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1. 发明申请

WO2007133465A3 A LASER ILLUMINATION SYSTEM IN FLUORESCENT MICROSCOPY 审中-公开
标题翻译：荧光显微镜中的激光照射系统
公开(公告)号：WO2007133465A3
公开(公告)日：2008-09-25
申请号：PCT/US2007010727
申请日：2007-05-03
申请人： IMMUNIVEST CORP , GREVE JAN , SCHREUDER FREDERIK
发明人： GREVE JAN , SCHREUDER FREDERIK
IPC分类号： G06F19/00 , G06T7/40
CPC分类号： G01N33/54326 , Y10T436/143333
摘要： Devices and methods for automated collection and image analysis are disclosed that enable identification or classification of microscopic objects aligned or deposited on surfaces. Such objects, e.g. detectably labeled rare target cells, are magnetically or non-magnetically immobilized and subjected to Time Delay Integration imaging (TDI). Incorporation of TDl technology into image cytometry analysis, like CellTracks®, makes it possible to image moving objects with very high sensitivity and signal-to-noise ratios. Implementation of TDI camera technology with dual excitation and multispectral imaging of enriched.rare cells provides a rapid system for detection, enumeration, differentiation and characterization of imaged rare cells on the basis of size, morphology and immunophenotype.
摘要翻译：公开了用于自动收集和图像分析的装置和方法，其能够识别或分类对准或沉积在表面上的微观物体。这些物体，例如。可检测标记的罕见靶细胞是磁性或非磁性固定的并经受时间延迟积分成像（TDI）。结合TDI技术进行图像细胞分析，如CellTracks®，可以以非常高的灵敏度和信噪比对运动物体进行成像。基于大小，形态和免疫表型，实现具有双激发和多光谱成像的TDI相机技术，用于富集细胞提供快速检测，计数，分化和表征成像稀有细胞的系统。

2. 发明申请

WO2005049168A3 METHOD AND APPARATUS FOR PRE-ENRICHMENT AND RECOVERY OF CELLS FROM DENSIFIED WHOLE BLOOD 审中-公开
标题翻译：用于预处理和恢复来自透明血液的细胞的方法和装置
公开(公告)号：WO2005049168A3
公开(公告)日：2005-09-09
申请号：PCT/US2004038609
申请日：2004-11-17
申请人： IMMUNIVEST CORP , GROSS STEVEN , RUTNER HERMAN
发明人： GROSS STEVEN , RUTNER HERMAN
IPC分类号： A01N1/02 , B01D20060101
CPC分类号： A01N1/02 , A01N1/0263
摘要： The present invention describes reagents, methods and apparatus for pre-processing of blood samples to obtain blood fractions containing substantially all target cells in reduced specimen volumes that are suitable for subsequent further enrichment. Sample processor systems are described for enriching cell populations having densities of less than approximately 1.09 g/ml from about 30 ml whole blood. Whole blood is combined with a cell compatible dense reagent to raise the density to about 1.09 g/ml. Centrifugation causes the target cells and most of the WBC in the buffy coat layer to accumulate at the top under a low-density buffer overlay. The reduced sample volumes are suitable for subsequent immunomagnetic or other enrichment methods prior to detection and enumeration. These processor systems, in conjunction with other enrichment procedures, facilitate detection of rare target cells, such as circulating tumor cells (CTC) that are useful markers in cancer diagnosis and monitoring of therapeutic response.
摘要翻译：本发明描述了用于预处理血液样品以获得含有基本上所有靶细胞的血液成分的试剂，方法和装置，其中所述靶细胞在减少的样品体积中适合于随后的进一步富集。描述了用于从约30ml全血中富集密度小于约1.09g / ml的细胞群的样品处理器系统。将全血与细胞相容的致密试剂结合，将密度提高至约1.09μg/ ml。离心导致目标细胞和血沉棕黄层中的大部分WBC在低密度缓冲层覆盖下在顶部积聚。在检测和计数之前，减少的样品体积适用于随后的免疫磁性或其它富集方法。这些处理器系统与其他富集程序相结合，便于检测罕见的靶细胞，例如循环肿瘤细胞（CTC），它们是癌症诊断和治疗反应监测中有用的标志物。

