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    Mig-6 knockout mice and elucidation of association of Mig-6 with early onset degenerative joint disease and role as a tumor suppressor
    1.
    发明授权
    Mig-6 knockout mice and elucidation of association of Mig-6 with early onset degenerative joint disease and role as a tumor suppressor 有权
    Mig-6敲除小鼠，并阐明Mig-6与早发性退行性关节病的关联以及作为肿瘤抑制因子的作用

    公开(公告)号：US08466339B2

    公开(公告)日：2013-06-18

    申请号：US11917557

    申请日：2006-06-15

    申请人： Yu-Wen Zhang ,  George F. Vande Woude

    发明人： Yu-Wen Zhang ,  George F. Vande Woude

    IPC分类号： A01K67/027 ,  A01K67/00 ,  A01K67/033 ,  G01N33/00

    CPC分类号： C12Q1/686 ,  A01K67/0276 ,  A01K2217/075 ,  A01K2227/105 ,  A01K2267/03 ,  A01K2267/0368 ,  C12N15/8509 ,  C12N2517/02 ,  C12N2800/30

    摘要： Disruption of mitogen inducible gene 6 (Mig-6) in mice by homologous recombination (KO mice) led to early onset osteoarthritis (OA) as revealed by simultaneous enlargement and deformity of multiple joints, degradation of articular cartilage and the development of bony outgrowths or osteophytes within the joint space. Because of the striking similarity to human OA, Mig-6 KO mice are a useful animal model for studying the mechanism of this disease and for testing new drugs or therapies for treating OA. These KO mice also developed epithelial hyperplasia, adenoma, and adenocarcinoma in organs such as lung, gallbladder, and bile duct. Mig-6 is therefore a tumor suppressor gene and is a candidate gene for the frequent Ip36 genetic alterations found in lung cancer. It can be used as a tumor biomarker as well as a target for cancer therapy.

    摘要翻译： 通过同源重组（KO小鼠）破坏小鼠中的促分裂原诱导基因6（Mig-6）导致早发性骨关节炎（OA），如通过多关节的同时扩大和畸形显示的，关节软骨的退化和骨质生长的发展或 骨赘在联合空间内。 由于与人OA的惊人相似，Mig-6 KO小鼠是研究这种疾病机制和检测新药物或治疗OA疗法的有用动物模型。 这些KO小鼠也在器官如肺，胆囊和胆管中发展出上皮增生，腺瘤和腺癌。 因此，Mig-6是一种肿瘤抑制基因，是肺癌发生频繁Ip36遗传改变的候选基因。 它可以用作肿瘤生物标志物，也可以用作癌症治疗的靶标。

    Immune-compromised transgenic mice expressing human hepatocyte growth factor (hHGF)
    2.
    发明授权
    Immune-compromised transgenic mice expressing human hepatocyte growth factor (hHGF) 有权
    表达人肝细胞生长因子（hHGF）的免疫受损转基因小鼠

    公开(公告)号：US07968762B2

    公开(公告)日：2011-06-28

    申请号：US11571947

    申请日：2005-07-12

    申请人： George F. Vande Woude ,  Yu-wen Zhang ,  Nariyoshi Shinomiya

    发明人： George F. Vande Woude ,  Yu-wen Zhang ,  Nariyoshi Shinomiya

    IPC分类号： A01K67/027 ,  A01K67/00 ,  A01K67/033 ,  G01N33/00 ,  C12N15/00

    CPC分类号： A01K67/0271 ,  A01K67/0275 ,  A01K2217/052 ,  A01K2217/15 ,  A01K2217/203 ,  A01K2217/206 ,  A01K2227/105 ,  A01K2267/01 ,  A01K2267/0331 ,  C07K14/4753 ,  C12N15/8509

    摘要： A transgenic animal model for evaluating growth, survival and/or metastasis of xenotransplanted normal or tumor cells or tissue is disclosed, in which a human growth factor, hHGF stimulates growth in vivo of human cells or tissue. A strain of Tg mice on the C3H background that is immunocompromised as a result of a homozygous scid gene has been bred which express a nucleic acid encoding hHGF/SE The ectopically expressed hHGF/SF ligand significantly enhances growth of human tumor cell lines and explanted tumor cells or tissue that express the Met receptor for hHGF. Such animals also have an enlarged normal livers and greater than normal liver regenerative capacity. Any Met-expressing hHGF-dependent human cells, including hepatocytes and various stem cells can survive and grow in such animals.

