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1. 发明申请

WO2005039492A3 IMPROVED COMBINATION BACTERIOLYTIC THERAPY FOR THE TREATMENT OF TUMORS 审中-公开
公开(公告)号：WO2005039492A3
公开(公告)日：2005-06-30
申请号：PCT/US2004034625
申请日：2004-10-21
申请人： UNIV JOHNS HOPKINS , 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： A01N63/00 , A61K20060101
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.

2. 发明申请

WO2005039491A9 CERTAIN IMPROVED COMBINATION BACTERIOLYTIC THERAPY FOR THE TREATMENT OF TUMORS 审中-公开
标题翻译：一些改进的组合治疗肿瘤的微生物治疗
公开(公告)号：WO2005039491A9
公开(公告)日：2005-06-02
申请号：PCT/US2004034624
申请日：2004-10-21
申请人： UNIV JOHNS HOPKINS , 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： A01N63/00 , A61K20060101 , 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。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，引起快速，大规模的出血性坏死。相比之下，稳定微管的药物，如紫杉烷多西紫杉醇和MAC-321，导致肿瘤缓慢减退，杀死大部分肿瘤细胞。肿瘤细胞灌注不良区域的剩余细胞可以被孢子细菌消灭机制研究表明，微管不稳定剂，而不是微管稳定剂，从根本上减少了血液流向肿瘤，从而扩大了孢子可能发芽的缺氧生态位。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。

3. 发明申请

WO2005039491A3 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：WO2005039491A3
公开(公告)日：2005-06-23
申请号：PCT/US2004034624
申请日：2004-10-21
申请人： UNIV JOHNS HOPKINS , 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： A01N63/00 , A61K20060101
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度毒性的情况下引起几种肿瘤的消退。

4. 发明申请

WO2005039492A9 IMPROVED COMBINATION BACTERIOLYTIC THERAPY FOR THE TREATMENT OF TUMORS 审中-公开
标题翻译：改进的联合用于治疗肿瘤的细菌疗法
公开(公告)号：WO2005039492A9
公开(公告)日：2005-06-02
申请号：PCT/US2004034625
申请日：2004-10-21
申请人： UNIV JOHNS HOPKINS , 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： A01N63/00 , A61K20060101 , 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，如紫杉类多西紫杉醇，则导致缓慢的肿瘤消退，从而杀死大多数肿瘤细胞。肿瘤灌注不足区域的剩余细胞可以被脊椎化细菌消灭。机理研究表明，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缺氧生态位。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度毒性的情况下引起几种肿瘤的消退。

5. 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。

6. 发明申请

WO2006002142A3 IMAGING INFECTION WITH COMPOUNDS THAT BIND TO THYMIDINE KINASE 审中-公开
标题翻译：使用与酪氨酸激酶结合的化合物成像感染
公开(公告)号：WO2006002142A3
公开(公告)日：2006-05-04
申请号：PCT/US2005021888
申请日：2005-06-20
申请人： UNIV JOHNS HOPKINS , POMPER MARTIN G , BETTEGOWDA CHETAN , FOSS CATHERINE , ZHOU SHIBIN , KINZLER KENNETH , VOGELSTEIN BERT
发明人： POMPER MARTIN G , BETTEGOWDA CHETAN , FOSS CATHERINE , ZHOU SHIBIN , KINZLER KENNETH , VOGELSTEIN BERT
IPC分类号： A61K49/00 , A61K51/00 , A61K101 , A61K123
CPC分类号： A61K51/1241 , A61K51/0491 , A61K51/1231
摘要： The instant invention provides a method for diagnosing an infection in a subject by administering to the subject a compound suitable for imaging which binds to a thymidine kinase present in the infecting organism, and obtaining an image of the subject to determine the presence and location of the compound, wherein a localization of the compound is indicative that the subject has an infection.
摘要翻译：本发明提供了一种用于通过向受试者施用适合于与感染生物体中存在的胸腺嘧啶激酶结合的成像的化合物并且获得受试者的图像来确定受试者的感染的存在和位置的方法，化合物，其中化合物的定位表明受试者具有感染。

