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1. 发明申请

WO2013074438A1 DIFFERENTIAL IDENTIFICATION OF PANCREATIC CYSTS 审中-公开
标题翻译：胰蛋白酶的差异鉴定
公开(公告)号：WO2013074438A1
公开(公告)日：2013-05-23
申请号：PCT/US2012/064629
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.
摘要翻译：超过2％的成年人患有胰腺囊肿，其中一部分进展到具有致命后果的侵入性损伤。为了评估胰腺肿瘤囊肿的基因组景观，我们确定了每个主要肿瘤性囊肿类型的八个手术切除的囊肿的肿瘤上皮的DNA的外显子序列：浆液性囊腺瘤（SCA），管内乳头状粘液性肿瘤（IPMN），粘液性囊性肿瘤（MCN）和固体假乳头状肿瘤（SPN）。 SPN是低度恶性肿瘤，IPMNs和MCNs而不是SCA具有进展为癌症的能力。我们发现SCA，IPMNs，MCNs和SPN分别包含10 = 4.6,27 = 12,16 = 7.6和2.9 = 2.1肿瘤体细胞突变。在确定的突变中，E3泛素连接酶组分特别值得注意。八个SCA中的四个包含VHL的突变，VHL是VHL泛素连接酶复合物的关键组分，其先前与肾细胞癌，SCA和其他肿瘤相关。八个IPMN中的六个和八个MCN中的三个携带RNF43的突变，RNF43是编码具有内在E3泛素连接酶活性的蛋白质的基因，其在以前没有发现在任何人类癌症中被遗传改变。 RNF43中失活突变的优势不平凡地将其建立为IPMNs和MCNs的抑制因子。 SPNs具有极少的遗传改变，但总是包含CTNNB1的突变，其先前证明可以通过E3泛素连接酶抑制编码的蛋白质（β-catenin）的降解。这些结果突出了泛素连接酶在这些肿瘤中的重要作用，对囊性肿瘤患者的诊断和治疗具有重要意义。

2. 发明申请

WO2022272014A1 COMPUTATIONAL TECHNIQUES FOR THREE-DIMENSIONAL RECONSTRUCTION AND MULTI-LABELING OF SERIALLY SECTIONED TISSUE 审中-公开
公开(公告)号：WO2022272014A1
公开(公告)日：2022-12-29
申请号：PCT/US2022/034827
申请日：2022-06-24
申请人： THE JOHNS HOPKINS UNIVERSITY
发明人： KIEMEN, Ashley , WU, Pei-Hsun , WOOD, Laura D. , WIRTZ, Denis Gaston , HRUBAN, Ralph , SNEIDER, Alexandra , GU, Luo , HABIBI, Mehran , KIM, Joo Ho
IPC分类号： G06T15/08 , G06T7/11 , G06T19/20
摘要： This document generally describes methods and systems for generating digital reconstructions of tissue from humans or other species. The method can, for example, include receiving, at a computing system, image data of a tissue sample, where one or more sections of the tissue sample are stained with hematoxylin and eosin (H&E), registering the image data to generate registered image data, identifying tissue subtypes based on application of a machine learning model to the registered image data, annotating the identified tissue subtypes to generate annotated image data, and determining a digital volume of the tissue sample in three dimensional (3D) space based on the annotated image data. The disclosed technology can provide for single-cell analysis and other analysis of tissue samples, such as early detection of cancer in human tissue samples.