3. 发明申请

WO03018757A3 STABILIZATION OF CELLS AND BIOLOGICAL SPECIMENS FOR ANALYSIS 审中-公开
标题翻译：细胞稳定和生物样本分析
公开(公告)号：WO03018757A3
公开(公告)日：2003-09-12
申请号：PCT/US0226867
申请日：2002-08-23
申请人： IMMUNIVEST CORP , RAO GALLA CHANDRA , HERMANN MELISSA , RUTNER HERMAN , TERSTAPPEN LEON
发明人： RAO GALLA CHANDRA , HERMANN MELISSA , RUTNER HERMAN , TERSTAPPEN LEON
IPC分类号： G01N33/48 , A01N1/00 , A01N1/02 , C12Q1/02 , G01N33/49 , G01N33/543 , G01N33/569 , G01N33/574
CPC分类号： A01N1/02 , A01N1/00 , A01N1/0226 , G01N33/54333 , G01N33/574
摘要： Compositions and methods for stabilizing rare cells in blood specimens, preserving the quality of blood specimens, and also serving as cell fixatives are disclosed which minimize losses of target cells (for example, circulating tumor cells) and formation of debris and aggregates from target cells, non-target cells and plasma components, thereby allowing more accurate analysis and classification of circulating tumor cells (CTC) and, ultimately, of tumor burdens in cancer patients. Stabilization of specimens is particularly desirable n protocols requiring rare cells enrichment from blood specimens drawn from cancer patients. Exposure of such specimens to potentially stressful conditions encountered, for example, in normal processing, mixing, shaking, delays due to transporting the blood, has been observed to not only diminish the number of CTC but also to generate debris and aggregates in the blood specimens that were found to interfere with accurate enumeration of target cells, if present. Stabilizers are necessary to discriminate between in vivo CTC disintegration and in vitro sample degredation.
摘要翻译：公开了用于稳定血液标本中稀有细胞，保持血液标本质量以及用作细胞固定剂的组合物和方法，其使靶细胞（例如，循环肿瘤细胞）的损失最小化，并从靶细胞形成碎片和聚集体，非靶细胞和血浆成分，从而允许更准确地分析和分类循环肿瘤细胞（CTC），最终导致癌症患者的肿瘤负担。标本的稳定是特别需要的，需要来自癌症患者的血液标本稀有细胞富集的方案。已经观察到这些样品暴露于例如在正常加工，混合，摇动，由于运送血液引起的延迟所遇到的潜在压力条件下，不仅减少了CTC的数量，而且在血样中产生碎片和聚集体被发现干扰靶细胞的准确计数（如果存在）。鉴别体内CTC分解和体外样品降解是必需的稳定剂。

4. 发明申请

WO2007145942A3 A RAPID, SEMI-AUTOMATED METHOD TO DETECT RESPIRATORY VIRUS INFECTED CELLS IN NASOPHARYNGEAL SAMPLES USING DIRECT FLUORESCENT ANTIBODY 审中-公开
标题翻译：使用直接荧光抗体检测天疱疮样本中呼吸道感染细胞的快速半自动方法
公开(公告)号：WO2007145942A3
公开(公告)日：2008-10-30
申请号：PCT/US2007013234
申请日：2007-06-05
申请人： IMMUNIVEST CORP , CHAPMAN NATHAN , CLASS JAMES , CONNELLY MARK CARLE , PAGE JIMMY , RAO GALLA CHANDRA , TERSTAPPEN LEON W M M
发明人： CHAPMAN NATHAN , CLASS JAMES , CONNELLY MARK CARLE , PAGE JIMMY , RAO GALLA CHANDRA , TERSTAPPEN LEON W M M
IPC分类号： C12Q1/70
CPC分类号： G01N33/56983 , G01N33/582
摘要： Tests for rapid viral detection which rely on antigen detection vary considerably in their sensitivity and the turn-around-time (TAT) for a result. Point of care (POC) tests have a 15- 20 min TAT and are easy to use. POC tests find utility in physician's offices, microbiology labs and in virology labs during the second and third shift. However, the sensitivity of these tests is widely reported to be low 1,2, particularly out of season. Direct specimen testing using Cytospin3,4 or smear preparations has been reported to be more sensitive but requires 60-90 min, is tedious to perform, currently lacks standardization, leads to relatively large numbers of specimens with insufficient number of cells to conduct the test (QNS>20%), and requires a medium complex lab with skilled technologists performing and interpreting the fluorescent staining results. The present invention describes a method which combines the TAT of the POC tests with the higher sensitivity and ability to assess the specimen quality available with direct specimen testing.
摘要翻译：依赖于抗原检测的快速病毒检测的检测在其灵敏度和周转时间（TAT）方面差异很大。护理点（POC）测试具有15-20分钟的TAT，易于使用。 POC测试在第二和第三班期间在医生的办公室，微生物实验室和病毒学实验室中发现效用。然而，这些测试的敏感度被广泛报道为低1,2，特别是季节。据报道，使用Cytospin3,4或涂片制剂的直接标本检测更为敏感，但需要60-90分钟，乏味表现，目前缺乏标准化，导致相对较多的标本数量不足的标本进行测试 QNS> 20％），并且需要具有技术熟练技术人员的中等复杂实验室来执行和解释荧光染色结果。本发明描述了一种将POC测试的TAT与具有较高灵敏度和评估可用于直接标本测试的样品质量的能力相结合的方法。

