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1. 发明申请

WO2003050502A3 PROSPECTIVE IDENTIFICATION AND CHARACTERIZATION OF BREAST CANCER STEM CELLS 审中-公开
公开(公告)号：WO2003050502A3
公开(公告)日：2003-06-19
申请号：PCT/US2002/039191
申请日：2002-12-06
申请人： REGENTS OF THE UNIVERSITY OF MICHIGAN , CLARKE, Michael, F. , WICHA, Max, S. , AL-HAJJ, Mohammad
发明人： CLARKE, Michael, F. , WICHA, Max, S. , AL-HAJJ, Mohammad
IPC分类号： A61K31/00
摘要： Human breast tumors contain heterogeneous cancer cells. Using an animal xenograft model in which human breast cancer cells were grown in immunocompromised mice, we found that only a small minority of breast cancer cells had the capacity to form new tumors. The ability to form new tumors was not a stochastic property, rather certain populations of cancer cells were depleted for the ability to form new tumors, while other populations were enriched for the ability to form new tumors. Tumorigenic cells could be distinguished from non-tumorigenic cancer cells based on surface marker expression. We prospectively identified and isolated the tumorigenic cells as CD44?+¿CD24?-/lo¿LINEAGE?-¿. As few as 100 cells from this population were able to form tumors the animal xenograft model, while tens of thousands of cells from non-tumorigenic populations failed to form tumors. The tumorigenic cells could be serially passaged, each time generating new tumors containing an expanded numbers of CD44?+¿CD24?-/low¿Lineage?-¿tumorigenic cells as well as phenotypically mixed populations of non-tumorigenic cancer cells. This is reminiscentof the ability of normal stem cells to self-renew and differentiate. The expression of potential therapeutic targets also differed between the tumorigenic and non-tumorigenic populations. Notch activation promoted the survival of the tumorigenic cells, and a blocking antibody against Notch4 induced tumorigenic breast cancer cells to undergo apoptosis.

2. 发明申请

WO2003050502A2 PROSPECTIVE IDENTIFICATION AND CHARACTERIZATION OF BREAST CANCER STEM CELLS 审中-公开
标题翻译：乳腺癌干细胞的前瞻性鉴定和表征
公开(公告)号：WO2003050502A2
公开(公告)日：2003-06-19
申请号：PCT/US2002/039191
申请日：2002-12-06
申请人： REGENTS OF THE UNIVERSITY OF MICHIGAN , CLARKE, Michael, F. , WICHA, Max, S. , AL-HAJJ, Mohammad
发明人： CLARKE, Michael, F. , WICHA, Max, S. , AL-HAJJ, Mohammad
IPC分类号： G01N
CPC分类号： C07K16/28 , A61K38/1703 , A61K47/6897 , A61K47/6901 , A61K2039/505 , B82Y5/00 , C07K16/3015 , C12N5/0695
摘要： Human breast tumors contain heterogeneous cancer cells. Using an animal xenograft model in which human breast cancer cells were grown in immunocompromised mice, we found that only a small minority of breast cancer cells had the capacity to form new tumors. The ability to form new tumors was not a stochastic property, rather certain populations of cancer cells were depleted for the ability to form new tumors, while other populations were enriched for the ability to form new tumors. Tumorigenic cells could be distinguished from non-tumorigenic cancer cells based on surface marker expression. We prospectively identified and isolated the tumorigenic cells as CD44 + CD24 -/lo LINEAGE - . As few as 100 cells from this population were able to form tumors the animal xenograft model, while tens of thousands of cells from non-tumorigenic populations failed to form tumors. The tumorigenic cells could be serially passaged, each time generating new tumors containing an expanded numbers of CD44 + CD24 -/low Lineage?- ¿tumorigenic cells as well as phenotypically mixed populations of non-tumorigenic cancer cells. This is reminiscentof the ability of normal stem cells to self-renew and differentiate. The expression of potential therapeutic targets also differed between the tumorigenic and non-tumorigenic populations. Notch activation promoted the survival of the tumorigenic cells, and a blocking antibody against Notch4 induced tumorigenic breast cancer cells to undergo apoptosis.
摘要翻译：人乳腺肿瘤包含异质癌细胞。使用动物异种移植模型，其中人乳腺癌细胞在免疫受损小鼠中生长，我们发现只有少数乳腺癌细胞具有形成新肿瘤的能力。形成新肿瘤的能力不是随机性质，而是癌细胞的某些群体耗尽形成新肿瘤的能力，而其他群体则富集形成新肿瘤的能力。基于表面标志物表达，致瘤细胞可以与非致瘤性癌细胞区分开。我们前瞻性地将致瘤细胞鉴定并分离为CD44 + CD24 < - / lo> LINEAGE - 。来自该群体的少至100个细胞能够形成肿瘤动物异种移植模型，而来自非致瘤基因群的数万个细胞未能形成肿瘤。致瘤细胞可以连续传代，每次产生含有扩增数量的CD44 + CD24 - / low> Lineage - 致瘤细胞的新肿瘤以及非致瘤性癌细胞的表型混合群体。这让人想起正常干细胞自我更新和分化的能力。潜在的治疗靶点的表达也在致瘤性和非致瘤性群体之间不同。 Notch活化促进致瘤细胞的存活，并且阻断Notch4诱导的致瘤性乳腺癌细胞进行细胞凋亡的抗体。

