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61. 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。

62. 发明申请

WO2011103236A3 PERSONALIZED TUMOR BIOMARKERS 审中-公开
标题翻译：个性化肿瘤生物标志物
公开(公告)号：WO2011103236A3
公开(公告)日：2012-02-09
申请号：PCT/US2011025152
申请日：2011-02-17
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , KINZLER KENNETH W , VELCULESCU VICTOR , DIAZ LUIS , LEARY REBECCA J
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , VELCULESCU VICTOR , DIAZ LUIS , LEARY REBECCA J
IPC分类号： C12Q1/68 , C12N15/11 , C40B40/06
CPC分类号： C12Q1/6886 , C12Q2600/156
摘要： Clinical management of human cancer is dependent on the accurate monitoring of residual and recurrent tumors. We have developed a method, called personalized analysis of rearranged ends (PARE), which can identify translocations in solid tumors. Analysis of four colorectal and two breast cancers revealed an average of nine rearranged sequences (range 4 to 15) per tumor. Polymerase chain reaction with primers spanning the breakpoints were able to detect mutant DNA molecules present at levels lower than 0.001% and readily identified mutated circulating DNA in patient plasma samples. This approach provides an exquisitely sensitive and broadly applicable approach for the development of personalized biomarkers to enhance the clinical management of cancer patients.
摘要翻译：人类癌症的临床管理取决于对残留和复发性肿瘤的准确监测。我们开发了一种称为重排末端（PARE）的个性化分析方法，可以识别实体瘤易位。对4例结直肠癌和2例乳腺癌的分析显示，每个肿瘤平均有9个重排序列（范围4至15）。与跨越断点的引物的聚合酶链反应能够检测出低于0.001％的突变型DNA分子，并且容易鉴定出患者血浆样品中突变的循环DNA。这种方法为个性化生物标志物的开发提供了一种非常灵敏和广泛适用的方法，以加强癌症患者的临床管理。

63. 发明申请

WO2006127607A3 PI3K PATHWAY MUTATIONS IN CANCER 审中-公开
标题翻译：癌症中PI3K路径突变
公开(公告)号：WO2006127607A3
公开(公告)日：2011-05-26
申请号：PCT/US2006019748
申请日：2006-05-23
申请人： UNIV JOHNS HOPKINS , PARSONS DONALD WILLIAM , WANG TIAN-LI PH D , SAMUELS YARDENA , BARDELLI ALBERTO , LENGAUER CHRISTOPHER , VELCULESCU VICTOR , KINZLER KENNETH W , VOGELSTEIN BERT
发明人： PARSONS DONALD WILLIAM , WANG TIAN-LI PH D , SAMUELS YARDENA , BARDELLI ALBERTO , LENGAUER CHRISTOPHER , VELCULESCU VICTOR , KINZLER KENNETH W , VOGELSTEIN BERT
IPC分类号： C40B30/06
CPC分类号： C12Q1/6883 , C12Q1/485 , C12Q2600/136 , C12Q2600/156 , G01N33/5044 , G01N33/57419
摘要： Given the important role of protein kinases in pathways affecting cellular growth and invasion, we have analyzed 340 serine/threonine kinases for genetic mutations in colorectal cancers. Mutations in eight genes were identified, including three members of the phosphatidylinositol-3- kinase (PI3K) pathway; the alterations in the latter genes each occurred in different tumors and did not overlap with mutations in PIK3CA or other non-serine-threonine kinase (STK) members of the PI3K pathway, suggesting that mutations in any of these genes had equivalent tumorigenic effects. These data demonstrate that the PI3K pathway is a major target for mutational activation in colorectal cancers and provide new opportunities for therapeutic intervention.
摘要翻译：鉴于蛋白激酶在影响细胞生长和侵袭的途径中的重要作用，我们已经分析了340个丝氨酸/苏氨酸激酶在结肠直肠癌中的遗传突变。鉴定出8个基因的突变，包括磷脂酰肌醇-3-激酶（PI3K）途径的3个成员; 后一种基因的改变各自发生在不同的肿瘤中，并且不与PIK3CA或PI3K途径的其他非丝氨酸 - 苏氨酸激酶（STK）成员的突变重叠，这表明任何这些基因中的突变具有相等的致瘤作用。这些数据表明，PI3K通路是结直肠癌突变激活的主要靶标，为治疗干预提供新的机会。