    摘要翻译： 公开了用于评估异种移植的正常或肿瘤细胞或组织的生长，存活和/或转移的转基因动物模型，其中人生长因子hHGF刺激人细胞或组织的体内生长。 已经培育了作为纯合scid基因的免疫受损的C3H背景上的Tg小鼠的菌株，其表达编码hHGF / SE的核酸。异位表达的hHGF / SF配体显着增强人肿瘤细胞系和外植体肿瘤的生长 表达hHGF的Met受体的细胞或组织。 这样的动物也具有扩大的正常肝脏并且大于正常的肝脏再生能力。 任何Met表达的hHGF依赖性人细胞，包括肝细胞和各种干细胞都可以在这样的动物中存活和生长。

    MIG-6 KNOCKOUT MICE AND ELUCIDATION OF ASSOCIATION OF MIG-6 WITH EARLY ONSET DEGENERATIVE JOINT DISEASE AND ROLE AS A TUMOR SUPPRESSOR
    3.
    发明申请
    MIG-6 KNOCKOUT MICE AND ELUCIDATION OF ASSOCIATION OF MIG-6 WITH EARLY ONSET DEGENERATIVE JOINT DISEASE AND ROLE AS A TUMOR SUPPRESSOR 有权
    MIG-6 KNOCKOUT MICE和MIG-6与早期ONSET降解性联合病变和作为肿瘤抑制剂的作用的关联

    公开(公告)号：US20110099644A1

    公开(公告)日：2011-04-28

    申请号：US11917557

    申请日：2006-06-15

    申请人： Yu-Wen Zhang ,  George F. Vande Woude

    发明人： Yu-Wen Zhang ,  George F. Vande Woude

    IPC分类号： G01N33/00 ,  A01K67/027 ,  C12N5/10 ,  C07H21/04 ,  C12N15/63 ,  C12N15/873 ,  C12Q1/68 ,  C40B30/04

    CPC分类号： C12Q1/686 ,  A01K67/0276 ,  A01K2217/075 ,  A01K2227/105 ,  A01K2267/03 ,  A01K2267/0368 ,  C12N15/8509 ,  C12N2517/02 ,  C12N2800/30

    摘要： The molecular mechanism underlying degenerative joint disease, also known as osteoarthritis (OA), is not fully understood. Disruption of mitogen inducible gene 6 (Mig-6) in mice by homologous recombination (KO mice) led to early onset OA as revealed by simultaneous enlargement and deformity of multiple joints, degradation of articular cartilage and the development of bony outgrowths or osteophytes within the joint space. The latter appeared to be derived from proliferation of mesenchymal progenitor cells followed by differentiation into chondrocytes. Because of the striking similarity to human OA, Mig-6 KO mice are a useful animal model for studying the mechanism of this disease and for testing new drugs or therapies for treating OA. These KO mice also developed epithelial hyperplasia, adenoma, and adenocarcinoma in organs such as lung, gallbladder, and bile duct. Mig-6 is therefore a tumor suppressor gene and is a candidate gene for the frequent Ip36 genetic alterations found in lung cancer. It can be used as a tumor biomarker as well as a target for cancer therapy. Mig-6 is located in human chromosome Ip36, a locus frequently associated with human lung cancer. Mig-6 is a negative regulator of EGF signaling, and like EGF, was induced by HGF/SF in human lung cancer cell lines. Frequently the receptors EGFR and Met were co-expressed, and Mig-6 was induced by both EGF and HGF/SF in a MAPK-dependent fashion. Not all tumor lines express Mig-6 in response to either EGF or HGF/SF. In these cases, missense and nonsense mutations in the Mig-6 coding region were found, as was evidence for Mig-6 transcriptional silencing.

    摘要翻译： 退行性关节病（也称为骨关节炎（OA））的分子机制尚未完全了解。 通过同源重组（KO小鼠）破坏小鼠中的促分裂原诱导基因6（Mig-6）导致早期发作OA，其通过多个关节的同时扩大和畸形显示，关节软骨的降解以及骨内生长或骨赘的发育 联合空间。 后者似乎源自间充质祖细胞的增殖，然后分化成软骨细胞。 由于与人OA的惊人相似，Mig-6 KO小鼠是研究这种疾病机制和检测新药物或治疗OA疗法的有用动物模型。 这些KO小鼠也在器官如肺，胆囊和胆管中发展出上皮增生，腺瘤和腺癌。 因此，Mig-6是一种肿瘤抑制基因，是肺癌发生频繁Ip36遗传改变的候选基因。 它可以用作肿瘤生物标志物，也可以用作癌症治疗的靶标。 Mig-6位于人类染色体Ip36，这是经常与人类肺癌相关的基因座。 Mig-6是人肺癌细胞系中HGF / SF诱导的EGF信号传导的负调节因子，如EGF。 EGFR和Met共同受体共同表达，并且MAPK依赖型EGF和HGF / SF诱导Mig-6。 不是所有的肿瘤细胞系都响应于EGF或HGF / SF表达Mig-6。 在这些情况下，发现Mig-6编码区的错义和无义突变，Mig-6转录沉默的证据也是如此。

