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11. 发明申请

WO2016010879A1 SUPPRESSION OF MYELOID DERIVED SUPPRESSOR CELLS AND IMMUNE CHECKPOINT BLOCKADE 审中-公开
标题翻译：抑制髓磷脂抑制细胞和免疫检测点块
公开(公告)号：WO2016010879A1
公开(公告)日：2016-01-21
申请号：PCT/US2015/040107
申请日：2015-07-13
申请人： THE JOHNS HOPKINS UNIVERSITY
发明人： ZHOU, Shibin , VOGELSTEIN, Bert , KINZLER, Kenneth W. , KIM, KiBem
IPC分类号： A61K31/44 , A61K31/706 , A61K39/395 , A61P35/00
CPC分类号： A61K39/39558 , A61K31/437 , A61K31/4406 , A61K31/706 , A61K35/742 , A61K39/3955 , A61K45/06 , A61K2039/505 , C07K16/2818 , C07K2317/34 , C07K2317/92 , A61K2300/00
摘要： Impressive responses have been observed in patients treated with checkpoint inhibitory anti-PD-1 or anti-CTLA-4 antibodies. However, immunotherapy against poorly immunogenic cancers remains a challenge. Treatment with both anti-PD-1 and anti-CTLA-4 antibodies were unable to eradicate large, modestly immunogenic CT26 tumors or metastatic 4T1 tumors. However, co-treatment with epigenetic modulating drugs and checkpoint inhibitors markedly improved treatment outcomes, curing more than 80% of them. Functional studies revealed that the primary targets of the epigenetic modulators were myeloid-derived suppressor cells (MDSCs). A PI3K-inhibitor that reduced circulating MDSCs also cured 80% of mice with metastatic 4T1 tumors when combined with immune checkpoint inhibitors. Thus, cancers resistant to immune checkpoint blockade can be cured by eliminating MDSCs.
摘要翻译：在使用检查点抑制性抗PD-1或抗CTLA-4抗体治疗的患者中观察到令人印象深刻的反应。然而，针对不良免疫原性癌症的免疫治疗仍然是一个挑战。用抗PD-1和抗CTLA-4抗体的治疗不能消除大的，适度的免疫原性CT26肿瘤或转移性4T1肿瘤。然而，与表观遗传调节药物和检查点抑制剂的共同治疗显着改善了治疗结果，治愈了其中80％以上。功能研究表明，表观遗传调节剂的主要靶标是骨髓来源的抑制细胞（MDSCs）。结合免疫检查点抑制剂，减少循环MDSCs的PI3K抑制剂也可治愈80％转移性4T1肿瘤小鼠。因此，通过消除MDSC可以治愈抗免疫检查点阻断的癌症。

12. 发明申请

WO2012142213A2 SAFE SEQUENCING SYSTEM 审中-公开
标题翻译：安全排序系统
公开(公告)号：WO2012142213A2
公开(公告)日：2012-10-18
申请号：PCT/US2012/033207
申请日：2012-04-12
申请人： THE JOHNS HOPKINS UNIVERSITY , 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。

13. 发明申请

WO2012071096A2 ARID1A AND PPP2R1A MUTATIONS IN CANCER 审中-公开
标题翻译： ARID1A和PPP2R1A突变在癌症中
公开(公告)号：WO2012071096A2
公开(公告)日：2012-05-31
申请号：PCT/US2011/050487
申请日：2011-09-06
申请人： THE JOHNS HOPKINS UNIVERSITY , 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 , C12N5/09 , G01N33/68 , A61K31/7088 , C12N15/11
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：在可用于检测癌症的方法中可以使用两种基因，即ARID1A（富含AT的交互结构域的蛋白质1A）和PPP2R1A（蛋白质磷酸酶2，调节亚基1，α）诊断癌症，有助于诊断癌症，确认癌症的诊断，鉴别癌症的适当治疗，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，肺癌癌症，成神经管细胞瘤，胰腺癌和前列腺癌。