5. 发明申请

WO2008030381A3 METHODS FOR RANKING CELLULAR IMAGES 审中-公开
标题翻译：排序细胞图像的方法
公开(公告)号：WO2008030381A3
公开(公告)日：2008-10-16
申请号：PCT/US2007019045
申请日：2007-08-30
申请人： IMMUNIVEST CORP , KEIJ JAN , SILVIA JOHN C
发明人： KEIJ JAN , SILVIA JOHN C
IPC分类号： G01N33/48 , G06G7/48
CPC分类号： G01N15/1475
摘要： The methods described in this invention are used to analyze images of circulating tumor cells (CTC). Images are acquired from a number of platforms, including multiparameter flow cytometry, the CellSporter fluorescent microscopy imaging system and CellTracks Analyzer. These images are then ranked based on various properties and are presented to the user in order of most likely to least likely positive CTC events. The ranking method is useful to diagnose, monitor, and screen disease based on circulating rare cells, such as malignancy as determined by CTC.
摘要翻译：本发明描述的方法用于分析循环肿瘤细胞（CTC）的图像。图像从许多平台获得，包括多参数流式细胞术，CellSporter荧光显微镜成像系统和CellTracks分析仪。然后根据各种属性对这些图像进行排序，并按照最可能发生的最不利的正CTC事件的顺序呈现给用户。排名方法可用于诊断，监测和筛选基于循环稀有细胞（如CTC确定的恶性肿瘤）的疾病。

6. 发明申请

WO2005098046A3 METHODS FOR THE DETERMINATION OF CELL SPECIFIC BIOMARKERS 审中-公开
标题翻译：用于确定细胞特异性生物标志物的方法
公开(公告)号：WO2005098046A3
公开(公告)日：2005-12-15
申请号：PCT/US2005010940
申请日：2005-03-31
申请人： IMMUNIVEST CORP , O'HARA SHAWN MARK , SMIMOV DENIS
发明人： O'HARA SHAWN MARK , SMIMOV DENIS
IPC分类号： C07H21/02 , C12M1/34 , C12N15/11 , C12Q1/68
CPC分类号： C12Q1/6881 , C12Q2600/158
摘要： The present invention provides methods for the reduction of the considerate amount of white cell background that interferes with meaningful analysis of a patient's food sample when the analysis involves rare cell analysis. Nucleic acid profile analysis of targeted rare cells is obtained from an individual patient's enriched blood sample by subtracting the white cell nucleic acid content from the same enriched sample, prior to positive selection of the target cell content. Subsequent profile analysis of the remaining nucleic acids allow for specific mRNA expression profiles having improved signal-to-noise. The methods are useful in profiling of cells isolated from tissues or body fluids and serves as an adjunct to clinical diagnosis of diverse carcinomas including early stage detection and classification of circulating tumor cells. Monitoring of nucleic acid and protein profiles of cells either in conventional or microarray formats, facilitates management of therapeutic intervention including staging, monitoring response to therapy, confirmation of remission and detection of regression.
摘要翻译：本发明提供了当分析涉及稀有细胞分析时减少白细胞背景的考虑量的方法，其干扰对患者食物样品的有意义的分析。通过在正选择靶细胞含量之前从相同的富集样品中减去白细胞核酸含量，从个体患者富集的血液样品中获得靶向稀有细胞的核酸谱分析。剩余核酸的后续分析表明具有改善的信噪比的特异性mRNA表达谱。该方法可用于从组织或体液分离的细胞分析，并且作为包括早期检测和循环肿瘤细胞分类的不同癌症的临床诊断的辅助物。以常规或微阵列形式监测细胞的核酸和蛋白质谱，有助于治疗干预的管理，包括分期，监测对治疗的反应，缓解的确认和回归的检测。

