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1. 发明申请

WO9944063B1 TUMOR TISSUE MICROARRAYS FOR RAPID MOLECULAR PROFILING 审中-公开
标题翻译：肿瘤组织微阵列用于快速分子检测
公开(公告)号：WO9944063B1
公开(公告)日：1999-12-02
申请号：PCT/US9904001
申请日：1999-02-24
申请人： US HEALTH , LEIGHTON STEPHEN B , KONONEN JUHA , KALLIONIEMI OLLI
发明人： LEIGHTON STEPHEN B , KONONEN JUHA , KALLIONIEMI OLLI
IPC分类号： B01L3/00 , C12M1/00 , C12N15/09 , C12Q1/02 , C12Q1/68 , G01N1/08 , G01N1/28 , G01N1/36 , G01N33/50 , G01N33/543 , G01N33/566 , G02B21/34 , G01N1/04
CPC分类号： B01L3/5085 , B01J2219/00659 , B01J2219/00702 , G01N1/08 , G01N1/36 , G01N33/5005 , G01N33/54306 , G01N2001/282 , G01N2001/368 , G02B21/34
摘要： An array-based technology facilitates rapid correlated gene copy number and expression profiling of a very large numbers of human tumors. Hundreds of cylindrical tissue biopsies (diameter 0.6 mm) from morphologically representative regions of individual tumors can be arrayed in a single paraffin block. Consecutive sections from such arrays provide targets for parrallel in situ visualization and quantitation of DNA, RNA or protein targets. For example, amplifications of six loci (mybL2, erbB2, Cyclin-D1, myc, 17q23 and 20q13) were rapidly determined by fluorescence in situ hybridization from 372 ethanol-fixed breast cancers. Stratification of tumors by estrogen receptor and p53 expression data revealed dictinct patterns of gene amplification in the various subgroups of breast cancer that may have prognostic utility. The tissue array technology is useful in the rapid molecular profiling of hundreds of normal and pathological tissue specimens or cultured cells.
摘要翻译：基于阵列的技术促进了大量人类肿瘤的快速相关基因拷贝数和表达谱分析。来自单个肿瘤的形态学代表性区域的数百个圆柱形组织活检（直径0.6mm）可排列在单个石蜡块中。这些阵列的连续部分提供了平行原位可视化和定量DNA，RNA或蛋白质靶标的目标。例如，通过来自372个乙醇固定的乳腺癌的荧光原位杂交快速确定6个基因座（mybL2，erbB2，Cyclin-D1，myc，17q23和20q13）的扩增。通过雌激素受体和p53表达数据对肿瘤进行分层揭示了可能具有预后效用的乳腺癌各亚组中基因扩增的排斥模式。组织阵列技术可用于数百个正常和病理组织标本或培养细胞的快速分子分析。

