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  • American Association for Cancer Research (AACR)  (6)
  • 2010-2014  (6)
  • 1
    Online Resource
    Online Resource
    Abstract 5233: MicroRNA in biofluid as robust biomarkers for cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5233-5233
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5233-5233
    Abstract: microRNAs constitute a class of small cellular RNAs (typically 19-23 nt) that function as post-transcriptional regulators of gene expression. Current estimates indicate that more than one third of the human cellular transcriptome is regulated by this small class of RNA (∼2000 miRNA). The study of extracellular microRNAs and their potential as pathophysiological markers has greatly expanded in the last couple of years. microRNAs have been shown to be actively exported from tissues into the circulation through a variety of mechanisms including exosome and microvesicle transport, and complexing with RNA binding proteins or HDL. The high relative stability of microRNAs in common clinical source materials (FFPE blocks, plasma, serum, urine, saliva, etc.) and the ability of microRNA expression profiles to accurately classify discrete tissue types and specific disease states have positioned microRNAs as promising new biomarkers for diagnostic application in cancer. We have applied Exiqons highly sensitive LNA™-based qPCR platform for detection of microRNAs, which has enabled microRNA profiling in biofluids where levels are extremely low. The platform uses a single RT reaction to conduct full miRNome profiling and allows high-throughput profiling of microRNAs without the need for pre-amplification. Thousands of biofluid samples including serum/plasma and urine have been profiled to determine normal reference ranges for circulating microRNAs as well as to identify biomarkers of disease. Extensive data qualification and analysis methods have been developed and are central parameters to secure high quality data from biofluids. The methods can quickly and robustly be applied in biomarker discovery and validation projects. We will present examples from our collaborative cancer diagnostic projects. Also we have developed a new exosome enrichment method and will present a comparison of microRNA profiles obtained with this method to profiles obtained with different commercial available exosome isolation methods and standard profiles of whole plasma and serum. Citation Format: Thorarinn Blondal, Anni Thomsen, Jörg Krummheyer, Peter Mouritzen, Ditte Andreasen, Maria Theilum, Jan Stenvang, Claus L. Andersen, Hans J. Nielsen, Nils Brünner. MicroRNA in biofluid as robust biomarkers for cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5233. doi:10.1158/1538-7445.AM2014-5233
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-5233
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Abstract 1214: TIMP-1 and the TIMP-1 interacting cell surface protein CD63 in cultured astrocytoma derived spheroids: expression and co-expression with stem cell markers
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 1214-1214
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 1214-1214
    Abstract: In previous studies we have shown that the immunohistochemical expression of TIMP-1 (tissue inhibitor of metalloproteinases-1) and CD63 increases with tumor grade in astrocytomas grade II-IV. Moreover, we demonstrated that a high TIMP-1 protein expression in glioblastomas was associated with a shorter overall patient survival. Recent studies have suggested that TIMP-1 can prevent chemo-induced apoptosis and in a study, using human breast epithelial cells (MCF10A), it was demonstrated that the interaction of TIMP-1 and CD63 is necessary for the TIMP-1 anti-apoptotic pathway. The aim of the present study was to investigate the expression of TIMP-1 and CD63 in cultured organotypic multicellular spheroids (OMS) and cell line spheroids (CLS) derived from astrocytomas in order to assess spheroid models for future studies involving TIMP-1, CD63 and chemo-resistance. By investigating the spheroids immunohistochemically, we wanted to elucidate if TIMP-1 and CD63 are co-expressed within the spheroids and whether they are expressed by tumor stem like-cells, since these cells are known to be more resistant to chemotherapeutic treatment. In the present study OMS from nine astrocytomas and CLS from three commercial astrocytoma cell lines were included as well as the glioblastoma tumor stem cell line SJ-1 made in our laboratory. In general high levels of CD63 protein was detected in all the original tumors, whereas TIMP-1 was moderately expressed. TIMP-1 and CD63 expression in OMS was similar to the expression in the original tumors. TIMP-1 was expressed at low to moderate levels in CLS, whereas CD63 was expressed by all tumor cells in all spheroids. TIMP-1/CD63 double immunofluorescence staining was performed on selected OMS and CLS showing tumor cells expressing both proteins. Furthermore, double staining was performed with TIMP-1 and the stem cell markers CD133, nestin and Sox2 demonstrating that a population of the tumor stem like-cells expressed TIMP-1. In conclusion, this study shows that spheroid models can be used in future studies investigating the role of TIMP-1 and CD63 in chemo-induced apoptosis. Furthermore, these results indicate that a fraction of the tumor stem like-cells could be protected by TIMP-1/CD63 interaction. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1214.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-1214
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 3
    Online Resource
    Online Resource
    Abstract 1157: MicroRNA-625-3p is associated with response to first-line oxaliplatin-based treatment of metastatic colorectal cancer.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1157-1157
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1157-1157