3. 发明申请

WO2008092002A2 COMPOSITIONS AND METHODS FOR TREATING AND DIAGNOSING PANCREATIC CANCER 审中-公开
标题翻译：治疗和诊断胰腺癌的组合物和方法
公开(公告)号：WO2008092002A2
公开(公告)日：2008-07-31
申请号：PCT/US2008/051910
申请日：2008-01-24
申请人： THE REGENTS OF THE UNIVERSITY OF MICHIGAN , WICHA, Max, S. , CLARKE, Michael, F. , SIMEONE, Diane, M.
发明人： WICHA, Max, S. , CLARKE, Michael, F. , SIMEONE, Diane, M.
IPC分类号： A61K48/00
CPC分类号： C12N5/0695 , A01K2267/0331
摘要： The present invention relates to the field of oncology and provides novel compositions and methods for diagnosing and treating pancreatic cancer. In particular, the present invention provides pancreatic cancer stem cells useful for the study, diagnosis, and treatment of solid tumors.
摘要翻译：本发明涉及肿瘤学领域，并提供了用于诊断和治疗胰腺癌的新型组合物和方法。具体而言，本发明提供了用于实体瘤的研究，诊断和治疗的胰腺癌干细胞。

4. 发明申请

WO1989011491A1 ANTIBODIES TO HUMAN MAMMARY CELL GROWTH INHIBITOR AND METHODS OF PRODUCTION AND USE 审中-公开
标题翻译：人类细胞生长抑制剂的抗体及其生产和使用方法
公开(公告)号：WO1989011491A1
公开(公告)日：1989-11-30
申请号：PCT/US1989002215
申请日：1989-05-22
申请人： THE REGENTS OF THE UNIVERSITY OF MICHIGAN
发明人： THE REGENTS OF THE UNIVERSITY OF MICHIGAN , ERVIN, Paul, R., Jr. , WICHA, Max, S. , KAMINSKI, Mark, S. , CODY, Robert, L.
IPC分类号： C07K15/00
CPC分类号： G01N33/57415 , A61K38/00 , C07K14/475 , C07K16/22
摘要： Polyclonal antibody from animal antiserum and monoclonal antibodies produced by hybridoma cell lines bind to a mammary cell specific growth inhibitor secreted by NHMC. When purified by affinity monoclonal antibody chromatography, the inhibitor of the present invention exhibits peaks of activity at about 47,000 and about 63,000-67,000, as measured by SDS-PAGE. The growth inhibitor is present in the sera of normal females, but is absent or present in decreased levels in the sera of normal males and female breast cancer patients. Binding assays of the antibody to the inhibitor can be used to diagnose the presence of breast cancer, to screen for those at high risk breast cancer, and to monitor patient levels of inhibitor in mammary tissue and serum during treatment.
摘要翻译：来自动物抗血清的多克隆抗体和由杂交瘤细胞系产生的单克隆抗体结合到由NHMC分泌的乳腺细胞特异性生长抑制剂。当通过亲和单克隆抗体色谱法纯化时，本发明的抑制剂通过SDS-PAGE测量显示约47,000和约63,000-67,000的活性峰。生长抑制剂存在于正常女性的血清中，但在正常男性和女性乳腺癌患者的血清中不存在或呈现降低的水平。抗体对抑制剂的结合分析可用于诊断乳腺癌的存在，筛选高危乳腺癌患者，并监测治疗期间乳腺组织和血清中的抑制剂水平。