14. 发明申请

WO2006002142A2 IMAGING INFECTION WITH COMPOUNDS THAT BIND TO THYMIDINE KINASE 审中-公开
标题翻译：用与甲状腺素激酶结合的化合物成像感染
公开(公告)号：WO2006002142A2
公开(公告)日：2006-01-05
申请号：PCT/US2005/021888
申请日：2005-06-20
申请人： THE JOHNS HOPKINS UNIVERSITY , 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
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诊断受试者感染的方法，其通过向受试者施用适合于成像的化合物，其与存在于感染生物体中的胸苷激酶结合，并获得受试者的图像以确定化合物的存在和位置，其中化合物的定位表明该对象具有感染。

15. 发明申请

WO2005062812A3 A rAAV-BASED SYSTEM FOR SOMATIC CELL GENE DISRUPTION 审中-公开
公开(公告)号：WO2005062812A3
公开(公告)日：2005-07-14
申请号：PCT/US2004/042597
申请日：2004-12-21
申请人： THE JOHNS HOPKINS UNIVERSITY , VOGELSTEIN, Bert , KINZLER, Kenneth, W. , KOHLI, Manu , RAGO, Carlo
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth, W. , KOHLI, Manu , RAGO, Carlo
IPC分类号： C12N15/63
摘要： Emerging evidence suggests that recombinant adeno-associated viral (rAAV) vectors can be used for specific gene targeting in human somatic cells. We have developed an rAAV vector construction procedure employing fusion PCR and a single cloning step that considerably simplifies the knockout process. We demonstrate its utility by disrupting genes at specific positions within human colon cancer cells as well as within immortalized normal epithelial cells. This technology should be broadly applicable to in vitro studies that require the manipulation of the human genome.

16. 发明申请

WO2004082458A3 TYROSINE KINOME 审中-公开
公开(公告)号：WO2004082458A3
公开(公告)日：2004-09-30
申请号：PCT/US2004/004452
申请日：2004-02-18
申请人： THE JOHNS HOPKINS UNIVERSITY , BARDELLI, Alberto , PARSONS, Will , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： BARDELLI, Alberto , PARSONS, Will , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C12Q1/68
摘要： Protein kinases are important signaling molecules involved in tumorigenesis. Mutational analysis of the human tyrosine kinase gene family (98 genes) identified somatic alterations in -20% of colorectal cancers, with the majority of mutations occurring in NTRK3, FES, GUCY2F and a previously uncharacterized tyrosine kinase gene called MCCK/MLK4. Most alterations were in conserved residues affecting key regions of the kinase domain. These data represent a paradigm for the unbiased analysis of signal transducing genes in cancer and provide useful targets for therapeutic intervention.

17. 发明申请

WO2003065870A2 DIGITAL AMPLIFICATION FOR DETECTION OF MISMATCH REPAIR DEFICIENT TUMOR CELLS 审中-公开
标题翻译：用于检测缺陷修复缺血性肿瘤细胞的数字放大
公开(公告)号：WO2003065870A2
公开(公告)日：2003-08-14
申请号：PCT/US2003/001062
申请日：2003-01-29
申请人： THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE , VOGELSTEIN, Bert , TRAVERSO, Giovanni, C. , KINZLER, Kenneth, W.
发明人： VOGELSTEIN, Bert , TRAVERSO, Giovanni, C. , KINZLER, Kenneth, W.
IPC分类号： A61B
CPC分类号： C12Q1/6886 , C12Q1/6851 , C12Q1/686 , C12Q2600/156 , C12Q2549/119 , C12Q2527/143
摘要： The detection of mutations in fecal DNA represents a promising, non-invasive approach for detecting colorectal cancers in average risk populations. One of the first practical applications of this technology involves the examination of microsatellite markers to sporadic cancers with mismatch repair deficiencies. As such cancers nearly always occur in the proximal colon, this test is useful as an adjunct to sigmoidoscopy, which detects only distal colorectal lesions.
摘要翻译：检测粪便DNA中的突变代表了一种有希望的非侵入性方法，用于检测平均危险人群中的结肠直肠癌。该技术的第一个实际应用之一涉及将微卫星标记物检查到具有错配修复缺陷的散发性癌症。因为这样的癌症几乎总是发生在近端结肠，这个测试是有用的乙状结肠镜检查的附件，只检测远端结肠直肠病变。

