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41. 发明申请

WO2005010145A3 METHOD AND COMPOSITIONS FOR DETECTION AND ENUMERATION OF GENETIC VARIATIONS 审中-公开
标题翻译：用于检测和遗传变异计算的方法和组合物
公开(公告)号：WO2005010145A3
公开(公告)日：2005-08-11
申请号：PCT/US2004015587
申请日：2004-06-09
申请人： UNIV JOHNS HOPKINS , DRESSMAN DEVIN , YAN HAI , KINZLER KENNETH W , VOGELSTEIN BERT
发明人： DRESSMAN DEVIN , YAN HAI , KINZLER KENNETH W , VOGELSTEIN BERT
IPC分类号： C07H21/04 , C12N20060101 , C12N15/10 , C12Q1/68
CPC分类号： C12Q1/6858 , C07H21/04 , C12N15/1075 , C12Q1/686 , C12Q2565/537 , C12Q2563/149 , C12Q2563/143
摘要： Many areas of biomedical research depend on the analysis of uncommon variations in individual genes or transcripts. Here we describe a method that can quantify such variation at a scale and ease heretofore unattainable. Each DNA molecule in a collection of such molecules is converted into a single particle to which thousands of copies of DNA identical in sequence to the original are bound. This population of beads then corresponds to a one-to-one representation of the starting DNA molecules. Variation within the original population of DNA molecules can then be simply assessed by counting fluorescently-labeled particles via flow cytometry. Millions of individual DNA molecules can be assessed in this fashion with standard laboratory equipment. Moreover, specific variants can be isolated by flow sorting and employed for further experimentation. This approach can be used for the identification and quantification of rare mutations as well as to study variations in gene sequences or transcripts in specific populations or tissues.
摘要翻译：生物医学研究的许多领域取决于对个别基因或转录本中罕见变异的分析。在这里我们描述一种方法，可以量化这种变化的规模和缓解迄今为止无法实现。这些分子集合中的每个DNA分子都被转化为一个单一的颗粒，数千个拷贝的DNA序列与原始序列相同。然后这个珠子群对应于起始DNA分子的一对一表示。然后可以通过流式细胞术计数荧光标记的颗粒来简单评估原始DNA分子群体内的变化。数百万个体DNA分子可以用这种方式用标准的实验室设备进行评估。此外，可以通过流分选分离特定的变体并用于进一步的实验。这种方法可用于鉴定和量化罕见突变，以及研究特定人群或组织中基因序列或转录本的变异。

42. 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。

43. 发明申请

WO2004036171A2 DISEASE DETECTION BY DIGITAL PROTEIN TRUNCATION ASSAYS 审中-公开
标题翻译：数字蛋白质功能测定的疾病检测
公开(公告)号：WO2004036171A2
公开(公告)日：2004-04-29
申请号：PCT/US0236143
申请日：2002-12-04
申请人： UNIV JOHNS HOPKINS , TRAVERSO C GIOVANNI , KINZLER KENNETH W , VOGELSTEIN BERT
发明人： TRAVERSO C GIOVANNI , KINZLER KENNETH W , VOGELSTEIN BERT
IPC分类号： G01N33/483 , C12N15/09 , C12Q1/68 , G01N27/447 , G01N33/574 , G01N33/68 , G01N
CPC分类号： C12Q1/6886 , C12Q2600/156 , G01N33/68
摘要： Genetic diseases can be diagnosed by detection of mutations in causative genes. Protein truncation assays can be used to detect gene products of truncation-type mutations. However, the sensitivity of the assays is often insufficient to detect mutations present in a sample of DNA at a low frequency. Sensitivity can be increased by dividing samples so that the signal generated by a mutant allele comprises a larger fraction of the total alleles than prior to dividing. Thus a previously undetectable signal generated by the mutant allele can become detectable in the assay. Such increased sensitivity permits detection at early stages and in samples having high levels of other alleles.
摘要翻译：可以通过检测致病基因突变来诊断遗传疾病。蛋白质截短测定法可用于检测截短型突变的基因产物。然而，测定的灵敏度通常不足以在低频下检测DNA样品中存在的突变。可以通过分割样本来增加灵敏度，使得由突变等位基因产生的信号包含总分子数之前比分裂前的更大部分。因此，在测定中可以检测到由突变等位基因产生的以前不可检测的信号。这种增加的灵敏度允许早期检测和具有高水平其他等位基因的样品。