5. 发明公开

EP2106439A2 COMPOSITIONS AND METHODS FOR TREATING AND DIAGNOSING PANCREATIC CANCER 有权
标题翻译： US BS BS EN BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS BS
公开(公告)号：EP2106439A2
公开(公告)日：2009-10-07
申请号：EP08728211.7
申请日：2008-01-24
申请人： The Regents of the University of Michigan
发明人： WICHA, Max, S. , CLARKE, Michael, F. , SIMEONE, Diane, M.
IPC分类号： C12N5/00 , C12N5/02 , G01N33/53
CPC分类号： C12N5/0695 , A01K2267/0331
摘要： The present invention relates to the field of oncology and provides novel compositions and methods for diagnosing and treating pancreatic cancer. In particular, the present invention provides pancreatic cancer stem cells useful for the study, diagnosis, and treatment of solid tumors.
摘要翻译：本发明涉及肿瘤学领域，并提供用于诊断和治疗胰腺癌的新型组合物和方法。特别地，本发明提供了可用于实体瘤的研究，诊断和治疗的胰腺癌干细胞。

6. 发明申请

WO1995011301A1 P53-MEDIATED APOPTOSIS 审中-公开
标题翻译： P53介导的APOPTOSIS
公开(公告)号：WO1995011301A1
公开(公告)日：1995-04-27
申请号：PCT/US1994011923
申请日：1994-10-19
申请人： THE REGENTS OF THE UNIVERSITY OF MICHIGAN
发明人： THE REGENTS OF THE UNIVERSITY OF MICHIGAN , CLARKE, Michael, F. , RYAN, James, Joseph , NUNEZ, Gabriel , WICHA, Max, S.
IPC分类号： C12N15/12
CPC分类号： A61K38/1709 , A61K48/00 , C07K14/4746 , C07K14/82 , C12N2799/022
摘要： The invention is directed to methods of reducing the viability of a proliferating mammalian cells such as cancer cells. In one method cells deficient in p53 activity and in p53 suppressor activity of one or more p53-interacting regulatory proteins cell viability is reduced by increasing the level or activity of p53 in the cell. In another method viability of cells exhibiting p53 activity and p53 suppressor activity of one or more p53-interacting regulatory proteins is reduced by reducing the suppressor activity of the one or more p53-interacting regulatory proteins. Further, cell viability is reduced in cells deficient in p53 activity and exhibiting p53 suppressor activity of one or more p53-interacting regulatory proteins by a method that includes: (a) increasing the level or activity of p53 in the cell, and (b) reducing the suppressor activity of the one or more p53-interacting regulatory proteins. Also, included are methods of selectively reducing the viability of proliferating cancer cells compared to nonproliferating normal cells within a mixed population of cells and to methods of selectively reducing the viability of chronic granulocytic leukemia cells within a sample of proliferating bone marrow cells.
摘要翻译：本发明涉及减少增殖的哺乳动物细胞如癌细胞的活力的方法。在一种方法中，一种或多种p53相互作用的调节蛋白的p53活性和p53抑制活性缺乏的细胞通过增加细胞中p53的水平或活性来降低细胞活力。在另一种方法中，通过降低一种或多种p53相互作用的调节蛋白的抑制活性来降低表现出一种或多种p53相互作用调节蛋白的p53活性和p53抑制活性的细胞的存活力。此外，通过包括以下方法的一种或多种p53相互作用的调节蛋白的p53抑制活性表现出p53活性缺陷的细胞的细胞活力降低，（a）增加细胞中p53的水平或活性，（b）降低一种或多种p53相互作用的调节蛋白的抑制活性。此外，包括与混合细胞群体内的非增殖性正常细胞相比选择性降低增殖性癌细胞的存活力的方法以及选择性降低增殖性骨髓细胞样品内慢性粒细胞白血病细胞活力的方法。

