAHMMUTATIONEN的检测
公开(公告)号：EP0847450A1
公开(公告)日：1998-06-17
申请号：EP96930551.0
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 , G01N33
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.

78. 发明公开

EP4384637A1 METHODS FOR SIMULTANEOUS MUTATION DETECTION AND METHYLATION ANALYSIS 审中-实审
公开(公告)号：EP4384637A1
公开(公告)日：2024-06-19
申请号：EP22856660.0
申请日：2022-08-12
申请人： The Johns Hopkins University
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth W. , PAPADOPOULOS, Nickolas , MATTOX, Austin , COHEN, Joshua David , WANG, Yuxuan
IPC分类号： C12Q1/6876 , C12Q1/6855
CPC分类号： C12Q1/6806

79. 发明公开

EP4305155A1 ENGINEERED IMMUNE CELLS AND USES THEREOF 审中-实审
公开(公告)号：EP4305155A1
公开(公告)日：2024-01-17
申请号：EP22768100.4
申请日：2022-03-11
申请人： The Johns Hopkins University
发明人： HWANG, Michael S. , DOUGLASS, Jacqueline , HSIUE, Emily Han-Chung , KINZLER, Kenneth W. , MOG, Brian J. , PAPADOPOULOS, Nickolas , PEARLMAN, Alexander H. , VOGELSTEIN, Bert , ZHOU, Shibin
IPC分类号： C12N5/22 , C12N5/0783 , A61K35/17 , A61K38/17 , A61K39/395 , A61P35/00 , A61P35/02

80. 发明公开

EP4294841A1 METHODS AND MATERIALS FOR TREATING CLONAL T CELL EXPANSIONS 审中-实审
公开(公告)号：EP4294841A1
公开(公告)日：2023-12-27
申请号：EP22706972.1
申请日：2022-02-15
申请人： The Johns Hopkins University
发明人： HWANG, Michael S. , KINZLER, Kenneth W. , MOG, Brian J. , PAPADOPOULOS, Nickolas , PARDOLL, Andrew , PAUL, Suman , VOGELSTEIN, Bert , ZHOU, Shibin
IPC分类号： C07K16/28 , C07K16/30 , A61P35/00

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