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51. 发明申请

WO2005113824A2 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：WO2005113824A2
公开(公告)日：2005-12-01
申请号：PCT/US2005/017105
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。

52. 发明申请

WO2005076984A2 THYMIDYLATE SYNTHASE GENE AND METASTASIS 审中-公开
标题翻译：甲基合成酶基因和METASTASIS
公开(公告)号：WO2005076984A2
公开(公告)日：2005-08-25
申请号：PCT/US2005/003776
申请日：2005-02-07
申请人： THE JOHN HOPKINS UNIVERSITY , WANG, Tian-LI , DIAZ, Luis , LENGAUER, Christoph , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： WANG, Tian-LI , DIAZ, Luis , LENGAUER, Christoph , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C12Q1/68 , G01N33/48 , G01N33/50 , G06F19/00
CPC分类号： C12Q1/6886 , C12Q2600/106 , C12Q2600/136
摘要： Thymidylate synthase (TYMS) gene amplification was observed in 23% of 31 5-FU resistant liver metastases, while no amplification was observed in metastases of patients that had not been treated with 5-FU. Patients with metastases containing TYMS amplification had a substantially shorter median survival (329 days) than those without amplification (1021 days, p
摘要翻译：在31例5-FU耐药性肝转移患者中，23例患者观察到胸苷酸合成酶（TYMS）基因扩增，而未用5-FU治疗的患者转移灶未观察到扩增。含有TYMS扩增的转移患者的中位生存期（329天）比没有扩增的患者显着更短（1021天，p <0.01）。 TYMS的遗传扩增对复发性结肠直肠癌患者的治疗具有重要意义。

53. 发明申请

WO2005039491A2 CERTAIN IMPROVED COMBINATION BACTERIOLYTIC THERAPY FOR THE TREATMENT OF TUMORS 审中-公开
标题翻译：某些改进的联合用于治疗肿瘤的细菌疗法治疗
公开(公告)号：WO2005039491A2
公开(公告)日：2005-05-06
申请号：PCT/US2004/034624
申请日：2004-10-21
申请人： THE JOHN HOPKINS UNIVERSITY , 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： A61K
CPC分类号： A61K35/742 , A61K31/195 , A61K31/4045 , A61K38/06 , 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 HTI-286 and vinorelbine, caused rapid, massive hemorrhagic necrosis when used in combination with spores. In contrast, agents that stabilized microtubules, such as the taxanes docetaxel and MAC-321, resulted in slow tumor regressions that killed most neoplastic cells. Remaining cells in the poorly perfused regions of tumors could be eradicated by sporulated 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.
摘要翻译：目前用于治疗癌症的方法部分地由于药物不能影响肿瘤血管化程度差的区域而受到限制。我们发现厌氧菌的孢子与微管相互作用的药物联合使用会导致肿瘤血管和血管腔的破坏。发现两类微管抑制剂发挥显着不同的作用。一些抑制微管合成的药物如HTI-286和长春瑞滨，当与孢子结合使用时会引起快速，大量的出血性坏死。相反，稳定微管的药物，如紫杉类多西他赛和MAC-321，导致缓慢的肿瘤消退，从而杀死大多数肿瘤细胞。机体研究表明，微管去稳定剂，但不是微管稳定剂，从根本上减少了血液流向肿瘤，从而扩大了孢子可能发芽的低氧生态位。单次静脉注射孢子加选定的微管相互作用剂能够在没有过量毒性的情况下引起几种肿瘤的消退。