7. 发明申请

WO1989011492A1 HUMAN MAMMARY CELL GROWTH INHIBITOR AND METHODS OF PRODUCTION AND USE 审中-公开
标题翻译：人类细胞生长抑制剂及其生产和使用方法
公开(公告)号：WO1989011492A1
公开(公告)日：1989-11-30
申请号：PCT/US1989002214
申请日：1989-05-22
申请人： THE REGENTS OF THE UNIVERSITY OF MICHIGAN
发明人： THE REGENTS OF THE UNIVERSITY OF MICHIGAN , ERVIN, Paul, R., Jr. , WICHA, Max, S. , CODY, Robert, L.
IPC分类号： C07K15/06
CPC分类号： C07K16/22 , A61K38/00 , C07K14/475 , C07K2317/74 , G01N33/57415
摘要： A human mammary cell growth inhibitor, and novel compositions comprising enhanced and purified concentrations thereof, inhibits the growth of human mammary cells. Inhibitor of the present invention purified by monoclonal antibody affinity chromatography comprises a thermolabile protein and has peaks of inhibitory activity at molecular weights of about 47,000 and about 63,000-67,000, as determined by SDS-PAGE. The inhibitory activity of the inhibitor is mammary cell specific, and is both calcium and dose-dependent. Increased production of the inhibitor can be induced by growth of inhibitor-secreting human mammary cells in low concentrations of calcium. The inhibitor can be used prophylactically to decrease the risk of breast cancer, to screen for the risk or presence of breast cancer, and as a therapeutic agent for the treatment of breast cancer.
摘要翻译：人乳腺细胞生长抑制剂和包含其增强和纯化浓度的新组合物抑制人乳腺细胞的生长。通过单克隆抗体亲和层析纯化的本发明的抑制剂包含热不稳定蛋白质，并且通过SDS-PAGE测定具有分子量约47,000和约63,000-67,000的抑制活性峰。抑制剂的抑制活性是乳腺细胞特异性，是钙和剂量依赖性。增加抑制剂的产生可以通过在低浓度的钙中生长分泌抑制剂的人类乳腺细胞来诱导。该抑制剂可用于预防性地降低乳腺癌的风险，筛查乳腺癌的风险或存在，以及作为治疗乳腺癌的治疗剂。

8. 发明公开

EP1343871A2 ISOLATION AND USE OF SOLID TUMOR STEM CELLS 有权
标题翻译：分离和干细胞的实体瘤USE
公开(公告)号：EP1343871A2
公开(公告)日：2003-09-17
申请号：EP01956101.8
申请日：2001-08-02
申请人： THE REGENTS OF THE UNIVERSITY OF MICHIGAN
发明人： CLARKE, Michael, F. , MORRISON, Sean, J.,Univ. of Michigan Med. School , WICHA, Max, S. , AL-HAJJ, Muhammad,Dept. of Internal Medicine
IPC分类号： C12N5/06 , C12N5/08 , C12N5/10 , A61K39/00 , C12Q1/68 , C12Q1/02 , A01K67/027 , A61K39/395 , A61K49/00
CPC分类号： C12N5/0695 , A01K67/0271 , A61K39/39558 , A61K2039/505 , A61K2039/5152 , A61K2039/5158 , C07K14/705 , C07K14/70585 , C07K14/71 , C07K16/28 , C07K16/2863 , C07K16/30 , C12N2501/42 , C12N2503/00 , C12N2503/02 , C12Q1/6886 , G01N33/5011 , G01N33/57492
摘要： A small percentage of cells within an established solid tumor have the properties of stem cells. These solid tumor stem cells give rise both to more tumor stem cells and to the majority of cells in the tumor that have lost the capacity for extensive proliferation and the ability to give rise to new tumors. Thus, solid tumor heterogeneity reflects the presence of tumor cell progeny arising from a solid tumor stem cell. We have developed a xenograft model in which we have been able to establish tumors from primary tumors via injection of tumors in the mammary gland of severely immunodeficient mice. These xenograft assay have allowed us to do biological and molecular assays to characterize clonogenic solid tumor stem cells. We have also developed evidence that strongly implicates the Notch pathway, especially Notch 4, as playing a central pathway in carcinogenesis.