64. 发明申请

WO2010118016A3 DIGITAL QUANTIFICATION OF DNA METHYLATION 审中-公开
标题翻译： DNA甲基化的数字量化
公开(公告)号：WO2010118016A3
公开(公告)日：2011-04-07
申请号：PCT/US2010030084
申请日：2010-04-06
申请人： UNIV JOHNS HOPKINS , UNIV CASE WESTERN RESERVE , VOGELSTEIN BERT , KINZLER KENNETH W , LI MENG , DIAZ LUIS , PAPADOPOULOS NICKOLAS , MARKOWITZ SANFORD
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , LI MENG , DIAZ LUIS , PAPADOPOULOS NICKOLAS , MARKOWITZ SANFORD
IPC分类号： C12Q1/68 , C12N15/11 , G01N33/52
CPC分类号： C12Q1/6816 , C12Q1/6886 , C12Q2600/154 , C12Q2565/501 , C12Q2527/125 , C12Q2523/125
摘要： Abnormal DNA methylation can be used as a biomarker in cancer patients. For such purposes, it is important to determine precisely the fraction of methylated molecules in an analyzed sample. A technology we term Methyl-BEAMing achieves this goal. Individual bisulfite-treated DNA molecules can be PCR-amplified within aqueous nanocompartments containing beads, resulting in a population of beads each containing thousands of copies of the template molecule. After hybridization with probes specific for methylated sequences, the beads can be analyzed by flow cytometry. This approach enables detection and enumeration of one methylated molecule in a population of ~5000 unmethylated molecules. Methyl-BEAMing provides digital quantification of rare methylation events and is generally applicable to the assessment of methylated genes in clinical samples.
摘要翻译： DNA甲基化异常可用作癌症患者的生物标志物。为此目的，重要的是精确测定分析样品中甲基化分子的分数。我们称之为甲基BEAMing的技术实现了这一目标。单独的亚硫酸氢盐处理的DNA分子可以在含有珠粒的含水纳米间隔内进行PCR扩增，导致每个珠粒群含有数千份拷贝的模板分子。与特异于甲基化序列的探针杂交后，可以通过流式细胞术分析珠粒。这种方法能够检测和计数一个约5000个非甲基化分子的一个甲基化分子。甲基BEAMing提供罕见甲基化事件的数字量化，通常适用于临床样品中甲基化基因的评估。

65. 发明申请

WO2010028098A4 PATHWAYS UNDERLYING PANCREATIC TUMORIGENESIS AND AN HEREDITARY PANCREATIC CANCER GENE 审中-公开
标题翻译：胰岛素瘤和遗传性胰腺癌基因途径
公开(公告)号：WO2010028098A4
公开(公告)日：2010-08-19
申请号：PCT/US2009055802
申请日：2009-09-03
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , KINZLER KENNETH W , PARSONS D WILLIAMS , JONES SIAN , ZHANG XIAOSONG , LIN JIMMY CHANG-HO , LEARY REBECCA J , ANGENENDT PHILIPP , PAPADOPOULOS NICKOLAS , VELCULESCU VICTOR , PARMIGIANI GIOVANNI , KARCHIN RACHEL , KERN SCOTT , HRUBAN RALPH , ESHLEMAN JAMES R , GOGGINS MICHAEL , KLEIN ALISON
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , PARSONS D WILLIAMS , JONES SIAN , ZHANG XIAOSONG , LIN JIMMY CHANG-HO , LEARY REBECCA J , ANGENENDT PHILIPP , PAPADOPOULOS NICKOLAS , VELCULESCU VICTOR , PARMIGIANI GIOVANNI , KARCHIN RACHEL , KERN SCOTT , HRUBAN RALPH , ESHLEMAN JAMES R , GOGGINS MICHAEL , KLEIN ALISON
IPC分类号： C12Q1/68
CPC分类号： G01N33/57438 , C12Q1/6886 , C12Q2600/156 , G01N2800/50
摘要： This invention relates to new insights into the pathogenesis of pancreatic cancers by analyzing the genes altered in 24 pancreatic tumors. First, we determined the sequences of 23,781 transcripts, representing 20,583 protein-encoding genes, in DNA from these tumors. Second, we searched for homozygous deletions and amplifications using microarrays querying one million single nucleotide polymorphisms in each sample. Third, we analyzed the transcriptomes of the same samples using SAGE and next-generation sequencing-by-synthesis technologies We found that pancreatic cancers contain an average of 63 genetic alterations, of which 49 are point mutations, 8 are homozygous deletions, and 6 are amplifications. Further analyses revealed a core set of 12 regulatory processes or pathways that were each genetically altered in 70 % to 100 % of the samples. The data suggest that dysregulation of this core set of pathways is responsible for the major features of pancreatic tumorigenesis.
摘要翻译：本发明涉及通过分析在24个胰腺肿瘤中改变的基因而对胰腺癌的发病机理的新见解。首先，我们确定了来自这些肿瘤的DNA中23,781个转录物的序列，代表20,583个蛋白质编码基因。其次，我们使用微阵列查询每个样本中一百万个单核苷酸多态性来寻找纯合子缺失和扩增。第三，我们使用SAGE和下一代合成测序技术分析了相同样品的转录组我们发现胰腺癌平均含有63个基因改变，其中49个是点突变，8个是纯合子缺失，6个是扩增。进一步的分析揭示了12个监管程序或途径的核心组合，每个过程或途径在70％到100％的样本中均被遗传改变。数据表明这种核心途径的失调调节是胰腺肿瘤发生的主要特征的原因。