54. 发明申请

WO2005017182A2 MULTI-COLOR IN VITRO TRANSLATION 审中-公开
标题翻译：多色翻译
公开(公告)号：WO2005017182A2
公开(公告)日：2005-02-24
申请号：PCT/US2004/019097
申请日：2004-07-21
申请人： THE JOHNS HOPINKS UNIVERSITY SCHOOL OF MEDICINE , TRAVERSO, Carlo, Giovanni , DIEHL, Frank , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： TRAVERSO, Carlo, Giovanni , DIEHL, Frank , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C12Q
CPC分类号： G01N33/6845 , G01N33/542
摘要： In vitro translation is a widely used tool for both analytical and preparative purposes. For analytical purposes, small amounts of proteins are synthesized and visualized through labeled amino acids incorporated during translation. The radioactively labeled amino acids originally used, such as [ 35 S]methionine or [ 14 C]leucine, have been superceded by the addition of antigenic tags or the incorporation of biotin-labeled or fluorescently-labeled amino acids. Such non-radioactive tags are simpler to visualize following translation and do not pose a radiation hazard. Among the non-radioactive tags, fluorescently labeled-lysine is the most convenient, as proteins that have incorporated this amino acid can be directly visualized following gel electrophoresis. Multiple fluorophores introduced into proteins significantly extend their utility, particularly for the comparison of in vitro translated proteins from related sources. This methodology can be employed for several purposes, including the simplified detection of rare truncating mutations in clinical samples from cancer patients.
摘要翻译：体外翻译是用于分析和制备目的的广泛使用的工具。为了分析的目的，通过在翻译过程中并入的标记氨基酸合成少量蛋白质并使其可视化。最初使用的放射性标记的氨基酸，例如[35 S]甲硫氨酸或[[14 C]亮氨酸）已经通过加入抗原标签或引入生物素标记或荧光标记的氨基酸而被替代。这种非放射性标签更容易可视化翻译，并且不会造成辐射危害。在非放射性标签中，荧光标记的赖氨酸是最方便的，因为结合了该氨基酸的蛋白质可以在凝胶电泳后直接显现。引入蛋白质的多种荧光团显着扩展其效用，特别是用于比较来自相关来源的体外翻译蛋白质。该方法可用于多种目的，包括简化检测癌症患者临床样品中罕见的截短突变。

55. 发明申请

WO2008021288A2 CONSENSUS CODING SEQUENCES OF HUMAN BREAST AND COLORECTAL CANCERS 审中-公开
标题翻译：人类乳腺癌和彩色癌症的共识编码序列
公开(公告)号：WO2008021288A2
公开(公告)日：2008-02-21
申请号：PCT/US2007/017866
申请日：2007-08-13
申请人： JOHNS HOPKINS UNIVERSITY , SJOBLOM, Tobias , JONES, Sian , PARSONS, D., Williams , WOOD, Laura, D. , LIN, Jimmy , BARBER, Thomas , MANDELKER, Diana , VOGELSTEIN, Bert , KINZLER, Kenneth, W. , VELCULESU, Victor, E.
发明人： SJOBLOM, Tobias , JONES, Sian , PARSONS, D., Williams , WOOD, Laura, D. , LIN, Jimmy , BARBER, Thomas , MANDELKER, Diana , VOGELSTEIN, Bert , KINZLER, Kenneth, W. , VELCULESU, Victor, E.
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6886 , C12Q2600/106 , C12Q2600/156
摘要： Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ~90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention and monitoring.
摘要翻译：分析11个乳房和11个结直肠癌中的13,023个基因显示，个体肿瘤平均累积了〜90个突变基因，但只有其中一个子集对肿瘤过程有贡献。使用严格的标准来描绘这一亚型，我们确定了189个基因（平均每个肿瘤11个），以显着的频率突变。这些基因绝大多数不知道在肿瘤中被遗传改变，并被预测会影响广泛的细胞功能，包括转录，粘附和侵袭。这些数据定义了两种人类癌症类型的遗传景观，为诊断和治疗干预和监测提供了新的目标。

56. 发明申请

WO2005039492A2 IMPROVED COMBINATION BACTERIOLYTIC THERAPY FOR THE TREATMENT OF TUMORS 审中-公开
标题翻译：改进组合治疗肿瘤的微生物治疗
公开(公告)号：WO2005039492A2
公开(公告)日：2005-05-06
申请号：PCT/US2004/034625
申请日：2004-10-21
申请人： THE JOHN HOPKINS UNIVERSITY , 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： A61K
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.
摘要翻译：目前用于治疗癌症的方法在一定程度上受到药物不能影响肿瘤血管不足的区域的限制。我们已经发现，厌氧细菌的孢子与与微管相互作用的药物组合可能导致肿瘤的血管和非血管性腔室的破坏。发现两类微管抑制剂发挥显着不同的作用。抑制微管合成的一些药物，如长春瑞滨，当与孢子结合使用时，引起快速，大规模的出血性坏死。相比之下，稳定微管（如紫杉烷多西紫杉醇）的药物导致肿瘤消退缓慢，导致大多数肿瘤细胞死亡。肿瘤不良灌注区域中的剩余细胞可以被杂音细菌消灭。机理研究表明，微管不稳定剂，而不是微管稳定剂，从根本上减少了流向肿瘤的血液，从而扩大了孢子可以发芽的缺氧生态位。在没有过量毒性的情况下，单次静脉注射孢子加选择的微管相互作用剂能够引起几种肿瘤的回归。