9. 发明申请

WO2014070776A1 MICROFLUIDIC DEVICE AND METHOD FOR DETECTING RARE CELLS 审中-公开
标题翻译：用于检测稀有细胞的微流体装置和方法
公开(公告)号：WO2014070776A1
公开(公告)日：2014-05-08
申请号：PCT/US2013/067315
申请日：2013-10-29
申请人： THE REGENTS OF THE UNIVERSITY OF MICHIGAN
发明人： NAGRATH, Sunitha , YOON, Hyeun, Joong , LIN, Eric , WICHA, Max, S. , BAEZ, Lianette, Rivera , SIMEONE, Diane, M.
IPC分类号： G01N35/08 , G01N33/48 , C12Q1/04
CPC分类号： G01N15/1056 , B01L3/502715 , B01L3/502753 , B01L3/502761 , B01L2200/0652 , B01L2300/0816 , B01L2300/0864 , B01L2300/0883 , G01N15/0272 , G01N33/5005 , G01N33/574 , G01N2015/0065 , G01N2015/008 , G01N2015/0288 , G01N2015/1006 , G01N2015/1081
摘要： A microfluidic device for detecting rare cells in a fluid sample comprises the rare cell and other cells. The microfluidic device comprises an inlet for receiving the fluid sample, a labyrinth channel structure in fluid communication with the inlet, and an outlet in fluid communication with the labyrinth channel structure for collecting the rare cells separated from the other cells in the fluid sample. The labyrinth channel structure comprises at least one channel through which the fluid sample flows. The at least one channel has a plurality of segments and a plurality of corners with each corner defined between adjacent segments. The presence of the plurality of corners induces separation of the rare cells from the other cells in the fluid sample as the rare cells move to a first equilibrium position within the at least one channel when a ratio of inertial lift forces (F Z ) and Dean flow (F D ) of the fluid sample is from 2 to 10.
摘要翻译：用于检测流体样品中稀有细胞的微流体装置包括稀有细胞和其它细胞。微流体装置包括用于接收流体样品的入口，与入口流体连通的迷宫式通道结构，以及与迷宫式通道结构流体连通的出口，用于收集与流体样品中的其它细胞分离的稀有细胞。迷宫通道结构包括流体样品流过的至少一个通道。所述至少一个通道具有多个段和多个角，其中每个角在相邻段之间限定。当惯性提升力（FZ）和Dean流量的比率（FZ）和Dean流动时，多个拐角的存在引起稀少细胞与流体样本中的其它细胞的分离，因为稀有细胞移动到至少一个通道内的第一平衡位置（FD）为2〜10。

10. 发明授权

EP1343871B1 ISOLATION AND USE OF SOLID TUMOR STEM CELLS 有权
标题翻译：分离和干细胞的实体瘤USE
公开(公告)号：EP1343871B1
公开(公告)日：2015-10-07
申请号：EP01956101.8
申请日：2001-08-02
申请人： The Regents of The University of Michigan
发明人： CLARKE, Michael, F. , MORRISON, Sean, J., Univ. of Michigan Med. School , WICHA, Max, S. , AL-HAJJ, Muhammad, Dept. of Internal Medicine
IPC分类号： C07K14/705 , C07K14/71 , C07K16/28 , C07K16/30 , A01K67/027 , A61K39/395 , C12N5/095 , C12Q1/68 , G01N33/50 , G01N33/574 , A61K39/00
CPC分类号： C12N5/0695 , A01K67/0271 , A61K39/39558 , A61K2039/505 , A61K2039/5152 , A61K2039/5158 , C07K14/705 , C07K14/70585 , C07K14/71 , C07K16/28 , C07K16/2863 , C07K16/30 , C12N2501/42 , C12N2503/00 , C12N2503/02 , C12Q1/6886 , G01N33/5011 , G01N33/57492
摘要： A small percentage of cells within an established solid tumor have the properties of stem cells. These solid tumor stem cells give rise both to more tumor stem cells and to the majority of cells in the tumor that have lost the capacity for extensive proliferation and the ability to give rise to new tumors. Thus, solid tumor heterogeneity reflects the presence of tumor cell progeny arising from a solid tumor stem cell. We have developed a xenograft model in which we have been able to establish tumors from primary tumors via injection of tumors in the mammary gland of severely immunodeficient mice. These xenograft assay have allowed us to do biological and molecular assays to characterize clonogenic solid tumor stem cells. We have also developed evidence that strongly implicates the Notch pathway, especially Notch 4, as playing a central pathway in carcinogenesis.

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