66. 发明申请

WO2010065576A2 THE ANTISENSE TRANSCRIPTOMES OF CELLS 审中-公开
标题翻译：细胞的抗原转录物
公开(公告)号：WO2010065576A2
公开(公告)日：2010-06-10
申请号：PCT/US2009066313
申请日：2009-12-02
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , KINZLER KENNETH W , HE YIPING , VELCULESCU VICTOR , PAPADOPOULOS NICKOLAS
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , HE YIPING , VELCULESCU VICTOR , PAPADOPOULOS NICKOLAS
IPC分类号： C12N15/11 , C12Q1/68 , G06F19/22
CPC分类号： C12Q1/6844 , G06F19/22 , C12Q2539/113 , C12Q2523/125 , C12Q2521/107
摘要： Transcription in mammalian cells can be assessed at a genome-wide level, but it has been difficult to reliably determine whether individual transcripts are derived from the Plus- or Minus-strands of chromosomes. This distinction can be critical for understanding the relationship between known transcripts (sense) and the complementary antisense transcripts that may regulate them. Here we describe a technique that can be used to (i) identify the DNA strand of origin for any particular RNA transcript and (ii) quantify the number of sense and antisense transcripts from expressed genes at a global level. We examined five different human cell types and in each case found evidence for antisense transcripts in 2900 to 6400 human genes. The distribution of antisense transcripts was distinct from that of sense transcripts, was non-random across the genome, and differed among cell types. Antisense transcripts thus appear to be a pervasive feature of human cells, suggesting that they are a fundamental component of gene regulation.
摘要翻译：哺乳动物细胞中的转录可以在全基因组范围内进行评估，但是难以可靠地确定个体转录本是否衍生自染色体的加号或阴影链。这种区别对于了解已知转录物（有义）和可能调节它们的互补反义转录物之间的关系可能是至关重要的。在这里，我们描述了一种可用于（i）识别任何特定RNA转录物的DNA链起源的技术，（ii）在全球范围内量化来自表达基因的正义和反义转录本的数量。我们检查了五种不同的人类细胞类型，并且在每种情况下都发现2900至6400个人类基因中的反义转录物的证据。反义转录物的分布与有义转录物的分布不同，在基因组中是非随机的，并且在细胞类型之间不同。因此，反义转录物似乎是人类细胞的普遍特征，表明它们是基因调控的基本组成部分。