3. 发明申请

WO2004006837A3 MESOTHELIN VACCINES AND MODEL SYSTEMS 审中-公开
公开(公告)号：WO2004006837A3
公开(公告)日：2004-01-22
申请号：PCT/US2003/021643
申请日：2003-07-14
申请人： THE JOHNS HOPKINS UNIVERSITY , JAFFEE, Elizabeth , WU, Tzyy-Choou , HUNG, Chien-Fu , HRUBAN, Ralph
发明人： JAFFEE, Elizabeth , WU, Tzyy-Choou , HUNG, Chien-Fu , HRUBAN, Ralph
IPC分类号： A01N63/00 , A01K67/00 , A01K67/027 , A01K67/033 , A61K35/12 , A61K38/00 , A61K39/00 , A61K39/38 , A61K39/385 , C07K5/00 , C07K7/00 , C07K16/00 , C07K17/00 , C12N1/20 , C12N5/00 , C12N5/02 , C12N5/06 , C12N5/08 , G01N33/00
摘要： Mesothelin can be used as an immunotherapeutic target. It induces a cytolytic T cell response. Portions of mesothelin which induce such responses are identified. Vaccines can be either polynucleotide- or polypeptide-based. Carriers for raising a cytolytic T cell response include bacteria and viruses. A mouse model for testing vaccines and other anti-tumor therapeutics and prophylactics comprises a strongly mesothelin-expressing, transformed peritoneal cell line.

4. 发明申请

WO2015041788A1 TERT PROMOTER MUTATIONS IN UROTHELIAL NEOPLASIA 审中-公开
标题翻译：在厄瓜多尔NEOPLASIA的TERT促销者突击
公开(公告)号：WO2015041788A1
公开(公告)日：2015-03-26
申请号：PCT/US2014/051808
申请日：2014-08-20
申请人： THE JOHNS HOPKINS UNIVERSITY
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth W. , DIAZ, Luis , PAPADOPOULOS, Nickolas , NETTO, George J. , HRUBAN, Ralph , KINDE, Isaac A.
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6886 , C12Q2600/156
摘要： TERT promoter mutations occur in both papillary and flat lesion bladder cancers, are the most frequent genetic alterations identified to date in noninvasive precursor lesions of the bladder, are detectable in urine, and appear to be strongly associated with bladder cancer recurrence. The TERT promoter mutations are useful urinary biomarker for both the early detection and monitoring of bladder neoplasia.
摘要翻译： TERT启动子突变发生在乳头状和扁平病变膀胱癌中，是迄今为止在膀胱非侵入性前体病变中鉴定的最常见的遗传改变，在尿液中是可检测的，并且似乎与膀胱癌复发密切相关。 TERT启动子突变是膀胱肿瘤早期检测和监测的有用的尿生物标志物。

5. 发明申请

WO2012094401A2 GENES FREQUENTLY ALTERED IN PANCREATIC NEUROENDOCRINE TUMORS 审中-公开
标题翻译：在胰腺神经内分泌肿瘤中常见改变的基因
公开(公告)号：WO2012094401A2
公开(公告)日：2012-07-12
申请号：PCT/US2012/020199
申请日：2012-01-04
申请人： THE JOHNS HOPKINS UNIVERSITY , VOGELSTEIN, Bert , KINZLER, Kenneth W. , VELCULESCU, Victor , DIAZ, Luis , PAPADOPOULOS, Nikolas , JIAO, Yuchen , HRUBAN, Ralph
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth W. , VELCULESCU, Victor , DIAZ, Luis , PAPADOPOULOS, Nikolas , JIAO, Yuchen , HRUBAN, Ralph
IPC分类号： C12Q1/68 , G01N33/574 , G01N33/58
CPC分类号： C12Q1/6886 , C12Q2600/106 , C12Q2600/112 , C12Q2600/118 , C12Q2600/156 , G01N33/57438 , G01N2800/52
摘要： Pancreatic Neuroendocrine Tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. To explore the genetic basis of PanNETs, we determined the exomic sequences of ten non-familial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. Remarkably, the most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN-1, which encodes menin, a component of a histone methyltransferase complex; and 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain associated protein) and ATRX (alpha thalassemia/mental retardation syndrome X-linked). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. We also found mutations in genes in the mTOR (mammalian target of rapamycin) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors.
摘要翻译：胰腺神经内分泌肿瘤（PanNETs）是罕见但临床上重要的胰腺瘤形成形式。为了探索PanNET的遗传基础，我们确定了10个非家族性PanNET的外显子序列，然后筛选58个额外PanNET中最常见的突变基因。值得注意的是，最经常突变的基因指定涉及染色质重塑的蛋白质：MEN-1中44％的肿瘤具有体细胞失活突变，MEN-1编码组蛋白甲基转移酶复合物的组分; 和43％在编码由DAXX（死亡域相关蛋白）和ATRX（α地中海贫血/智力低下综合征X连锁）组成的转录/染色质重塑复合体的两个亚基中的任一个的基因中具有突变。临床上，MEN1和DAXX / ATRX基因的突变与更好的预后相关。我们还在14％的肿瘤中发现了mTOR（哺乳动物雷帕霉素靶标）途径中的基因突变，这一发现可能潜在地用于将患者分层以用mTOR抑制剂治疗。