    Abstract: The backbone of current oncologic treatment of metastatic colorectal cancer (mCRC) consists of fluoropyrimidine together with either oxaliplatin (XELOX/FOLFOX) or irinotecan (XELIRI/FOLFIRI). With an overall objective response rate of approximately 50% for either treatment combination, a major unsolved problem is that no predictors of response to these treatments currently are available. To address this issue, we profiled 742 microRNAs in laser-capture microdissected cancer cells from responding and non-responding patients receiving XELOX/FOLFOX as first-line treatment for mCRC, and identified, among others, high expression of miR-625-3p, miR-181b and miR-27b to be associated with poor clinical response. In a validation cohort of 98 mCRC patients treated first-line with XELOX, high expression of miR-625-3p was confirmed to be associated with poor response (OR 6.25, 95%CIOR [1.8; 21.0]). Independent analyses showed that miR-625-3p was not dysregulated between normal and cancer samples, nor was its expression associated with recurrence of stage II or III disease, indicating that miR-625-3p solely is a response marker. Finally, we also found that these miRNAs are up-regulated in oxaliplatin resistant HCT116/oxPt (miR-625-3p, miR-181b and miR-27b) and LoVo/oxPt (miR-181b) CRC cell lines as compared with their isogenic parental cells. Altogether, our results suggest an association between miR-625-3p and response to first-line oxaliplatin based chemotherapy of mCRC. Citation Format: Mads H. Rasmussen, Niels F. Jensen, Line S. Tarpgaard, Camilla Qvortrup, Maria U. Rømer, Jan Stenvang, Tine P. Hansen, Lise-Lotte Christensen, Jan Lindebjerg, Flemming Hansen, Benny V. Jensen, Torben F. Hansen, Anders M. Jakobsen, Per Pfeiffer, Nils Brünner, Torben F. Ørntoft, Claus L. Andersen. MicroRNA-625-3p is associated with response to first-line oxaliplatin-based treatment of metastatic colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1157. doi:10.1158/1538-7445.AM2013-1157
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-1157
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    Abstract 2816: Discovery of a miRNA-based RT-qPCR signature able to detect early stage colorectal cancer in blood plasma
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2816-2816
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2816-2816
    Abstract: Colorectal cancer (CRC) ranks 4th in terms of prevalence and 2nd in number of deaths among cancers of the western world. Although early detection results in improved survival, and regular screening has been proven clinically to lower mortality from CRC, screening rates among the 50-75 year old population are unsatisfactory. There is therefore a clear unmet need for a quick, sensitive, specific, and convenient screening assay to select at risk individuals for definitive diagnosis by colonoscopy. Cellular miRNA profiles vary according to cell type and state, and cellular miRNAs are exported to extracellular fluids by both malignant cells and cells of the immune system. Blood plasma and serum miRNAs are stable under standard clinical sampling protocols and are therefore promising candidates for minimally invasive biomarkers for diverse pathological conditions. To screen for miRNAs in plasma, we developed an LNA-enhanced miRNA RT-qPCR platform with unprecedented sensitivity, selectivity and ease-of-use. An extensive informatics infrastructure has been put in place to allow semi-automated sample- and data-QC, and data analysis of large datasets. A reference melting curve database has been implemented to ensure the integrity of each data point, and appropriate controls monitor plate-to-plate and day-to-day variation. Different normalization protocols are routinely evaluated to ensure correct normalization of the dataset prior to data analysis. Using this platform, we have performed a two-phased discovery program in plasma samples from stage II/III CRC patients and age- and gender-matched colonoscopy-verified healthy controls. A genome wide screen in blood plasma profiled 730 individual miRNAs from 50 stage II cancers and 50 matched controls. This allowed us to develop a candidate panel of miRNAs detectable in plasma and to calculate an appropriate design for the full discovery study. In the second phase of the program we profiled the candidate 378 individual miRNAs in 120 stage II CRC, 50 stage III, and 170 matched controls. The results of these screens have given us a list of miRNAs that are statistically significantly altered between cancers and healthy volunteers. Some of the differentially expressed miRNAs include miRNAs with known roles in cancer and/or inflammatory processes. From this list we have developed a diagnostic miRNA signature that we are moving into assay development. We will present our diagnostic miRNA signature and plans for our first validation study where we will test the signature in samples from a 5,000 patient retrospective clinical trial as well as future plans to test prospectively in an ongoing clinical trial recruiting ∼5,000 symptomatic individuals. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2816. doi:10.1158/1538-7445.AM2011-2816
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-2816
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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    detail.hit.zdb_id: 410466-3
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  • 5
    Online Resource
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    Abstract LB-476: A universal method for elimination of haemolyzed plasma samples that improves miRNA signature performance for early detection of colorectal cancer
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. LB-476-LB-476
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. LB-476-LB-476