2. 发明申请

WO9944062B1 CELLULAR ARRAYS FOR RAPID MOLECULAR PROFILING 审中-公开
标题翻译：细胞阵列用于快速分子分析
公开(公告)号：WO9944062B1
公开(公告)日：1999-11-04
申请号：PCT/US9904000
申请日：1999-02-24
申请人： US HEALTH , KALLIONIEMI OLLI , KONONEN JUHA , LEIGHTON STEPHEN B , SAUTER GUIDO
发明人： KALLIONIEMI OLLI , KONONEN JUHA , LEIGHTON STEPHEN B , SAUTER GUIDO
IPC分类号： G01N33/48 , B01L3/00 , C12Q1/04 , C12Q1/24 , C12Q1/28 , C12Q1/68 , G01N1/08 , G01N1/28 , G01N1/31 , G01N1/36 , G01N33/50 , G01N33/543 , G01N33/566 , G01N33/574 , G01N37/00 , G02B21/34
CPC分类号： G02B21/34 , B01J2219/00659 , B01J2219/00702 , B01L3/5085 , C12Q1/6811 , G01N1/08 , G01N1/312 , G01N1/36 , G01N33/5005 , G01N33/54306 , G01N2001/282 , G01N2001/368 , G06F19/20 , G06F19/24
摘要： A method is disclosed for rapid molecular profiling of tissue or other cellular specimens by placing a donor specimen in an assigned location in a recipient array, providing copies of the array, and performing a different biological analysis of each copy. In one embodiment, the copies of the array are formed by placing elongated specimens in a three dimensional matrix, and cutting sections from the matrix to form multiple copies of a two dimensional array that can then be subjected to the different biological analyses. Alternatively, the array can be formed from cell suspensions such that identical multiple copies of an array are formed, in which corresponding positions in the copies of the array have samples from the same or similar specimen. The results of the different biological analyses are compared to determine if there are correlations between the results of the different biological analyses at each assigned location. In some embodiments, the specimens may be tissue specimens from different tumors, which are subjected to multiple parallel molecular (including genetic and immunological) analyses. The results of the parallel analyses are then used to detect common molecular characteristics of the tumor type, which can subsequently be used in the diagnosis or treatment of the disease. The biological characteristics of the tissue can be correlated with clinical or other information, to detect characteristics associated with the tissue, such as susceptibility or resistance to particular types of drug treatment. Other examples of suitable tissues which can be placed in the matrix include tissue from transgenic or model organisms, or cellular suspensions (such as cytological preparations or specimens of liquid malignancies or cell lines).
摘要翻译：公开了一种方法，用于通过将供体样本放置在受体阵列中的指定位置，提供阵列的拷贝以及对每个拷贝进行不同的生物学分析来对组织或其他细胞样本进行快速分子谱分析。在一个实施例中，通过将细长样本放置在三维矩阵中形成阵列的副本，并且从该矩阵切割部分以形成二维阵列的多个副本，然后可以对这些副本进行不同的生物分析。或者，阵列可以由细胞悬浮液形成，从而形成阵列的相同多个拷贝，其中阵列拷贝中的对应位置具有来自相同或相似样本的样本。对不同生物学分析的结果进行比较，以确定每个指定地点的不同生物学分析结果之间是否存在相关性。在一些实施方案中，标本可以是来自不同肿瘤的组织标本，其经历多个平行分子（包括遗传和免疫学）分析。平行分析的结果然后用于检测肿瘤类型的常见分子特征，其随后可用于疾病的诊断或治疗。组织的生物学特征可以与临床或其他信息相关联，以检测与组织相关的特征，例如对特定类型的药物治疗的敏感性或抗性。可以放置在基质中的合适组织的其他例子包括来自转基因或模型生物体的组织，或细胞悬浮液（例如细胞学制剂或液体恶性肿瘤或细胞系的样本）。

3. 发明申请

WO0120044A3 SIGNAL COUNTING FOR IN SITU HYBRIDIZATION 审中-公开
标题翻译：用于原位杂交的信号计数
公开(公告)号：WO0120044A3
公开(公告)日：2002-05-10
申请号：PCT/US0025465
申请日：2000-09-15
申请人： US HEALTH , KALLIONIEMI OLLI P , KONONEN JUHA , BUDENDORF LUKAS , DOUGHERTY EDWARD R , GRIGORYAN ARTYOM M
发明人： KALLIONIEMI OLLI P , KONONEN JUHA , BUDENDORF LUKAS , DOUGHERTY EDWARD R , GRIGORYAN ARTYOM M
IPC分类号： C12Q1/68 , G01N15/14
CPC分类号： G06K9/0014 , C12Q1/6809 , C12Q1/6816 , C12Q1/6841 , G01N15/1475 , C12Q2543/10 , C12Q2565/601 , C12Q2565/518 , C12Q2539/113
摘要： Fluorescently tagged nucleic acid probe signals are counted in biological specimens by determining a ratio of signals from a test probe to signals of a reference probe. Probe signals need not be counted with reference to cells, nuclei, or nuclear contours. Gene amplification or deletion can thus be detected by analyzing the ratio. Successive image slices are obtained by confocal microscopy, and the images are digitized. The digital images are transformed and analyzed to combine contiguous fluorescent signal segments in successive optical sections to identify discrete probe signals, or spots. Spots overlapping in the axial and transverse dimensions of a three-dimensional representation of the biological specimens can be distinguisghed. A graphical user interface presents various features for consideration by a user, who can provide guidance to a computer system counting the spots. Various features directed to identifying spot clusters and autofluorescent material can increase accuracy of spot counting.
摘要翻译：荧光标记的核酸探针信号通过确定来自测试探针的信号与参考探针的信号的比率而在生物样品中计数。探针信号不需要参照细胞，核或核轮廓进行计数。因此可以通过分析比例来检测基因扩增或缺失。通过共聚焦显微镜获得连续的图像切片，并且图像被数字化。转换和分析数字图像以在连续的光学部分中组合连续的荧光信号段，以识别离散的探针信号或斑点。可以区分在生物样本的三维表示的轴向和横向尺寸上重叠的斑点。图形用户界面呈现用户考虑的各种特征，用户可以为计算点的计算机系统提供指导。针对识别斑点簇和自发荧光材料的各种特征可以提高斑点计数的准确性。