    Immune-Compromised Transgenic Mice Expressing Human Hepatocyte Growth Factor (Hhgf)
    4.
    发明申请
    Immune-Compromised Transgenic Mice Expressing Human Hepatocyte Growth Factor (Hhgf) 有权
    表达人类肝细胞生长因子（hHGF）的免疫缺陷型转基因小鼠

    公开(公告)号：US20080196110A1

    公开(公告)日：2008-08-14

    申请号：US11571947

    申请日：2005-07-12

    申请人： George F. Vande Woude ,  Yu-wen Zhang ,  Nariyoshi Shinomiya

    发明人： George F. Vande Woude ,  Yu-wen Zhang ,  Nariyoshi Shinomiya

    IPC分类号： G01N33/53 ,  A01K67/027 ,  C12N15/00 ,  C12P21/00 ,  C12N5/06

    CPC分类号： A01K67/0271 ,  A01K67/0275 ,  A01K2217/052 ,  A01K2217/15 ,  A01K2217/203 ,  A01K2217/206 ,  A01K2227/105 ,  A01K2267/01 ,  A01K2267/0331 ,  C07K14/4753 ,  C12N15/8509

    摘要： A transgenic animal model for evaluating growth, survival and/or metastasis of xenotransplanted normal or tumor cells or tissue is disclosed, in which a human growth factor, hHGF stimulates growth in vivo of human cells or tissue. A strain of Tg mice on the C3H background that is immunocompromised as a result of a homozygous scid gene has been bred which express a nucleic acid encoding hHGF/SE The ectopically expressed hHGF/SF ligand significantly enhances growth of human tumor cell lines and explanted tumor cells or tissue that express the Met receptor for hHGF. Such animals also have an enlarged normal livers and greater than normal liver regenerative capacity. Any Met-expressing hHGF-dependent human cells, including hepatocytes and various stem cells can survive and grow in such animals.

    摘要翻译： 公开了用于评估异种移植的正常或肿瘤细胞或组织的生长，存活和/或转移的转基因动物模型，其中人生长因子hHGF刺激人细胞或组织的体内生长。 已经培育了作为纯合scid基因的免疫受损的C3H背景上的Tg小鼠的菌株，其表达编码hHGF / SE的核酸。异位表达的hHGF / SF配体显着增强人肿瘤细胞系和外植体肿瘤的生长 表达hHGF的Met受体的细胞或组织。 这样的动物也具有扩大的正常肝脏并且大于正常的肝脏再生能力。 任何Met表达的hHGF依赖性人细胞，包括肝细胞和各种干细胞都可以在这样的动物中存活和生长。

    Biomarker and Method for Predicting Sensitivity to MET Inhibitors
    5.
    发明申请
    Biomarker and Method for Predicting Sensitivity to MET Inhibitors 审中-公开
    生物标志物和预测MET抑制剂敏感性的方法

    公开(公告)号：US20120100157A1

    公开(公告)日：2012-04-26

    申请号：US13270686

    申请日：2011-10-11

    申请人： George F. Vande Woude ,  Qian Xie

    发明人： George F. Vande Woude ,  Qian Xie

    IPC分类号： A61K39/395 ,  G01N21/64 ,  G01N21/76 ,  A61P35/00 ,  C12Q1/68 ,  C40B30/00 ,  C40B30/04 ,  G01N33/566 ,  G01N33/82

    CPC分类号： G01N33/57484 ,  G01N33/57407 ,  G01N2333/71 ,  G01N2800/52

    摘要： Methods for determining the responsiveness of a Met-related cancer in a subject to treatment with a Met inhibitor. Kits for performing the disclosed methods are also provided. The present invention also provides a method of treating glioblastomamultiforme (GBM) in a subject in need thereof, the method comprises administering a therapeutically effective dose of a Met inhibitor in combination with a therapeutically effective dose of a epithelial growth factor receptor (EGFR) inhibitor.

    摘要翻译： 用于测定受试者中Met相关癌症对Met抑制剂治疗的反应性的方法。 还提供了用于执行所公开的方法的套件。 本发明还提供在有需要的受试者中治疗胶质母细胞瘤菌（GBM）的方法，该方法包括与治疗有效剂量的上皮生长因子受体（EGFR）抑制剂组合施用治疗有效剂量的Met抑制剂。

    c-met siRNA adenovirus vectors inhibit cancer cell growth, invasion and tumorigenicity
    8.
    发明授权
    c-met siRNA adenovirus vectors inhibit cancer cell growth, invasion and tumorigenicity 有权
    c-met siRNA腺病毒载体抑制癌细胞生长，侵袭和致瘤性