57. 发明申请

WO2012099881A3 MUTANT PROTEINS AS CANCER-SPECIFIC BIOMARKERS 审中-公开
公开(公告)号：WO2012099881A3
公开(公告)日：2012-07-26
申请号：PCT/US2012/021553
申请日：2012-01-17
申请人： THE JOHN HOPKINS UNIVERSITY , 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
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.

58. 发明申请

WO2003104398A3 ALLELIC VARIATION IN HUMAN GENE EXPRESSION 审中-公开
公开(公告)号：WO2003104398A3
公开(公告)日：2003-12-18
申请号：PCT/US2003/017262
申请日：2003-06-04
申请人： JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE , YAN, Hai , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： YAN, Hai , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C12Q1/68
摘要： Genetically-determined variation in expression levels is an important component of human diversity and has significant implications for normal and abnormal human physiology. Using this genetically determined variation one can identify disease risk factors in individuals. One can associate such variations with birth defects, diseases, and non-disease traits. Such variations can be associated with susceptibility or resistance to the effects of drugs or other therapeutic interventions.

59. 发明申请

WO2003104398A2 ALLELIC VARIATION IN HUMAN GENE EXPRESSION 审中-公开
标题翻译：人类基因表达的ALLELIC变异
公开(公告)号：WO2003104398A2
公开(公告)日：2003-12-18
申请号：PCT/US2003/017262
申请日：2003-06-04
申请人： JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE , YAN, Hai , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： YAN, Hai , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C12N
CPC分类号： C12Q1/6883 , C12Q1/6876 , C12Q2600/156 , C12Q2600/158
摘要： Genetically-determined variation in expression levels is an important component of human diversity and has significant implications for normal and abnormal human physiology. Using this genetically determined variation one can identify disease risk factors in individuals. One can associate such variations with birth defects, diseases, and non-disease traits. Such variations can be associated with susceptibility or resistance to the effects of drugs or other therapeutic interventions.
摘要翻译：遗传决定的表达水平变异是人类多样性的重要组成部分，对正常和异常的人类生理学具有重要意义。使用这种遗传决定的变异可以识别个体的疾病风险因素。可以将这些变异与出生缺陷，疾病和非疾病特征联系起来。这种变化可能与药物或其他治疗干预的影响的易感性或抗性相关。

60. 发明申请

WO2004010846A2 DESIGN AND SYNTHESIS OF RENAL DIPEPTIDASE INHIBITORS 审中-公开
标题翻译：肾脏双磷脂酶抑制剂的设计与合成
公开(公告)号：WO2004010846A2
公开(公告)日：2004-02-05
申请号：PCT/US2003/023363
申请日：2003-07-28
申请人： THE JOHNS HOPKINS SCHOOL OF MEDICINE , KHAN, Saeed, R. , VOGELSTEIN, Bert , KINZLER, Kenneth, W. , GURULINGAPPA, Hallur , BUCKHAULTS, Phillip
发明人： KHAN, Saeed, R. , VOGELSTEIN, Bert , KINZLER, Kenneth, W. , GURULINGAPPA, Hallur , BUCKHAULTS, Phillip
IPC分类号： A61B
CPC分类号： C07F9/303 , A61K51/0489 , C07B59/004 , C07B2200/05
摘要： Aminophosphinic acid derivatives were synthesized as potential inhibitors of renal dipeptidase, an enzyme overexpressed in benign and malignant colon tumors. Several compounds showed potent enzyme-inhibitory activity. These compounds can be used therapeutically and diagnostically for treatment and detection of tumors.
摘要翻译：氨基次膦酸衍生物作为肾二肽酶的潜在抑制剂合成，所述肾二肽酶是在良性和恶性结肠肿瘤中过表达的酶。几种化合物显示出有效的酶抑制活性。这些化合物可用于治疗和诊断治疗和检测肿瘤。

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