公开(公告)号：EP4278012A1

公开(公告)日：2023-11-22

申请号：EP22740108.0

申请日：2022-01-14

申请人： CASE WESTERN RESERVE UNIVERSITY ,  The Johns Hopkins University

发明人： MARKOWITZ, Sanford ,  CHAK, Amitabh ,  WILLIS, Joseph ,  MOINOVA, Helen ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth ,  PAPADOPOULOS, Nickolas ,  BETTEWGOWDA, Chetan ,  DOUVILLE, Christopher

IPC分类号： C12Q1/6883 ,  C12Q1/6844 ,  C12Q1/6869

公开(公告)号：EP4239081A2

公开(公告)日：2023-09-06

申请号：EP23170939.5

申请日：2013-03-22

申请人： The Johns Hopkins University

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

IPC分类号： C12Q1/6827 ,  C12Q1/6883

摘要： Massively parallel sequencing of cell-free, maternal plasma DNA was recently demonstrated to be a safe and effective screening method for fetal chromosomal aneuploidies. Here, we report an improved sequencing method achieving significantly increased throughput and decreased cost by replacing laborious sequencing library preparation steps with PCR employing a single primer pair. Using this approach, samples containing as little as 4% trisomy 21 DNA could be readily distinguished from euploid samples.

公开(公告)号：EP3907297A1

公开(公告)日：2021-11-10

申请号：EP21173117.9

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： C12Q1/6806 ,  C12N15/11 ,  C12Q1/6874

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.

公开(公告)号：EP3730146A1

公开(公告)日：2020-10-28

申请号：EP20167187.2

申请日：2014-03-28

申请人： Biomed Valley Discoveries, Inc. ,  The Johns Hopkins University

发明人： SAHA, Saurabh ,  ZHOU, Shibin ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W.

IPC分类号： A61K35/66 ,  A61P35/00

摘要： The present invention provides, inter alia, methods for treating or ameliorating an effect of a solid tumor present in a human. These methods include administering intratumorally to the human a unit dose of C. novyi, preferably C. novyi NT, colony forming units (CFUs), which contains about 1 x 10 3 -1 x 10 7 CFUs suspended in a pharmaceutically acceptable carrier or solution. Methods for debulking a solid tumor present in a human, methods for ablating a solid tumor present in a human, a method for microscopically precise excision of tumor cells in a human, methods for treating or ameliorating an effect of a solid tumor that has metastasized to one or more sites in a human, unit doses of C. novyi, preferably C. novyi NT, CFUs, and kits for treating or ameliorating an effect of a solid tumor present in a human are also provided.

公开(公告)号：EP3714272A1

公开(公告)日：2020-09-30

申请号：EP18825819.8

申请日：2018-11-20

申请人： The Johns Hopkins University

发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  WANG, Qing ,  PAPADOPOULOS, Nickolas ,  ZHANG, Ming

IPC分类号： G01N33/574

公开(公告)号：EP3266879B1

公开(公告)日：2019-07-03

申请号：EP17168866.6

申请日：2009-09-03

申请人： The Johns Hopkins University ,  Duke University

发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth ,  PAPADOPOULOS, Nickolas ,  VELCULESCU, Victor ,  PARMIGIANI, Giovanni ,  KARCHIN, Rachel ,  JONES, Sian ,  YAN, Hai ,  BIGNER, Darell ,  KUAN, Chien-Tsun ,  RIGGINS, Gregory ,  PARSONS, Williams ,  ZHANG, Xiaosong ,  LIN, Jimmy Cheng-Ho ,  LEARY, Rebecca ,  ANGENENDT, Philipp

IPC分类号： C12Q1/68

公开(公告)号：EP2912468B1

公开(公告)日：2018-09-12

申请号：EP13851273.6

申请日：2013-10-17

申请人： The Johns Hopkins University

发明人： KINDE, Isaac ,  KINZLER, Kenneth W. ,  VOGELSTEIN, Bert ,  PAPADOPOULOS, Nickolas ,  DIAZ, Luis ,  BETTEGOWDA, Chetan ,  WANG, Yuxuan

IPC分类号： C12Q1/6886

CPC分类号： C12Q1/6886 ,  C12Q2600/154 ,  C12Q2600/156 ,  C12Q2600/158 ,  C12Q2600/16 ,  G01N33/57442 ,  G01N33/57449

摘要： The recently developed liquid-based Papanicolaou (Pap) smear allows not only cytologic evaluation but also collection of DNA for detection of HPV, the causative agent of cervical cancer. We tested these samples to detect somatic mutations present in rare tumor cells that might accumulate in the cervix once shed from endometrial and ovarian cancers. A panel of commonly mutated genes in endometrial and ovarian cancers was assembled and used to identify mutations in all 46 endometrial or cervical cancer tissue samples. We were able also able to identify the same mutations in the DNA from liquid Pap smears in 100% of endometrial cancers (24 of 24) and in 41% of ovarian cancers (9 of 22). We developed a sequence-based method to query mutations in 12 genes in a single liquid Pap smear without prior knowledge of the tumor's genotype.

公开(公告)号：EP3327139A1

公开(公告)日：2018-05-30

申请号：EP17191835.2

申请日：2010-04-06

申请人： The Johns Hopkins University ,  Case Western Reserve University

发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth ,  LI, Ming ,  DIAZ, Luis ,  PAPADOPOULOS, Nickolas ,  MARKOWITZ, Sanford

IPC分类号： C12Q1/68 ,  C12N15/11 ,  G01N33/52

CPC分类号： C12Q1/6816 ,  C12Q1/6886 ,  C12Q2600/154 ,  C12Q2565/501 ,  C12Q2527/125 ,  C12Q2523/125

摘要： Abnormal DNA methylation can be used as a biomarker in cancer patients. For such purposes, it is important to determine precisely the fraction of methylated molecules in an analyzed sample. A technology we term Methyl-BEAMing achieves this goal. Individual bisulfite-treated DNA molecules can be PCR-amplified within aqueous nanocompartments containing beads, resulting in a population of beads each containing thousands of copies of the template molecule. After hybridization with probes specific for methylated sequences, the beads can be analyzed by flow cytometry. This approach enables detection and enumeration of one methylated molecule in a population of ∼5000 unmethylated molecules. Methyl-BEAMing provides digital quantification of rare methylation events and is generally applicable to the assessment of methylated genes in clinical samples.

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。

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。