    公开(公告)号：US07872117B2

    公开(公告)日：2011-01-18

    申请号：US10599327

    申请日：2005-03-28

    申请人： Nariyoshi Shinomiya ,  George F. Vande Woude

    发明人： Nariyoshi Shinomiya ,  George F. Vande Woude

    IPC分类号： C07H21/04 ,  C12N15/00 ,  A61K31/70

    CPC分类号： C12N15/1135 ,  C12N2310/111 ,  C12N2310/14 ,  C12N2799/022

    摘要： Suppression of the Hepatocyte growth factor/scatter factor (HGF/SF)-Met signaling pathway by targeting the Met protein tyrosine kinase was tested as strategy for suppressing tumor growth. Using RNA interference (RNAi) technology and adenoviruses carrying siRNA (Ad Met siRNA) target sequences dramatically reduced Met expression in mouse, dog and human tumor cells. Met was suppressed using Ad Met siRNA in mouse mammary tumor (DA3) cells and Met-transformed (NIH3T3 (M114) cells as well as human prostate cancer, sarcoma, glioblastoma, gastric and ovarian cancer cells. Furthermore, the Ad Met siRNA infection reversed transformed cell morphology. Ad Met siRNA killed cancer cells by inducing apoptosis. RNAi targeting Met suppressed HGF/SF-mediated scattering as well as ligand-mediated invasion activity and growth of tumor cells. Met siRNA infection also abrogated downstream Met signaling to molecules such as Akt and p44/42 MAPK. Importantly, the Met siRNA triggered apoptosis was correlated to suppressed tumorigenicity in vivo. Intro-tumoral infection with c-met siRNA adenovirus vectors produced significant reduction in tumor growth. Thus Met RNAi is an effective weapon for targeting Met expression and for treating c-Met+ cancers.

    摘要翻译： 通过靶向Met蛋白酪氨酸激酶抑制肝细胞生长因子/分散因子（HGF / SF）-Met信号通路被测试作为抑制肿瘤生长的策略。 使用RNA干扰（RNAi）技术和携带siRNA（Ad Met siRNA）靶序列的腺病毒大大降低了小鼠，狗和人类肿瘤细胞中的Met表达。 Met在小鼠乳腺肿瘤（DA3）细胞和Met转化的（NIH3T3（M114）细胞以及人类前列腺癌，肉瘤，成胶质细胞瘤，胃癌和卵巢癌细胞中使用Ad Met siRNA进行抑制，此外，Ad Met siRNA感染逆转 Ad Met siRNA通过诱导凋亡来杀死癌细胞，RNAi靶向Met抑制HGF / SF介导的散射以及配体介导的侵袭活性和肿瘤细胞的生长Met siRNA感染也消除下游Met信号转导到分子，如 Akt和p44 / 42 MAPK。重要的是，Met siRNA引发的细胞凋亡与体内抑制的致瘤性相关，c-met siRNA腺病毒载体的肿瘤内感染导致肿瘤生长显着降低，因此Met RNAi是靶向Met的有效武器 表达和治疗c-Met +癌症。

    MONOCLONAL ANTIBODY WHICH BINDS MET IN FORMALIN-FIXED AND PARAFFIN-EMBEDDED TISSUES AND RELATED METHODS
    9.
    发明申请
    MONOCLONAL ANTIBODY WHICH BINDS MET IN FORMALIN-FIXED AND PARAFFIN-EMBEDDED TISSUES AND RELATED METHODS 有权
    其中含有FORMALIN-FIXED和PARAFFIN嵌入式组织的单克隆抗体及相关方法

    公开(公告)号：US20100285504A1

    公开(公告)日：2010-11-11

    申请号：US12679247

    申请日：2008-08-25

    申请人： Boliang Cao ,  George F. Vande Woude ,  Beatrice S. Knudsen ,  Ping Xu Zhao

    发明人： Boliang Cao ,  George F. Vande Woude ,  Beatrice S. Knudsen ,  Ping Xu Zhao

    IPC分类号： G01N33/53 ,  C07K16/18

    CPC分类号： C07K16/2863 ,  C07K2317/34 ,  Y10S435/975

    摘要： In a wide variety of human solid tumors, an aggressive, metastatic phenotype and poor clinical prognosis are associated with expression of the receptor tyrosine kinase Met. Disclosed herein are (a) a monoclonal antibody named Met4, which antibody is specific for Met, and (b) a hybridoma cell line that produces Met4. The Met4 antibody is particularly useful for detecting Met in formalin-fixed tissue. Methods of using the Met4 antibody for detection, diagnosis, prognosis, and evaluating therapeutic efficacy are provided.

    摘要翻译： 在各种人类实体瘤中，侵袭性，转移表型和差的临床预后与受体酪氨酸激酶Met的表达相关。 本文公开了（a）名为Met4的单克隆抗体，该抗体对Met特异，和（b）产生Met4的杂交瘤细胞系。 Met4抗体特异地用于检测福尔马林固定组织中的Met。 提供了Met4抗体用于检测，诊断，预后和评价治疗功效的方法。