67. 发明申请

WO2009011617A2 ANNELATED AZAHETEROCYCLES COMPRISING PYRIMIDINE FRAGMENT, METHOD FOR THE PRODUCTION THEREOF AND (PI3Ks) KINASE INHIBITORS 审中-公开
标题翻译：包含嘧啶片段的下述化合物，其生产方法和（PI3Ks）激酶抑制剂
公开(公告)号：WO2009011617A2
公开(公告)日：2009-01-22
申请号：PCT/RU2008000468
申请日：2008-07-16
申请人： CHEMICAL DIVERSITY RES INST JO , IVASHCHENKO ALEXANDER VASILIEV , TKACHENKO SERGEY YEVGENIEVICH , OKUN ILYA MATUSOVICH , SAVCHUK NIKOLAY FILIPPOVICH , IVASCHENKO ANDREY ALEXANDROVIC , KRAVCHENKO DMITRI VLADIMIROVIC , SCHMIDT-KITTLER OLEG , RAGO CARLO , PAPADOPOULOS NICKOLAS , VELCUELSU VICTOR , VOGELSTEIN BERT , KINZLER KENNETH W , TRIFILENKOV ANDREY SERGEEVICH , RIZHOVA ELENA ALEXANDROVNA , JIUXIANG ZHU
发明人： IVASHCHENKO ALEXANDER VASILIEVICH , TKACHENKO SERGEY YEVGENIEVICH , OKUN ILYA MATUSOVICH , SAVCHUK NIKOLAY FILIPPOVICH , IVASCHENKO ANDREY ALEXANDROVICH , KRAVCHENKO DMITRI VLADIMIROVICH , SCHMIDT-KITTLER OLEG , RAGO CARLO , PAPADOPOULOS NICKOLAS , VELCUELSU VICTOR , VOGELSTEIN BERT , KINZLER KENNETH W , TRIFILENKOV ANDREY SERGEEVICH , RIZHOVA ELENA ALEXANDROVNA , JIUXIANG ZHU
IPC分类号： C07D491/048 , A61K31/519 , A61P3/10 , A61P9/10 , A61P11/06 , A61P11/08 , A61P35/00 , C07D491/147 , C07D495/04
CPC分类号： C07D491/048 , C07D491/147 , C07D495/04
摘要： The invention relates to novel annelated azaheterocycles, comprising pyrimidine fragment, of general formula I in the form of free bases or pharmaceutically acceptable salts, to methods for producing said compounds, to pharmaceutical compositions containing said chemical compounds in the form of an active substance and to the use thereof for producing medicinal preparations for human beings and endotherms for treating diseases caused by the action of class I phosphoinositol kinases (PI3Ks) (and mutant isoforms thereof), in particular oncological, inflammatory and cardiovascular diseases. In said formula I, X is an oxygen of sulphur atom; Z is an oxygen atom, R1 is a hydrogen atom or optionally substituted C1-C6 alkyl, or Z is a hydrogen atom which, together with a carbon atom, with which it is bound, and R1, together with an nitrogen atom with which it is bound, close, via Z and R1, an optionally substituted annelated imidazoline cycle; R2 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl and optionally substituted heterocyclyl.
摘要翻译：本发明涉及新颖的含有游离碱形式的通式I的嘧啶片段或其药学上可接受的盐的新型氮杂杂环化合物，涉及制备所述化合物的方法，含有活性物质形式的所述化合物的药物组合物和其用于制备用于人类的药物制剂和用于治疗由I类磷酸肌醇激酶（PI3K）（及其突变体同种型）的作用引起的疾病的吸热疗法，特别是肿瘤学，炎症和心血管疾病。在所述式I中，X是硫原子的氧; Z是氧原子，R 1是氢原子或任选取代的C 1 -C 6烷基，或Z是与它结合的碳原子一起形成的氢原子，并且R 1与它所连接的氮原子一起通过Z和R1结合，任选取代的稠合咪唑啉环; R2是任选取代的烷基，任选取代的环烷基，任选取代的芳基和任选取代的杂环基。

68. 发明申请

WO2008021288A3 CONSENSUS CODING SEQUENCES OF HUMAN BREAST AND COLORECTAL CANCERS 审中-公开
标题翻译：人乳腺癌和结直肠癌共识编码序列
公开(公告)号：WO2008021288A3
公开(公告)日：2008-11-13
申请号：PCT/US2007017866
申请日：2007-08-13
申请人： UNIV JOHNS HOPKINS , SJOBLOM TOBIAS , JONES SIAN , PARSONS D WILLIAMS , WOOD LAURA D , LIN JIMMY , BARBER THOMAS , MANDELKER DIANA , VOGELSTEIN BERT , KINZLER KENNETH W , VELCULESU VICTOR E
发明人： SJOBLOM TOBIAS , JONES SIAN , PARSONS D WILLIAMS , WOOD LAURA D , LIN JIMMY , BARBER THOMAS , MANDELKER DIANA , VOGELSTEIN BERT , KINZLER KENNETH W , VELCULESU VICTOR E
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6886 , C12Q2600/106 , C12Q2600/156
摘要： Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ~90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention and monitoring.
摘要翻译：对11个乳腺癌和11个结直肠癌中的13023个基因的分析显示，个体肿瘤累积平均约90个突变基因，但是只有这些基因的一部分有助于肿瘤过程。使用严格的标准划定这个子集，我们确定了189个基因（平均每个肿瘤11个）以显着频率突变。绝大多数这些基因在肿瘤中并不知晓是遗传改变的，预计会影响广泛的细胞功能，包括转录，粘附和侵袭。这些数据定义了两种人类癌症类型的遗传情况，为诊断和治疗干预和监测提供了新的目标。

69. 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。

70. 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。

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