7. 发明申请

WO2007053245A3 METHODS AND COMPOSITION TO GENERATE UNIQUE SEQUENCE DNA PROBES, IABELING OF DNA PROBES AND THE USE OF THESE PROBES 审中-公开
标题翻译：产生独特序列DNA探针的方法和组合物，DNA探针的激发以及这些探针的使用
公开(公告)号：WO2007053245A3
公开(公告)日：2007-11-22
申请号：PCT/US2006036656
申请日：2006-09-20
申请人： IMMUNIVEST CORP , CONNELLY MARK CARLE , FOULK BRAD , KAGAN MICHAEL T , SWENNENHUIS JOOST F , TERSTAPPEN LEON W M M , TIBBE ARJAN G J , VERRANT JOHN A
发明人： CONNELLY MARK CARLE , FOULK BRAD , KAGAN MICHAEL T , SWENNENHUIS JOOST F , TERSTAPPEN LEON W M M , TIBBE ARJAN G J , VERRANT JOHN A
IPC分类号： C12P19/34 , C07H21/04
CPC分类号： C12Q1/6886 , C12Q1/34 , C12Q1/6811 , C12Q1/6876 , C12Q2600/106 , C12Q2600/156 , C12Q2600/158 , C12Q2533/101 , C12Q2531/113 , C12Q2521/301 , C12Q2563/131 , C12Q2563/103
摘要： The invention relates generally to the field of identification of DNA sequences, genes or chromosomes. Methods and composition to obtain Unique Sequence DNA probes are provided. Composition comprises of any double stranded DNA containing Unique Sequences from which the repetitive sequences are eliminated according to the method described in this invention. The invention also relates to the preservation of cells that have been identified after immunomagnetic selection and fluorescent labeling in order to further interrogate the cells of interest. Furthermore the invention relates to genetic analysis of cells that have been identified after immunomagnetic selection and fluorescent labeling.
摘要翻译：本发明一般涉及DNA序列，基因或染色体的鉴定领域。提供了获得独特序列DNA探针的方法和组成。组合物包含任何含有根据本发明描述的方法消除重复序列的独特序列的双链DNA。本发明还涉及在免疫磁性选择和荧光标记后已经鉴定的细胞的保存，以便进一步询问感兴趣的细胞。此外，本发明涉及在免疫磁性选择和荧光标记后已经鉴定的细胞的遗传分析。

8. 发明申请

WO2006104474A3 A METHOD FOR PREDICTING PROGRESSION FREE AND OVERALL SURVIVAL AT EACH FOLLOW-UP TIME POINT DURING THERAPY OF METASTATIC BREAST CANCER PATIENTS USING CIRCULATING TUMOR CELLS 审中-公开
标题翻译：一种使用循环肿瘤细胞治疗分娩乳腺癌患者治疗的每个后续时间点的免疫进行预测和总体存活的方法
公开(公告)号：WO2006104474A3
公开(公告)日：2007-02-22
申请号：PCT/US2005008602
申请日：2005-03-14
申请人： IMMUNIVEST CORP , ALLARD JEFFREY W , DOYLE GERALD V , HAYES DANIEL F , MILLER MICHAEL CRAIG , TERSTAPPEN LEON W M M
发明人： ALLARD JEFFREY W , DOYLE GERALD V , HAYES DANIEL F , MILLER MICHAEL CRAIG , TERSTAPPEN LEON W M M
IPC分类号： C12Q1/00 , G01N33/48 , G01N33/53 , G01N33/574
CPC分类号： G01N33/574
摘要： A cancer test having prognostic utility in predicting time to disease progression, overall survival, and response to therapy in patients with MBC based upon the presence and number of CTC's. The Cell Spotter® System is used to enumerate CTC's in blood. The system immunomagnetically concentrates epithelial cells, fluorescently labels the cells and identifies and quantifies CTC's. The absolute number of CTC's detected in the peripheral blood tumor load is, in part, a factor in prediction of survival, time to progression, and response to therapy. The mean time to survival of patients depended upon a threshold number of (5) CTC'' per 7.5 ml of blood. Detection of CTC's in metastatic cancer represents a novel prognostic factor in patients with metastatic cancers, suggests a biological role for the presence of tumor cells in the blood, and indicates that the detection of CTC's could be considered an appropriate surrogate marker for prospective therapeutic clinical trials.
摘要翻译：根据CTC的存在和数量，在预测MBC患者中预测疾病进展时间，总体生存期和对治疗反应的预后效果的癌症测试。 CellSpotter®系统用于列举血液中的四氯化碳。该系统免疫磁性浓缩上皮细胞，荧光标记细胞，识别和量化CTC。在外周血肿瘤负荷中检测到的四氯化碳的绝对数量部分是预测存活时间，进展时间和对治疗反应的因素。患者生存的平均时间取决于每7.5毫升血液的阈值数（5）CTC“。在转移性癌症中检测CTC代表转移性癌症患者的新型预后因素，表明血液中肿瘤细胞存在的生物学作用，并且表明CTC检测可被认为是前瞻性治疗性临床试验的适当替代标记。

