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41. 发明申请

WO9931240A3 14-3-3 sigma ARRESTS THE CELL CYCLE 审中-公开
标题翻译： 14-3-3西格玛实现细胞周期
公开(公告)号：WO9931240A3
公开(公告)日：1999-09-02
申请号：PCT/US9826924
申请日：1998-12-18
申请人： UNIV JOHNS HOPKINS , HERMEKING HEIKO , VOGELSTEIN BERT , KINZLER KENNETH W
发明人： HERMEKING HEIKO , VOGELSTEIN BERT , KINZLER KENNETH W
IPC分类号： A61K38/00 , A61K48/00 , C07K14/47 , C12N5/08 , C12N15/12 , A61K38/17 , C12N5/10 , C12N15/11 , C12N15/85 , G01N33/50
CPC分类号： C07K14/47 , A61K38/00 , A61K48/00
摘要： Exposure of colorectal cancer (CRC) cells to ionizing radiation results in a growth arrest, with cells blocked in both the G1 and G2 phases of the cell cycle. The G1 block has been shown to be due to the p53-mediated induction of the cyclin-dependent kinase inhibitor p21 , but the basis for the G2 arrest is unknown. Through a quantitative analysis of gene expression patterns in CRC cell lines, we have discovered that 14-3-3 sigma is strongly induced by gamma -irradiation and other DNA-damaging agents. The induction of 14-3-3 sigma is mediated by a p53-responsive element located 1.815 kb upstream of its transcription start site. Exogenous introduction of 14-3-3 sigma into cycling cells results in a G2 block similar to that observed following irradiation. These results document a molecular mechanism for G2/M control that is regulated in human cells by p53.
摘要翻译：将大肠癌（CRC）细胞暴露于电离辐射导致生长停滞，细胞周期的G1和G2期都阻断细胞。已经显示G1阻滞是由于p53介导的细胞周期蛋白依赖性激酶抑制剂p21 的诱导，但是G2停滞的基础是未知的。通过定量分析CRC细胞系中的基因表达模式，我们发现14-3-3σ强烈地被γ-照射和其他DNA损伤剂诱导。 14-3-3西格玛的诱导由位于其转录起始位点上游1.815kb的p53应答元件介导。向循环细胞中外源性引入14-3-3σ导致与在照射后观察到的相似的G2阻滞。这些结果记录了在人类细胞中由p53调节的G2 / M对照的分子机制。

42. 发明申请

WO9914356A3 P53-INDUCED APOPTOSIS 审中-公开
标题翻译： P53诱导的病变
公开(公告)号：WO9914356A3
公开(公告)日：1999-07-29
申请号：PCT/US9819300
申请日：1998-09-17
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , KINZLER KENNETH W , POLYAK KORNELIA
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , POLYAK KORNELIA
IPC分类号： C12N15/09 , C07K16/32 , C12P21/08 , C12Q1/68 , C07K16/00
CPC分类号： C12Q1/6809 , C12Q1/6886 , C12Q1/6897 , C12Q2539/103 , C12Q2600/136 , C12Q2600/142
摘要： The most well-documented biochemical property of p53 is its ability to transcriptionally activate genes. Many of the genes which are activated by p53 expression prior to the onset of apoptosis are predicted to encode proteins which could generate or respond to oxidative stress, including one that is implicated in apoptosis within plant meristems. p53 may result in apoptosis through a three-step process: (i) the transcriptional induction of specific redox-related genes; (ii) the formation of reactive oxygen species (ROS); and (iii) the oxidative degradation of mitochondrial components, rapidly leading to cell death. Transcription of other genes is decreased by p53. Examination of the level of transcription of p53-induced or -repressed genes can be used to determine p53 status, to diagnose cancer, and to evaluate cytotoxicity or carcinogenicity of a test agent.
摘要翻译：最有说明的p53生物化学性质是其转录激活基因的能力。许多在细胞凋亡发生前被p53表达激活的基因被预测编码能够产生或响应氧化应激的蛋白质，包括与植物分生组织内凋亡有关的蛋白质。 p53可能通过三步过程导致细胞凋亡：（i）特异性氧化还原相关基因的转录诱导; （ii）形成活性氧（ROS）; 和（iii）线粒体成分的氧化降解，迅速导致细胞死亡。其他基因的转录通过p53降低。检查p53诱导或抑制基因的转录水平可用于确定p53状态，诊断癌症，并评估测试药物的细胞毒性或致癌性。