4. 发明申请

WO2007024557A1 METHOD AND APPARATUS FOR PROTECTING BIOLOGICAL SPECIMENS 审中-公开
标题翻译：保护生物样本的方法和装置
公开(公告)号：WO2007024557A1
公开(公告)日：2007-03-01
申请号：PCT/US2006/031798
申请日：2006-08-16
申请人： BEECHER INSTRUMENTS, INC. , KONONEN, Juha , ROHWER-NUTTER, Dan
发明人： KONONEN, Juha , ROHWER-NUTTER, Dan
IPC分类号： B01L9/00 , B65D81/26
CPC分类号： B01L9/52 , B01L2300/0819 , B01L2300/0822 , B01L2300/10 , B01L2300/105
摘要： A biological specimen is preserved by surrounding the biological specimen with a protective enclosing structure. The protective enclosing structure reacts with corrosive components in the surrounding atmosphere or environment to reduce their degradative effect and also protects the preparations from bacterial and fungal growth.
摘要翻译：通过用保护性封闭结构围绕生物样本来保存生物样本。保护性封闭结构与周围大气或环境中的腐蚀性成分反应，以降低其降解作用，并保护制剂免受细菌和真菌生长。

5. 发明申请

WO0155450A3 AMPLIFIED GENES AT 17q23 审中-公开
标题翻译： 17q23放大基因
公开(公告)号：WO0155450A3
公开(公告)日：2003-01-23
申请号：PCT/US0102474
申请日：2001-01-24
申请人： US GOV HEALTH & HUMAN SERV , KALLIONIEMI ANNE H , MONNI OUTI M , BAERLUND MAARIT T , KONONEN JUHA T , KALLIONIEMI OLLI P
发明人： KALLIONIEMI ANNE H , MONNI OUTI M , BAERLUND MAARIT T , KONONEN JUHA T , KALLIONIEMI OLLI P
IPC分类号： C12Q1/68 , C12N15/11
CPC分类号： C12Q1/6886 , C12Q2600/118
摘要： The present disclosure provides new highly sensitive probes for the detection of neoplasms, including breast and other cancers. The probes bind selectively with target polynucleotide sequences found on the long arm of Chromosome 17, more particularly the region 17q23. In particular, such probes are to RAD51C, S6K, PAT1/APPBP2, TBX2, MUL, TRAP240, AA806470, AA635172, stSG39547, or G29449. Amplification or other mutation of any of RAD51C, S6K, PAT1/APPBP2, TBX2, MUL, TRAP240, AA806470, AA635172, stSG39547, or G29449 is frequently linked to cancer. Methods of using RAD51C, S6K, PAT1/APPBP2, TBX2, MUL, TRAP240, AA806470, AA635172, stSG39547, or G29449 biological materials in the diagnosis and treatment of neoplasia, and particularly breast cancer, are presented.
摘要翻译：本公开提供了用于检测肿瘤（包括乳腺癌和其他癌症）的新的高灵敏度探针。所述探针选择性地与染色体17的长臂上发现的靶多核苷酸序列结合，更特别地与17q23区结合。特别地，这样的探针是RAD51C，S6K，PAT1 / APPBP2，TBX2，MUL，TRAP240，AA806470，AA635172，stSG39547或G29449。 RAD51C，S6K，PAT1 / APPBP2，TBX2，MUL，TRAP240，AA806470，AA635172，stSG39547或G29449中的任何一个的扩增或其它突变经常与癌症相关。提出了RAD51C，S6K，PAT1 / APPBP2，TBX2，MUL，TRAP240，AA806470，AA635172，stSG39547或G29449生物学材料在诊断和治疗肿瘤特别是乳腺癌中的应用。