    Abstract: microRNAs (miRNAs) are short (∼21 bp) non-coding RNAs that regulate gene expression through post-transcriptional interactions with target messenger RNAs. miRNAs are exported to extracellular fluids by both malignant cells and cells of the immune system. Blood plasma and serum miRNAs are stable under standard clinical sampling protocols and have therefore attracted considerable interest for their potential as minimally invasive biomarkers for diverse pathological conditions, including various cancers. Although blood plasma contains as little as 1-20 ng of RNA per mL, plasma miRNAs are easily and reliably quantified using the highly sensitive and specific miRCURY LNA™ Universal RT microRNA PCR platform. However, the relative scarcity of miRNA in plasma creates a potential for contamination of the plasma miRNA expression profile by miRNAs from the cellular constituents in blood. One common cause of plasma sample rejection in clinical chemistry is haemolysis. If not identified, haemolysis can lead to erroneous results in a number of standard clinical laboratory tests, including blood potassium and lactate dehydrogenase (LDH) levels. Here we investigate the effect of sample haemolysis on plasma miRNA profiles. Using isolated red blood cells (RBCs) and genome-wide miRNA PCR profiling, we define the miRNome of RBCs. By spiking RBC extract into a non-haemolyzed plasma sample, we demonstrate that as little as 0.05% contamination of plasma can be detected as an increased expression level of a subset of miRNAs. We also define a set of plasma miRNAs that are not affected by haemolysis. Finally, we discover a miRNA qPCR QC signature that can be used to eliminate haemolyzed plasma samples. In a project aimed at defining a signature for the early detection of colorectal cancer (CRC) from a plasma sample, we screened 325 plasma samples from CRC patients and colonoscopy-verified CRC-negative controls. The samples were part of a clinical trial conducted in 7 different Danish hospitals, and were examined for the expression of 378 miRNAs previously detected in plasma. We show that haemolysis in this sample set correlates with hospital ID, and with the utilization of specific blood sample collection vials. Using our haemolysis signature, we eliminated haemolyzed samples and demonstrated that this step leads to a major improvement of CRC detection (ROC AUC increase from 0.67 to & gt;0.80). We conclude that haemolysis can be a cause of plasma miRNA profile contamination, and that elimination of haemolyzed samples using our miRNA haemolysis QC signature overcomes this clinical problem and leads to an increase in plasma miRNA biomarker performance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-476. doi:1538-7445.AM2012-LB-476
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-LB-476
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 6
    Online Resource
    Online Resource
    Early detection of colorectal cancer from patient blood plasma using microRNA-based q-rt-PCR
    American Association for Cancer Research (AACR) ; 2010
    In:  Clinical Cancer Research Vol. 16, No. 19_Supplement ( 2010-10-01), p. B2-B2
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 19_Supplement ( 2010-10-01), p. B2-B2
    Abstract: microRNAs (miRNAs) constitute a recently discovered class of small RNAs (typically 21-23 nt) that function as post-transcriptional regulators of gene expression. Current estimates indicate that more than one third of the cellular transcriptome is regulated by miRNAs, and that each miRNA potentially regulates hundreds of different mRNAs. As a consequence, miRNAs have been proposed to be master regulators of cellular state. This hypothesis has been borne out by a large number of studies demonstrating a causal link between miRNA dys-regulation and numerous disease states, including a diverse array of human cancers. Furthermore, the high stability of miRNA in common clinical source materials (e.g. FFPE blocks, plasma, serum, urine, saliva, etc.) and the ability of miRNA expression profiles to accurately classify discrete tissue types and disease states have positioned miRNA quantification as a promising new tool for a wide range of diagnostic applications. Colorectal cancer (CRC) ranks 4th in terms of prevalence and second in numbers of deaths among cancers of the western world. Although early detection of CRC leads to a favorable prognosis, and though CRC can easily be detected in the locally restricted state using a variety of diagnostic procedures, frequent late diagnosis means that CRC is still a leading cause of cancer mortality worldwide. Current procedures suffer from one or more disadvantages within areas such as cost, safety, inconvenience to the patient with the consequence of low compliance, lack of trained personnel, sensitivity etc, thereby precluding their adoption as a population screening tool. There is therefore an unmet need for a generally acceptable CRC screening assay. To facilitate discovery and clinical transfer of miRNA-based diagnostic markers, we developed a genome-wide LNA™-based miRNA q-rt-PCR platform with unparalleled sensitivity and robustness. The platform uses a single RT reaction to profile & gt;700 human miRNAs from 2 predefined 384 well plates and thus allows high-throughput profiling of miRNAs from important clinical sources without the need for pre-amplification. Using this system, we have profiled a large number of plasma samples from localized and regional CRC patients, and from matched healthy controls. An extensive QC system has been implemented in order to secure technical excellence and reveal any unwanted bias in the dataset. We will present our approaches to data normalization and the results of signature development using linear classification methods. We show that we can detect the majority of cancer cases with good specificity, using a cross-validation approach. In summary, our results show that minimally invasive early detection of CRC using a clinically viable approach is feasible.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/DIAG-10-B2
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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