7. 发明公开

EP2912468A4 PAPANICOLAOU TEST FOR OVARIAN AND ENDOMETRIAL CANCERS 有权
标题翻译： PAPANICOLAU测试FÜROVARIAL- UND内分泌素
公开(公告)号：EP2912468A4
公开(公告)日：2016-06-29
申请号：EP13851273
申请日：2013-10-17
申请人： UNIV JOHNS HOPKINS
发明人： KINDE ISAAC , KINZLER KENNETH W , VOGELSTEIN BERT , PAPADOPOULOS NICKOLAS , DIAZ LUIS , BETTEGOWDA CHETAN , WANG YUXUAN
IPC分类号： G01N33/574 , C12Q1/68 , G01N33/68
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.
摘要翻译：最近开发的基于液体的Papanicolaou（Pap）涂片不仅允许细胞学评估，还允许DNA的检测用于检测宫颈癌的致病因子HPV。我们测试了这些样品，以检测罕见的肿瘤细胞中存在的体细胞突变，其可能在子宫内膜和卵巢癌中从子宫颈积聚。组装了一组在子宫内膜和卵巢癌中常见突变的基因，用于鉴定所有46例子宫内膜癌或子宫颈癌组织样本中的突变。我们还能够在100％的子宫内膜癌（24例24例）和41％的卵巢癌（22例中的9例）中鉴定出来自液体巴氏涂片的DNA中的相同突变。我们开发了一种基于序列的方法来查询单个液体巴氏涂片中12个基因的突变，而无需了解肿瘤的基因型。

8. 发明公开

EP2734644A4 OLIGODENDROGLIOMA DRIVER GENES 有权
标题翻译：少枝胶质细胞驱动性基因
公开(公告)号：EP2734644A4
公开(公告)日：2015-03-18
申请号：EP12814956
申请日：2012-07-18
申请人： UNIV JOHNS HOPKINS , UNIV DUKE
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , BETTEGOWDA CHETAN , AGRAWAL NISHANT , BIGNER DARELL , YAN HAI , MCLENDON ROGER
IPC分类号： C12Q1/68
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.

9. 发明公开

EP2956556A4 TERT PROMOTER MUTATIONS IN GLIOMAS AND A SUBSET OF TUMORS 有权
标题翻译：在胶质瘤TERT启动子突变和部分量的肿瘤
公开(公告)号：EP2956556A4
公开(公告)日：2016-10-12
申请号：EP14751900
申请日：2014-02-18
申请人： UNIV DUKE , UNIV JOHNS HOPKINS
发明人： YAN HAI , VOGELSTEIN BERT , PAPADOPOULOS NICKOLAS , KINZLER KENNETH W , JIAO YUCHEN , BETTEGOWDA CHETAN , BIGNER DARELL D
IPC分类号： C12Q1/68 , C12N15/12
CPC分类号： C12Q1/6886 , C12Q2600/112 , C12Q2600/156
摘要： We surveyed 1,230 tumors of 60 different types and found that tumors could be divided into types with low (

10. 发明公开

EP1675465A4 IMPROVED COMBINATION BACTERIOLYTIC THERAPY FOR THE TREATMENT OF TUMORS 有权
标题翻译：改进的溶菌联合治疗肿瘤的治疗
公开(公告)号：EP1675465A4
公开(公告)日：2008-07-30
申请号：EP04809987
申请日：2004-10-21
申请人： UNIV JOHNS HOPKINS
发明人： DANG LONG , BETTEGOWDA CHETAN , KINZLER KENNETH W , VOGELSTEIN BERT
IPC分类号： A61K35/74 , A01N63/00 , A61K20060101 , A61K31/337 , A61K31/427 , A61K45/06 , A61P35/00
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.

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