6. 发明申请

WO2004010848A3 ONCOGENES USEFUL FOR THE IDENTIFICATION OF URINARY BLADDER CANCER 审中-公开
标题翻译：关于泌尿系癌症的鉴定有用的依据
公开(公告)号：WO2004010848A3
公开(公告)日：2005-01-20
申请号：PCT/US0323555
申请日：2003-07-25
申请人： DIOMEDA LIFE SCIENCES INC , SCHRAML PETER , TOMOVSKA SANJA , SAUTER GUIDO , SIMON RONALD , KONONEN JUHA
发明人： SCHRAML PETER , TOMOVSKA SANJA , SAUTER GUIDO , SIMON RONALD , KONONEN JUHA
IPC分类号： A61B20060101 , A61K38/00 , C12Q1/68
CPC分类号： C12Q1/6886 , A61K38/00 , C07K14/4748 , C12Q2600/112 , C12Q2600/118 , C12Q2600/136
摘要： Studies by Comparative Genome Hybridization (CGH) have shown that 6p22 is frequently amplified in invasive urinary bladder cancer. The E2F3 gene maps to 6p22 and encodes a transcription factor important for cell cycle regulation and DNA replication. To determine whether E2F3 resides in the 6p22 amplicon, 7 primary tumors and 3 cell lines known to have 6p22 amplification by CGH were examined by fluorescence in situ hybridization (FISH) using an E2F3-specific probe. All ten 6p22 amplified tumors showed E2F3 amplification. To further investigate the role of E2F3 in bladder cancer, a tissue microarray containing samples from 2317 bladder tumors was used for FISH and immunohistochemical expression analysis. E2F3 amplification was strongly associated with invasive tumor phenotype and high tumor grade (p
摘要翻译：比较基因组杂交（CGH）的研究表明6p22在侵袭性膀胱癌中经常被扩增。 E2F3基因映射到6p22，编码重要的细胞周期调节和DNA复制的转录因子。为了确定E2F3是否位于6p22扩增子中，通过使用E2F3特异性探针的荧光原位杂交（FISH）检查已知具有6p22扩增的7个原发肿瘤和3个细胞系。全部10个6p22扩增肿瘤显示E2F3扩增。为了进一步研究E2F3在膀胱癌中的作用，将含有来自2317膀胱肿瘤的样品的组织微阵列用于FISH和免疫组织化学表达分析。 E2F3扩增与侵袭性肿瘤表型和高肿瘤分级密切相关（p <0.0001）。 398例pTaG1 / G2肿瘤（1％）中只有4例，489例pT1-4癌中有110例（22％）具有E2F3扩增。高E2F3表达水平与高等级，晚期和E2F3基因扩增相关（p <0.0001）。为了评估E2F3表达是否与肿瘤增殖相关，分析了每个肿瘤的Ki67标记指数（LI）。高Ki67 LI和E2F3表达（p <0.0001）之间存在强烈的联系，与成绩和阶段无关。我们得出结论，E2F3经常在膀胱癌侵袭性膀胱癌（pT1-4期）中被扩增并过度表达。 E2F3表达似乎通过在膀胱肿瘤的子集中激活细胞增殖而为肿瘤细胞提供增长优势。