43. 发明申请

WO2005113824A3 PROTEIN TYROSINE PHOSPHATASE MUTATIONS IN CANCERS 审中-公开
标题翻译：蛋白质酪氨酸磷酸酶突变体
公开(公告)号：WO2005113824A3
公开(公告)日：2006-06-29
申请号：PCT/US2005017105
申请日：2005-05-16
申请人： WANG ZHENGHE , VELCULESCU VICTOR , KINZLER KENNETH W , VOGELSTEIN BERT
发明人： WANG ZHENGHE , VELCULESCU VICTOR , KINZLER KENNETH W , VOGELSTEIN BERT
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6886 , C12N9/16 , C12Q2600/112 , C12Q2600/136 , C12Q2600/156 , C12Q2600/158 , C12Y301/03048 , G01N33/5011 , G01N2333/916
摘要： Tyrosine phosphorylation, regulated by protein tyrosine phosphatases (PTPs) and kinases (PTKs), is important in signaling pathways underlying tumorigenesis. A mutational analysis of the tyrosine phosphatase gene superfamily in human cancers identified 83 somatic mutations in six PTPs (PTPRF, PTPRG, PTPRT, PTPN3, PTPN13, PTPN14) affecting 26 % of colorectal cancers and a smaller fraction of lung, breast and gastric cancers. Fifteen mutations were nonsense, frameshift or splice site alterations predicted to result in truncated proteins lacking phosphatase activity. Five missense mutations in the most commonly altered PTP (PTPRP) were biochemically examined and found to reduce phosphatase activity. Expression of wild-type but not a mutant PTPRT in human cancer cells inhibited cell growth. These observations suggest that the tyrosine phosphatase genes are tumor suppressor genes, regulating cellular pathways that may be amenable to therapeutic intervention.
摘要翻译：由蛋白酪氨酸磷酸酶（PTP）和激酶（PTK）调节的酪氨酸磷酸化在肿瘤发生的信号通路中是重要的。人类癌症中酪氨酸磷酸酶基因超家族的突变分析鉴定了影响26％结肠直肠癌和较小部分肺癌，乳腺癌和胃癌的6种PTPs（PTPRF，PTPRG，PTPRT，PTPN3，PTPN13，PTPN14）中的83个体细胞突变。十五个突变是无义，移位或剪接位点改变，预计会导致截短的蛋白质缺乏磷酸酶活性。在生物化学检查中发现最常改变的PTP（PTPRP）中的五个错义突变被发现可以降低磷酸酶活性。野生型但不是突变PTPRT在人类癌细胞中的表达抑制细胞生长。这些观察表明，酪氨酸磷酸酶基因是肿瘤抑制基因，调节可能适合于治疗性干预的细胞途径。

44. 发明申请

WO2013012927A3 OLIGODENDROGLIOMA DRIVER GENES 审中-公开
公开(公告)号：WO2013012927A3
公开(公告)日：2013-03-21
申请号：PCT/US2012047211
申请日：2012-07-18
申请人： UNIV JOHNS HOPKINS , UNIV DUKE , VOGELSTEIN BERT , KINZLER KENNETH W , BETTEGOWDA CHETAN , AGRAWAL NISHANT , PAPADOPOULOS NICKOLAS , BIGNER DARELL , YAN HAI , MCLENDON ROGER
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , BETTEGOWDA CHETAN , AGRAWAL NISHANT , PAPADOPOULOS NICKOLAS , BIGNER DARELL , YAN HAI , MCLENDON ROGER
IPC分类号： C12Q1/68 , C12N15/11
CPC分类号： C12Q1/6886 , C12Q2600/106 , C12Q2600/112 , C12Q2600/118 , C12Q2600/156 , C12Q2600/158
摘要： Oligodendrogliomas are the second most common malignant brain tumor in adults. These tumors often contain a chromosomal abnormality involving a pericentromeric fusion of chromosomes 1 and 19, resulting in losses of the entire short arm of the former and the long arm of the latter. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven anaplastic oligodendrogliomas with chromosome 1p and 19q losses. Among other changes, we found that that CIC (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six of the seven cases and that FUBP1 (far upstream element (FUSE) binding protein) on chromosome 1p was somatically mutated in two of the seven cases. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes.
摘要翻译：少突神经胶质瘤是成人中第二常见的恶性脑肿瘤。这些肿瘤通常含有涉及染色体1和19的pericentromer融合的染色体异常，导致前者的整个短臂和后者的长臂损失。为了确定这种改变的分子遗传基础，我们对染色体1p和19q丢失的7个间变性少突神经胶质瘤进行了外显子测序。在其他变化中，我们发现染色体19q上的CIC（果蝇基因capicua的同源物）在七个病例中的六个中发生体细胞突变，并且染色体1p上的FUBP1（远端上游元件（FUSE）结合蛋白）在两个体细胞突变在七宗个案中。 27例额外少突胶质瘤的检查发现12例和3例多发CIC和FUBP1突变的肿瘤，其中58％预计会导致编码蛋白截短。这些结果表明这些基因在少突胶质细胞的生物学和病理学中起关键作用。