6. 发明授权

EP2726869B1 SOMATIC MUTATIONS IN ATRX IN BRAIN CANCER 有权
标题翻译： ATRX在脑癌中的体细胞突变
公开(公告)号：EP2726869B1
公开(公告)日：2017-08-09
申请号：EP12804757.8
申请日：2012-06-28
申请人： Duke University , The Johns Hopkins University
发明人： YAN, Hai , BIGNER, Darell , VOGELSTEIN, Bert , KINZLER, Kenneth W. , MEEKER, Alan , HRUBAN, Ralph , PAPADAPOULOS, Nickolas , DIAZ, Luis , JIAO, Yuchen
IPC分类号： G01N33/53 , C12Q1/68 , A61K39/00 , A61K31/7105
CPC分类号： C12Q1/6886 , C07K16/40 , C12N15/1137 , C12Q2600/118 , C12Q2600/156 , G01N33/57407
摘要： We determined the sequence of ATRX and DAXX in 447 cancers from various sites. We found mutations most commonly in pediatric glioblastoma multiformae (GBM) (11.1%), adult GBM (6.5%), oligodendrogliomas (7.7%) and medulloblastomas (1.5%); and showed that Alternative Lengthening of Telomeres (ALT), a telomerase-independent telomere maintenance mechanism found in cancers that have not activated telomerase, perfectly correlated with somatic mutations of either gene. In contrast, neuroblastomas, and adenocarcinomas of the ovary, breast, and pancreas were negative for mutations in ATRX and DAXX. Alterations in ATRX or DAXX define a specific molecular pathway that is closely associated with an alternative telomere maintenance function in human cancers.
摘要翻译：我们在来自不同地点的447种癌症中确定了ATRX和DAXX的序列。我们发现小儿胶质母细胞瘤多形性（GBM）（11.1％），成人GBM（6.5％），少突胶质细胞瘤（7.7％）和成神经管细胞瘤（1.5％）中最常见突变; 并表明端粒替代延长（ALT）是一种端粒酶非依赖性端粒维持机制，在未激活端粒酶的癌症中发现，与任一基因的体细胞突变完全相关。相反，神经母细胞瘤和卵巢癌，乳腺癌和胰腺腺癌的ATRX和DAXX突变均为阴性。 ATRX或DAXX的改变定义了与人类癌症中替代的端粒维持功能密切相关的特定分子途径。