18. 发明申请

WO2003022863A1 SECRETED AND CELL SURFACE GENES EXPRESSED IN BENIGN AND MALIGNANT COLORECTAL TUMORS 审中-公开
标题翻译：分泌和细胞表面基因表达于胆管和恶性色素性肿瘤
公开(公告)号：WO2003022863A1
公开(公告)日：2003-03-20
申请号：PCT/US2002/028518
申请日：2002-09-09
申请人： THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE , BUCKHAULTS, Phillip , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： BUCKHAULTS, Phillip , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C07H21/04
CPC分类号： C07K14/495 , C07K14/47 , C07K14/705
摘要： Serial analysis of gene expression (SAGE) was used to identify transcripts encoding secreted or cell-surface proteins that were expressed in benign and malignant tumors of the colorectum. A total of 290,394 tags were analyzed from normal, adenomatous and cancerous colonic epithelium. Of the 21,343 different transcripts observed, 957 were found to be differentially expressed between normal and adenoma or between normal and cancer. Forty-nine transcripts were elevated ≥ 20-fold in adenomas, 40 transcripts were elevated ≥ 20-fold in cancers, and nine transcripts were elevated ≥ 20-fold in both. Product of six these nine transcripts (TGFBI, LYS, RDP, MIC-1, REGA, and DEHL) were predicted to be secreted or to reside on the cell surface and these were analyzed in more detail. The abnormal expression levels predicted by SAGE were confirmed by quantitative PCR analyses of each of these six genes. Moreover, the cell types responsible for the elevated expression were identified by in situ hybridization and by PCR analyses of epithelial cells immunoaffinity purified from primary tumors.
摘要翻译：基因表达（SAGE）的序列分析用于鉴定在结肠直肠癌和恶性肿瘤中表达的编码分泌的或细胞表面蛋白的转录物。从正常，腺瘤和癌性结肠上皮分析总共290,394个标签。在观察到的21,343种不同的转录物中，957被发现在正常和腺瘤之间或在正常和癌症之间差异表达。在腺瘤中，49个转录本升高了20倍，40个转录物在癌症中升高了20倍，而9个转录物在两者中升高了20倍。预计这六种转录本（TGFBI，LYS，RDP，MIC-1，REGA和DEHL）的六种产物被分泌或驻留在细胞表面上，并且更详细地分析这些转录物的产物。通过对这6种基因中的每一种进行定量PCR分析证实SAGE预测的异常表达水平。此外，通过原位杂交和通过从原发性肿瘤纯化的上皮细胞免疫亲和素的PCR分析来鉴定负责升高的表达的细胞类型。

19. 发明申请

WO2002076383A3 SECURIN IS REQUIRED FOR CHROMOSOMAL STABILITY IN HUMAN CELLS 审中-公开
公开(公告)号：WO2002076383A3
公开(公告)日：2002-10-03
申请号：PCT/US2002/006643
申请日：2002-03-20
申请人： THE JOHNS HOPKINS UNIVERSITY , 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
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.

20. 发明申请

WO2002010217A3 ENDOTHELIAL CELL EXPRESSION PATTERNS 审中-公开
公开(公告)号：WO2002010217A3
公开(公告)日：2002-02-07
申请号：PCT/US2001/024031
申请日：2001-08-01
申请人： THE JOHNS HOPKINS UNIVERSITY , ST. CROIX, Brad , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： ST. CROIX, Brad , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C12N15/12
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 f rom 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 79 differentially expressed genes, including 46 that were specifically elevated in tumor-associated endothelium. Experiments with representative genes from this group demonstrated that most were similarly expressed in teh endothelium of primary lung, breast, brain, and pancreatic cancers as well as in metastatic lesions of the liver. These 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 therapies in the future.

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