45. 发明申请

WO2012142213A3 SAFE SEQUENCING SYSTEM 审中-公开
标题翻译：安全排序系统
公开(公告)号：WO2012142213A3
公开(公告)日：2013-01-24
申请号：PCT/US2012033207
申请日：2012-04-12
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , KINZLER KENNETH W , PAPADOPOULOS NICKOLAS , KINDE ISAAC
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DNA模板的一小部分中的突变的鉴定对于在几个生物医学研究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，但是这些仪器中的错误率通常太高，无法确定罕见的变体。我们在这里描述了一种可以显着增加大规模并行测序仪器对此目的的灵敏度的方法。这种方法的一个例子是（Safe-Sequencing System），称为“Safe-SeqS”，包括（i）将唯一标识符（UID）分配给每个模板分子; （ii）每个唯一标记的模板分子的扩增以产生UID家族; 和（iii）扩增产物的冗余测序。具有相同UID的PCR片段是真正的突变体（“超突变体”），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的保真度，体外合成的寡核苷酸的准确性以及正常细胞的核和线粒体基因组中突变的流行率的效用。

46. 发明申请

WO2013006791A2 SEMI-DIGITAL LIGATION ASSAY 审中-公开
标题翻译：半数字结扎测定
公开(公告)号：WO2013006791A2
公开(公告)日：2013-01-10
申请号：PCT/US2012045757
申请日：2012-07-06
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , KINZLER KENNETH W
发明人： VOGELSTEIN BERT , KINZLER KENNETH W
CPC分类号： C12Q1/6827 , C12Q1/6883 , C12Q1/6886 , C12Q2527/107 , C12Q2561/125
摘要： Assays for detecting mutant sequences at particular locations, especially against a background of non-mutant sequences, employ thermocycling ligase reactions. Differentially labeled or sized probes can be used to distinguish wild-type and mutant sequences. Physico-chemical properties of the probes can be critical to successful detection. Mutation detection can be used for diagnosis, monitoring, or prognosticating diseases such as cancers.
摘要翻译：用于在特定位置检测突变体序列的分析，特别是针对非突变序列背景的分析采用热循环连接酶反应。差异标记或大小的探针可用于区分野生型和突变型序列。探针的物理化学特性对于成功检测至关重要。突变检测可用于诊断，监测或预测诸如癌症的疾病。

47. 发明申请

WO2012178034A2 MUTATIONS IN PANCREATIC NEOPLASMS 审中-公开
标题翻译：胰腺神经细胞的突变
公开(公告)号：WO2012178034A2
公开(公告)日：2012-12-27
申请号：PCT/US2012043783
申请日：2012-06-22
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , KINZLER KENNETH W , WU JIAN , DIAZ LUIS , PAPADOPOULOS NICKOLAS , MATTHAEI HANNO , HRUBAN RALPH , MAITRA ANIRBAN
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , WU JIAN , DIAZ LUIS , PAPADOPOULOS NICKOLAS , MATTHAEI HANNO , HRUBAN RALPH , MAITRA ANIRBAN
IPC分类号： C12Q1/68 , C12N15/11
CPC分类号： C12Q1/6886 , C12Q2600/112 , C12Q2600/156
摘要： To help reveal the pathogenesis of these lesions, we purified the DNA from Intraductal Papillary Mucinous Neoplasm (IPMN) cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. We identified recurrent mutations at codon 201 of GNAS. We found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight cases, the GNAS mutations present in the IPMNs were also found in the invasive lesion. GNAS mutations were not found in other types of cystic neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. These data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions.
摘要翻译：为了揭示这些病变的发病机制，我们从19名患者的导管内乳头状粘液性肿瘤（IPMN）囊肿液中纯化DNA，并搜索了在人类癌症中通常改变的169种基因中的突变。我们在GNAS的201号密码子处鉴定了复发性突变。我们发现GNAS突变存在于66％的IPMNs中，KRAS或GNAS突变可以在96％中鉴定。在8例中，我们可以研究与含有GNAS突变的IPMN相关的侵袭性腺癌。在这8例中有7例中，存在于IPMNs中的GNAS突变也在侵袭性损伤中发现。在其他类型的胰腺囊性肿瘤或与IPMN无关的侵袭性腺癌中未发现GNAS突变。这些数据表明，GNAS突变可以为囊性胰腺病变患者的诊断和治疗提供依据。