44. 发明申请

WO0159092A9 METHODS FOR GENERATING HYPERMUTABLE BACTERIA 审中-公开
标题翻译：产生超嗜热菌的方法
公开(公告)号：WO0159092A9
公开(公告)日：2002-10-24
申请号：PCT/US0104339
申请日：2001-02-12
申请人： UNIV JOHNS HOPKINS , NICOLAIDES NICHOLAS C , SASS PHILIP M , GRASSO LUIGI , VOGELSTEIN BERT , KINZLER KENNETH W
发明人： NICOLAIDES NICHOLAS C , SASS PHILIP M , GRASSO LUIGI , VOGELSTEIN BERT , KINZLER KENNETH W
IPC分类号： C12N15/01 , C12N15/10 , C12N1/20
CPC分类号： C12N15/1024 , C12N15/01 , C12N15/102
摘要： Bacteria are manipulated to create desirable output traits using dominant negative alleles of mismatch repair proteins. Enhanced hypermutation is achieved by combination of mismatch repair deficinecy and exogenously applied mutagens. Stable bacteria containing desirable output traits are obtained by restoring mismatch reparir activity to the bacteria.
摘要翻译：使用错配修复蛋白的显性负性等位基因操纵细菌以产生理想的产量性状。通过错配修复缺陷和外源应用的诱变剂的组合实现超强突变。通过恢复对细菌的错配reparir活性获得含有理想产量性状的稳定细菌。

45. 发明申请

WO02076383A2 SECURIN IS REQUIRED FOR CHROMOSOMAL STABILITY IN HUMAN CELLS 审中-公开
标题翻译： SECURIN需要人类细胞中的色素稳定性
公开(公告)号：WO02076383A2
公开(公告)日：2002-10-03
申请号：PCT/US0206643
申请日：2002-03-20
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , KINZLER KENNETH W , JALLEPALLI PRASAD , LENGAUER CHRISTOPH
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , JALLEPALLI PRASAD , LENGAUER CHRISTOPH
IPC分类号： C12N5/08 , C12N5/22 , G01N33/50 , A61K
CPC分类号： G01N33/5011
摘要： Securin-deficient cells and their securin-proficient counterparts are useful for screening potential anti-tumor agents. Potential therapeutic agents are screened for the ability to preferentially inhibit or kill a securin-deficient cell. The association of securin deficiency and chromosomal instability leading to aneuploidy, renders securin an excellent target for chemotherapeutic drug development.
摘要翻译： Securin缺陷型细胞及其精液细胞对应物可用于筛选潜在的抗肿瘤剂。筛选潜在的治疗剂以优先抑制或杀死缺血小细胞的能力。安非他酮缺乏症和染色体不稳定性导致非整倍体的结合，使Securin成为化疗药物开发的优秀目标。

46. 发明申请

WO0109386A3 DIGITAL AMPLIFICATION 审中-公开
标题翻译：数字放大
公开(公告)号：WO0109386A3
公开(公告)日：2002-09-12
申请号：PCT/US0020740
申请日：2000-07-31
申请人： UNIV JOHNS HOPKINS , KINZLER KENNETH W , VOGELSTEIN BERT
发明人： KINZLER KENNETH W , VOGELSTEIN BERT
IPC分类号： C12N15/09 , C12Q1/68
CPC分类号： C12Q1/6886 , C12Q1/6818 , C12Q1/6851 , C12Q1/686 , C12Q1/6874 , C12Q2600/156 , C12Q2600/158
摘要： The identification of pre-defined mutations expected to be present in a minor fraction of a cell population is important for a variety of basic research and clinical applications. The exponential, analog nature of the polymerase chain reaction is transformed into a linear, digital signal suitable for this purpose. Single molecules can be isolated by dilution and individual amplified; each product is then separately analyzed for the presence of mutations. The process provides a reliable and quantitative measure of the proportion of variant sequences within a DNA example.
摘要翻译：预期存在于细胞群体的较小部分中的预定义突变的鉴定对于各种基础研究和临床应用是重要的。聚合酶链反应的指数模拟性质被转化为适合于此目的的线性数字信号。单分子可以通过稀释和单独扩增分离; 然后分别分析每种产品的突变的存在。该过程提供了DNA样品中变体序列比例的可靠和定量测量。

47. 发明申请

WO0070089A9 CDX2 IS DOWNSTREAM MEDIATOR OF APC TUMOR SUPPRESSOR ACTIVITY 审中-公开
标题翻译： CDX2是APC肿瘤抑制剂活性的下调介质
公开(公告)号：WO0070089A9
公开(公告)日：2001-11-22
申请号：PCT/US0012893
申请日：2000-05-12
申请人： UNIV JOHNS HOPKINS , DACOSTA LUIS , VOGELSTEIN BERT , KINZLER KENNETH W , HE TONG CHUAN
发明人： DACOSTA LUIS , VOGELSTEIN BERT , KINZLER KENNETH W , HE TONG-CHUAN
IPC分类号： C07K14/47 , C07K14/705 , C12N5/08 , C12Q1/68
CPC分类号： C07K14/4702 , C07K14/705 , C12Q1/6897
摘要： Human CDX2, a homeobox gene, has been identified as a downstream effector of tumor suppressor APC. APC induces the transcription of CDX2. This newly found relationship permits specific drug screening assays as well as therapeutic and diagnostic methods.
摘要翻译：人CDX2是同源盒基因，已被鉴定为肿瘤抑制因子APC的下游效应物。 APC诱导CDX2的转录。这种新发现的关系允许特定的药物筛选测定以及治疗和诊断方法。