7. 发明申请

WO2004010848A8 ONCOGENES USEFUL FOR THE IDENTIFICATION OF URINARY BLADDER CANCER 审中-公开
标题翻译：可用于鉴别尿路膀胱癌的肿瘤
公开(公告)号：WO2004010848A8
公开(公告)日：2004-10-28
申请号：PCT/US0323555
申请日：2003-07-25
申请人： DIOMEDA LIFE SCIENCES INC , SCHRAML PETER , TOMOVSKA SANJA , SAUTER GUIDO , SIMON RONALD , KONONEN JUHA
发明人： SCHRAML PETER , TOMOVSKA SANJA , SAUTER GUIDO , SIMON RONALD , KONONEN JUHA
IPC分类号： A61B20060101 , A61K38/00 , C12Q1/68 , A61B
CPC分类号： C12Q1/6886 , A61K38/00 , C07K14/4748 , C12Q2600/112 , C12Q2600/118 , C12Q2600/136
摘要： Studies by Comparative Genome Hybridization (CGH) have shown that 6p22 is frequently amplified in invasive urinary bladder cancer. The E2F3 gene maps to 6p22 and encodes a transcription factor important for cell cycle regulation and DNA replication. To determine whether E2F3 resides in the 6p22 amplicon, 7 primary tumors and 3 cell lines known to have 6p22 amplification by CGH were examined by fluorescence in situ hybridization (FISH) using an E2F3-specific probe. All ten 6p22 amplified tumors showed E2F3 amplification. To further investigate the role of E2F3 in bladder cancer, a tissue microarray containing samples from 2317 bladder tumors was used for FISH and immunohistochemical expression analysis. E2F3 amplification was strongly associated with invasive tumor phenotype and high tumor grade (p
摘要翻译：通过比较基因组杂交（CGH）的研究已经显示6p22经常在侵入性膀胱癌中扩增。 E2F3基因定位于6p22并编码对细胞周期调控和DNA复制重要的转录因子。为了确定E2F3是否存在于6p22扩增子中，使用E2F3特异性探针通过荧光原位杂交（FISH）检查已知具有由CGH扩增6p22的7个原发性肿瘤和3个细胞系。所有10个6p22扩增的肿瘤显示E2F3扩增。为了进一步研究E2F3在膀胱癌中的作用，将含有来自2317个膀胱肿瘤的样品的组织微阵列用于FISH和免疫组织化学表达分析。 E2F3扩增与侵袭性肿瘤表型和高肿瘤等级强烈相关（各自p <0.0001）。 398个pTaG1 / G2肿瘤中仅有4个（1％），而489个pT1-4癌中有110个（22％）具有E2F3扩增。高E2F3表达水平与高年级，晚期和E2F3基因扩增相关（各自p <0.0001）。为了评估E2F3表达是否与肿瘤增殖相关，分析每种肿瘤的Ki67标记指数（LI）。高Ki67L1和E2F3表达之间存在强相关性（p <0.0001），其与级别和阶段无关。我们得出这样的结论：E2F3在侵入性生长的膀胱癌（阶段pT1-4）中经常被放大并过度表达。 E2F3表达似乎通过激活膀胱肿瘤亚群中的细胞增殖而为肿瘤细胞提供生长优势。

8. 发明申请

WO2004010848A2 ONCOGENES USEFUL FOR THE IDENTIFICATION OF URINARY BLADDER CANCER 审中-公开
标题翻译：关于泌尿系癌症的鉴定有用的依据
公开(公告)号：WO2004010848A2
公开(公告)日：2004-02-05
申请号：PCT/US2003/023555
申请日：2003-07-25
申请人： DIOMEDA LIFE SCIENCES, INC. , SCHRAML, Peter , TOMOVSKA, Sanja , SAUTER, Guido , SIMON, Ronald , KONONEN, Juha
发明人： SCHRAML, Peter , TOMOVSKA, Sanja , SAUTER, Guido , SIMON, Ronald , KONONEN, Juha
IPC分类号： A61B
CPC分类号： C12Q1/6886 , A61K38/00 , C07K14/4748 , C12Q2600/112 , C12Q2600/118 , C12Q2600/136
摘要： Studies by Comparative Genome Hybridization (CGH) have shown that 6p22 is frequently amplified in invasive urinary bladder cancer. The E2F3 gene maps to 6p22 and encodes a transcription factor important for cell cycle regulation and DNA replication. To determine whether E2F3 resides in the 6p22 amplicon, 7 primary tumors and 3 cell lines known to have 6p22 amplification by CGH were examined by fluorescence in situ hybridization (FISH) using an E2F3-specific probe. All ten 6p22 amplified tumors showed E2F3 amplification. To further investigate the role of E2F3 in bladder cancer, a tissue microarray containing samples from 2317 bladder tumors was used for FISH and immunohistochemical expression analysis. E2F3 amplification was strongly associated with invasive tumor phenotype and high tumor grade (p
摘要翻译：比较基因组杂交（CGH）的研究表明6p22在侵袭性膀胱癌中经常被扩增。 E2F3基因映射到6p22，编码重要的细胞周期调节和DNA复制的转录因子。为了确定E2F3是否位于6p22扩增子中，通过使用E2F3特异性探针的荧光原位杂交（FISH）检查已知具有6p22扩增的7个原发肿瘤和3个细胞系。全部10个6p22扩增肿瘤显示E2F3扩增。为了进一步研究E2F3在膀胱癌中的作用，将含有来自2317膀胱肿瘤的样品的组织微阵列用于FISH和免疫组织化学表达分析。 E2F3扩增与侵袭性肿瘤表型和高肿瘤分级密切相关（p <0.0001）。 398例pTaG1 / G2肿瘤（1％）中只有4例，489例pT1-4癌中有110例（22％）具有E2F3扩增。高E2F3表达水平与高等级，晚期和E2F3基因扩增相关（p <0.0001）。为了评估E2F3表达是否与肿瘤增殖相关，分析了每个肿瘤的Ki67标记指数（LI）。高Ki67 LI和E2F3表达（p <0.0001）之间存在强烈的联系，与成绩和阶段无关。我们得出结论，E2F3经常在膀胱癌侵袭性膀胱癌（pT1-4期）中被扩增并过度表达。 E2F3表达似乎通过在膀胱肿瘤的子集中激活细胞增殖而为肿瘤细胞提供增长优势。