48. 发明申请

WO2007149433A3 TUMOR-SPECIFIC DELIVERY OF THERAPEUTIC AGENTS VIA LIPOSOMASE 审中-公开
标题翻译：通过脂质体的肿瘤特异性递送治疗药物
公开(公告)号：WO2007149433A3
公开(公告)日：2008-11-06
申请号：PCT/US2007014274
申请日：2007-06-19
申请人： UNIV JOHNS HOPKINS , CHEONG IAN , ZHOU SHIBIN , KINZLER KENNETH W , VOGELSTEIN BERT
发明人： CHEONG IAN , ZHOU SHIBIN , KINZLER KENNETH W , VOGELSTEIN BERT
IPC分类号： A61K48/00
CPC分类号： A61K38/465 , A61K9/1271 , A61K9/1278 , A61K31/4545 , A61K31/4745 , A61K31/704 , A61K31/713 , A61K35/742 , A61K39/39558 , A61K47/64 , C12N9/20 , C12Y301/01003 , A61K2300/00
摘要： Clostridiu

49. 发明申请

WO2006034191A3 TEM17 BINDS TO CORTACTIN 审中-公开
标题翻译： TEM17为CORTACTIN
公开(公告)号：WO2006034191A3
公开(公告)日：2007-07-19
申请号：PCT/US2005033479
申请日：2005-09-20
申请人： UNIV JOHNS HOPKINS , ST CROIX BRAD , VOGELSTEIN BERT , KINZLER KENNETH W , NANDA AKASH , BUCKHAULTS PHILIP W
发明人： ST CROIX BRAD , VOGELSTEIN BERT , KINZLER KENNETH W , NANDA AKASH , BUCKHAULTS PHILIP W
IPC分类号： G01N33/53 , C07K14/47 , C07K16/18 , C12N15/12 , C12N15/62 , G01N33/567
CPC分类号： C07K14/4748
摘要： Tumor Endothelial Marker 17 (TEM17) was recently identified as an mRNA transcript overexpressed in the endothelium of vessels in human solid tumors. We have identified several new variants of TEMI7, derived by alternative splicing, that are intracellular (TEM17-I), secreted (TEM17-S), and on the cell surface membrane (TEM17-M) of tumor endothelium. We identified cortactin as a protein capable of binding to the extracellular region of both TEM17 and its closest homologue, TEM3, which is also expressed in tumor endothelium. The binding domain of cortactin is a 9-amino acid residue region in its plexin-like domain. These provide targets for the delivery of therapeutic and imaging agents to the vessels of solid tumors.
摘要翻译：肿瘤内皮标记17（TEM17）最近被鉴定为人类实体瘤血管内皮中过表达的mRNA转录物。我们已经确定了通过选择性剪接（细胞内（TEM17-I），分泌型（TEM17-S））和肿瘤内皮的细胞表面膜（TEM17-M）衍生的几种新的变体TEMI7。我们鉴定了皮质激素作为能够结合TEM17及其最近同源物TEM3的细胞外区域的蛋白质，TEM3也在肿瘤内皮中表达。皮质激素的结合结构域是其plexin样结构域中的9-氨基酸残基区域。这些为将实施肿瘤的血管递送治疗和显像剂提供了目标。

50. 发明申请

WO2004005883A3 SECRETED AND CYTOPLASMIC TUMOR ENDOTHELIAL MARKERS 审中-公开
标题翻译：分泌和肿瘤肿瘤内皮标记
公开(公告)号：WO2004005883A3
公开(公告)日：2006-07-27
申请号：PCT/US0316250
申请日：2003-07-02
申请人： UNIV JOHNS HOPKINS , ST CROIX BRAD , KINZLER KENNETH W , VOGELSTEIN BERT
发明人： ST CROIX BRAD , KINZLER KENNETH W , VOGELSTEIN BERT
IPC分类号： A61K39/395 , A61K38/00 , A61K38/17 , A61K38/18 , A61K38/19 , A61K38/39 , A61K38/44 , A61K38/47 , A61K38/48 , A61K38/49 , A61K38/55 , C12Q1/68 , G01N33/50 , G01N33/53 , G01N33/574
CPC分类号： G01N33/5011 , A61K38/00 , G01N33/5091 , G01N33/57484
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 many differentially expressed genes, including a large nujber of genes 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 fo the liver. Theses 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.
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，鉴定了主要在内皮中表达的170个以上的基因。正常和肿瘤衍生的内皮的比较显示许多差异表达的基因，包括在肿瘤相关内皮中特异性升高的大量的基因。来自该组的代表性基因的实验表明，大多数类似地在原发性肺，乳腺，脑和胰腺癌的内皮以及肝脏的转移性损伤中表达。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，对抗血管生成的发展具有重要意义。

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