48. 发明申请

WO9946384A3 HUMAN SMAD3 AND SMAD4 ARE SEQUENCE-SPECIFIC TRANSCRIPTION ACTIVATORS 审中-公开
标题翻译：人类SMAD3和SMAD4是序列特异性转录激活因子
公开(公告)号：WO9946384A3
公开(公告)日：1999-12-16
申请号：PCT/US9905443
申请日：1999-03-12
申请人： UNIV JOHNS HOPKINS , KERN SCOTT E , ZAWEL LEIGH , DAI JIA LE , VOGELSTEIN BERT , KINZLER KENNETH W
发明人： KERN SCOTT E , ZAWEL LEIGH , DAI JIA LE , VOGELSTEIN BERT , KINZLER KENNETH W
IPC分类号： C07K14/47 , C12N15/12 , C12Q1/68 , C07K16/18 , C12N5/10 , C12N15/11 , C12N15/85 , C12Q1/02 , G01N33/50 , G01N33/53
CPC分类号： C07K14/4702 , C12Q1/6897
摘要： Two human Smad proteins (Smad3 and Smad4) specifically recognize an identical 8 bp palindromic sequence (GTCTAGAC) (SEQ ID NO: 1). Tandem repeats of this palindrome confer striking TGF- beta responsiveness to a minimal promoter. This responsiveness is abrogated by a targeted deletion of the cellular Smad4 gene. DNA molecules comprising the 8 bp palindromic sequence can be used in assays for drug screening and diagnostically.
摘要翻译：两种人类Smad蛋白质（Smad3和Smad4）特异性识别相同的8bp回文序列（GTCTAGAC）（SEQ ID NO：1）。该回文序列的串联重复赋予对最小启动子显着的TGF-β反应性。这种反应性被细胞Smad4基因的靶向缺失所消除。包含8bp回文序列的DNA分子可用于药物筛选和诊断测定。

49. 发明申请

WO2012094401A3 GENES FREQUENTLY ALTERED IN PANCREATIC NEUROENDOCRINE TUMORS 审中-公开
标题翻译：普遍存在于胰腺神经元肿瘤中的基因
公开(公告)号：WO2012094401A3
公开(公告)日：2012-10-18
申请号：PCT/US2012020199
申请日：2012-01-04
申请人： UNIV JOHNS HOPKINS , 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）是一种罕见但临床上重要的胰腺肿瘤形式。为了探索PanNETs的遗传基础，我们确定了十个非家族PanNETs的外显子序列，然后筛选了58个额外的PanNET中最常见的突变基因。值得注意的是，最常突变的基因指定涉及染色质重塑的蛋白质：44％的肿瘤在MEN-1中具有体细胞失活突变，其编码menin，组蛋白甲基转移酶复合物的组分; 43％在编码由DAXX（死亡相关蛋白）和ATRX（α地中海贫血/智力迟钝综合征X连锁）组成的转录/染色质重塑复合物的两个亚基之一的基因中具有突变。在临床上，MEN1和DAXX / ATRX基因的突变与更好的预后相关。我们还发现在14％的肿瘤中mTOR（雷帕霉素的哺乳动物靶标）途径的基因突变，这种发现可能用于分层患者用mTOR抑制剂治疗。

50. 发明申请

WO2012071096A3 ARID1A AND PPP2R1A MUTATIONS IN CANCER 审中-公开
标题翻译：癌症中的ARID1A和PPP2R1A突变
公开(公告)号：WO2012071096A3
公开(公告)日：2012-08-16
申请号：PCT/US2011050487
申请日：2011-09-06
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , KINZLER KENNETH W , VELCULESCU VICTOR , PAPADOPOULOS NICKOLAS , JONES SIAN
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , VELCULESCU VICTOR , PAPADOPOULOS NICKOLAS , JONES SIAN
IPC分类号： C12Q1/68 , A61K31/7088 , C12N5/09 , C12N15/11 , G01N33/68
CPC分类号： C12Q1/6886 , A61K31/7088 , A61K31/711 , C12Q2600/156 , G01N33/5011
摘要： Two genes, ARID1A (AT-rich interactive domain-containing protein 1A) and PPP2R1A (protein-phosphatase 2, regulatory subunit 1, alpha), can be used in methods which are useful for detecting cancer, diagnosing cancer, contributing to a diagnosis of cancer, confirming a diagnosis of cancer, identifying appropriate treatments for cancer, monitoring treatment of cancer, and evaluating treatment protocols for cancer, including ovarian clear cell carcinoma, breast cancer, colon cancer, gastric cancer, lung cancer, medulloblastoma, pancreatic cancer, and prostate cancer.
摘要翻译：可用于检测癌症，诊断癌症，有助于诊断癌症的方法中使用两种基因ARID1A（含AT富含交互结构域的蛋白质1A）和PPP2R1A（蛋白质磷酸酶2，调节亚单位1，α）确定癌症的诊断，确定癌症的适当治疗，监测癌症的治疗，以及评估癌症的治疗方案，包括卵巢透明细胞癌，乳腺癌，结肠癌，胃癌，肺癌，成神经管细胞瘤，胰腺癌和前列腺癌。

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