9. 发明申请

WO9944063A3 TUMOR TISSUE MICROARRAYS FOR RAPID MOLECULAR PROFILING 审中-公开
标题翻译：用于快速分子分析的肿瘤组织微阵列
公开(公告)号：WO9944063A3
公开(公告)日：1999-11-04
申请号：PCT/US9904001
申请日：1999-02-24
申请人： US HEALTH , LEIGHTON STEPHEN B , KONONEN JUHA , KALLIONIEMI OLLI
发明人： LEIGHTON STEPHEN B , KONONEN JUHA , KALLIONIEMI OLLI
IPC分类号： B01L3/00 , C12M1/00 , C12N15/09 , C12Q1/02 , C12Q1/68 , G01N1/08 , G01N1/28 , G01N1/36 , G01N33/50 , G01N33/543 , G01N33/566 , G02B21/34 , G01N1/04
CPC分类号： B01L3/5085 , B01J2219/00659 , B01J2219/00702 , G01N1/08 , G01N1/36 , G01N33/5005 , G01N33/54306 , G01N2001/282 , G01N2001/368 , G02B21/34
摘要： An array-based technology facilitates rapid correlated gene copy number and expression profiling of a very large numbers of human tumors. Hundreds of cylindrical tissue biopsies (diameter 0.6 mm) from morphologically representative regions of individual tumors can be arrayed in a single paraffin block. Consecutive sections from such arrays provide targets for parrallel in situ visualization and quantitation of DNA, RNA or protein targets. For example, amplifications of six loci (mybL2, erbB2, Cyclin-D1, myc, 17q23 and 20q13) were rapidly determined by fluorescence in situ hybridization from 372 ethanol-fixed breast cancers. Stratification of tumors by estrogen receptor and p53 expression data revealed dictinct patterns of gene amplification in the various subgroups of breast cancer that may have prognostic utility. The tissue array technology is useful in the rapid molecular profiling of hundreds of normal and pathological tissue specimens or cultured cells.
摘要翻译：基于阵列的技术有助于快速相关的基因拷贝数和大量人类肿瘤的表达谱。从单个肿瘤的形态代表性区域的数百个圆柱形组织活组织检查（直径0.6mm）可以排列在单个石蜡块中。这些阵列的连续部分为DNA，RNA或蛋白质靶标的Parrallel原位可视化和定量提供了靶标。例如，通过来自372个乙醇固定的乳腺癌的荧光原位杂交来快速测定六个位点（mybL2，erbB2，细胞周期蛋白D1，myc，17q23和20q13）的扩增。通过雌激素受体和p53表达数据对肿瘤进行分层显示可能具有预后效用的各种乳腺癌亚组的基因扩增模式。组织阵列技术可用于数百个正常和病理组织标本或培养细胞的快速分子分析。

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