7. 发明公开

EP2726869A2 SOMATIC MUTATIONS IN ATRX IN BRAIN CANCER 有权
标题翻译： SOMATISCHE ATRX-MUTATIONEN BEI HIRNKREBS
公开(公告)号：EP2726869A2
公开(公告)日：2014-05-07
申请号：EP12804757.8
申请日：2012-06-28
申请人： Duke University , The Johns Hopkins University
发明人： YAN, Hai , BIGNER, Darell , VOGELSTEIN, Bert , KINZLER, Kenneth W. , MEEKER, Alan , HRUBAN, Ralph , PAPADAPOULOS, Nickolas , DIAZ, Luis , JIAO, Yuchen
IPC分类号： G01N33/53 , C12Q1/68 , A61K39/00 , A61K31/7105
CPC分类号： C12Q1/6886 , C07K16/40 , C12N15/1137 , C12Q2600/118 , C12Q2600/156 , G01N33/57407
摘要： We determined the sequence of ATRX and DAXX in 447 cancers from various sites. We found mutations most commonly in pediatric glioblastoma multiformae (GBM) (11.1%), adult GBM (6.5%), oligodendrogliomas (7.7%) and medulloblastomas (1.5%); and showed that Alternative Lengthening of Telomeres (ALT), a telomerase-independent telomere maintenance mechanism found in cancers that have not activated telomerase, perfectly correlated with somatic mutations of either gene. In contrast, neuroblastomas, and adenocarcinomas of the ovary, breast, and pancreas were negative for mutations in ATRX and DAXX. Alterations in ATRX or DAXX define a specific molecular pathway that is closely associated with an alternative telomere maintenance function in human cancers.
摘要翻译：我们确定了来自各个位点的447例癌症中ATRX和DAXX的序列。我们发现多形性小儿成釉细胞瘤（GBM）（11.1％），成人GBM（6.5％），少突神经胶质瘤（7.7％）和成神经管细胞瘤（1.5％）中最常见的突变; 并且表明，在未激活端粒酶的癌症中发现端粒酶不依赖端粒维持机制的替代延长端粒（ALT）与任一基因的体细胞突变完全相关。相比之下，ATRX和DAXX中的突变，母细胞瘤和卵巢癌，乳腺癌和胰腺癌的腺癌阴性。 ATRX或DAXX中的改变定义了与人类癌症中替代端粒维持功能密切相关的特定分子途径。

8. 发明授权

EP2780473B1 DIFFERENTIAL IDENTIFICATION OF PANCREATIC CYSTS 有权
标题翻译：胰腺癌的差异性鉴定
公开(公告)号：EP2780473B1
公开(公告)日：2017-07-19
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

9. 发明公开

EP2417268A2 DIAGNOSTIC METHOD USING PALB2 有权
标题翻译：与PALB2诊断步骤
公开(公告)号：EP2417268A2
公开(公告)日：2012-02-15
申请号：EP10749365.2
申请日：2010-03-05
申请人： The Johns Hopkins University
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth W. , PARSONS, D. Williams , JONES, Sian , KERN, Scott , HRUBAN, Ralph , ESHLEMAN, James R. , GOGGINS, Michael , KLEIN, Alison , HIDALGO, Manuel , VELCULESCU, Victor E.
IPC分类号： C12Q1/68 , G01N33/68 , G01N33/574
CPC分类号： C12Q1/6886 , A61K31/407 , C12Q2600/106 , C12Q2600/156 , C12Q2600/158 , G01N33/57438 , G01N2333/47
摘要： The present invention provides a method for detecting mutations in the
PALB2 gene in pancreatic cancer patients and in individuals having a family history of pancreatic cancer. Methods are also provided for diagnosing a predisposition to pancreatic cancer, for predicting a patient's response to pancreatic cancer therapies, and for treating pancreatic cancer, based on presence of a
PALB2 mutation or abberant
PALB2 gene expression in a patient.

10. 发明授权

EP2417268B1 DIAGNOSTIC METHOD USING PALB2 有权
标题翻译：与PALB2诊断步骤
公开(公告)号：EP2417268B1
公开(公告)日：2016-05-11
申请号：EP10749365.2
申请日：2010-03-05
申请人： The Johns Hopkins University
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth W. , PARSONS, D. Williams , JONES, Sian , KERN, Scott , HRUBAN, Ralph , ESHLEMAN, James R. , GOGGINS, Michael , KLEIN, Alison , HIDALGO, Manuel , VELCULESCU, Victor E.
IPC分类号： C12Q1/68 , G01N33/68 , G01N33/574
CPC分类号： C12Q1/6886 , A61K31/407 , C12Q2600/106 , C12Q2600/156 , C12Q2600/158 , G01N33/57438 , G01N2333/47

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