9. 发明申请

WO2006023563A2 A DIAGNOSTIC IMAGING DEVICE FOR THE ANALYSIS OF CIRCULATING RARE CELLS 审中-公开
标题翻译：一种诊断循环稀土细胞的诊断成像装置
公开(公告)号：WO2006023563A2
公开(公告)日：2006-03-02
申请号：PCT/US2005029260
申请日：2005-08-17
申请人： IMMUNIVEST CORP , COUMANS FRANK A W , MARLIN ARTHUR G , MODICA FRANK P , VERRANT JOHN A
发明人： COUMANS FRANK A W , MARLIN ARTHUR G , MODICA FRANK P , VERRANT JOHN A
IPC分类号： G06K9/00
CPC分类号： G01N21/6458 , G01N15/1463 , G01N2015/1465 , G01N2021/6441
摘要： The present invention provides a system for imaging circulating tumor cells from blood after enrichment. The system is designed to provide optimum use in a clinical laboratory setting with minimum laboratory bench top space. Operator intervention is minimized compared to other analytical methodologies. The system is useful in the enumeration and identification of target cells in a sample specimen for screening and detection of early stage pre-metastatic cancer, monitoring for disease remission in response to therapy and selection of more effective dose regimens or alternative therapies for individual patients.
摘要翻译：本发明提供了一种在富集后从血液中成像循环肿瘤细胞的系统。该系统设计用于在临床实验室环境中提供最佳实验室环境，并具有最小的实验室台面空间。与其他分析方法相比，操作员干预最小化。该系统可用于对样本标本中的靶细胞进行计数和鉴定，以筛选和检测早期转移前期癌症，监测治疗反应的疾病缓解率，以及为个别患者选择更有效的剂量方案或替代疗法。

10. 发明申请

WO2005028663A2 OPERATOR INDEPENDENT PROGRAMMABLE SAMPLE PREPARATION AND ANALYSIS SYSTEM 审中-公开
标题翻译：操作者独立的可编程样品制备和分析系统
公开(公告)号：WO2005028663A2
公开(公告)日：2005-03-31
申请号：PCT/US2004030429
申请日：2004-09-17
申请人： IMMUNIVEST CORP , BENDELE TERESA , HARBART THOMAS , HOWARD DAVE , KAGAN MICHAEL , KEENE DOUGLAS , LAPEUS DAVE , MAYES JARED , PAYNTER DOUGLAS , PROHASKA JERRY , RUTNER HERMAN
发明人： BENDELE TERESA , HARBART THOMAS , HOWARD DAVE , KAGAN MICHAEL , KEENE DOUGLAS , LAPEUS DAVE , MAYES JARED , PAYNTER DOUGLAS , PROHASKA JERRY , RUTNER HERMAN
IPC分类号： C12Q20060101 , G01N1/00 , G01N1/40 , G01N21/00 , G01N31/00 , G01N33/00 , G01N33/53 , G01N35/00 , G06T7/00 , H01L21/265 , C12Q
CPC分类号： G01N35/0098 , G01N1/40 , G06T7/70 , G06T2207/30004
摘要： The present invention provides a protocol and apparatus for enriching circulating tumor cells and other rare cells from blood, including debris and other components, from samples with high precision and at high throughput rates. This invention discloses an improved processing system from previously described semi-automated sample processing. The system further reduces operator intervention and hands-on time from prior systems. While this system has general utility in processing diverse materials, the system is configured for sample processing of biological specimens to provide an enriched fraction suitable for detection, enumeration and identification of target cells by appropriate analytical methodologies. The presence and quantities of such target cells in a sample specimen can utilized for screening and detection in disease such as cancer, assessing early stage pre-metastatic cancer, monitoring for disease remission in response to therapy and selection of more effective dose regimens or alternative therapies in case of relapse.
摘要翻译：本发明提供了一种用于从高精度和高生产率的样品中富集来自血液的循环肿瘤细胞和其它稀有细胞（包括碎片和其他成分）的方案和装置。本发明公开了一种来自先前描述的半自动化样品处理的改进的处理系统。该系统进一步减少了现有系统的操作员干预和实际操作时间。虽然该系统在处理不同材料方面具有一般效用，但是该系统被配置用于生物样品的样品处理，以通过适当的分析方法提供适合于靶细胞的检测，计数和鉴定的富集级分。样品样本中的这种靶细胞的存在和数量可以用于疾病如癌症中的筛选和检测，评估早期转移前癌症，响应于治疗监测疾病缓解和选择更有效的剂量方案或替代疗法在复发的情况下。

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