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53. IMI's CANCER-ID: Status of liquid biopsy standardization

Author

Pantel, Klaus, Terstappen, Leon W. M. M., Baggiani, Barbara, Krahn, Thomas, Schlange, Thomas, and Medical Cell Biophysics

Abstract

The CANCER-ID (www.cancer-id.eu) consortium was established in early 2015 with more than 30 partners as part of the Innovative Medicines Initiative (IMI), Europe's largest public-private partnership funded in equal parts by the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA). The goal is to develop standard operating procedures (SOPs) and qualify respective mature technologies for pre-analytical sample handling, enrichment, isolation and analysis of Circulating Tumor Cells (CTCs), circulating free tumor DNA (ctDNA) and microRNAs (miRNAs) as novel blood-based biomarkers in cancer liquid biopsy, with a particular focus on Non-Small Cell Lung Cancer (NSCLC) and HER2-treatment refractory breast cancer. Over the 5-year period of the project, CANCER-ID will evaluate different technologies in the field, testing their clinical utility in multicenter clinical studies in support of regulatory approval of these devices. During the first year of the project, a number of different technology platforms have been implemented at several partner sites to establish SOPs with standardized blood samples spiked with selected cancer cell lines as standards. An important outcome of these studies are pre-analytical sample handling procedures, e.g. using different fixatives and tube systems as well as biobanking protocols that allow shipment and standardized long-term storage of liquid biopsy material. Most importantly, the knowledge generated within IMI's CANCER-ID will be used to establish and validate SOPs for the analysis of patient blood samples using different technologies, which represents a promising diagnostic tool holding the potential for optimized treatment decisions and therapeutic monitoring of cancer patients. The international exchange of human patient samples for research purposes poses a number of regulatory challenges linked to the different legal and ethical environments. The diverse national regulations for clinical samples and data require coordinated monitoring of interactions and guidance of the different partner organizations. As close collaboration with regulatory authorities is crucial for CANCER-ID to achieve its objectives, the consortium has established a contact with CDER/FDA via a Critical Path Innovation Meeting (CPIM). We will discuss the CANCER-ID approach to meet these many requirements and will present a matrix for coordinating such international efforts with stakeholders from different organizations.

Published
2016

55. Intraspecies transfer of the chromosomal Acinetobacter baumannii blaNDM-1 carbapenemase gene

Author

Krahn, Thomas, Wibberg, Daniel, Maus, Irena, Winkler, Anika, Bontron, Séverine, Sczyrba, Alexander, Nordmann, Patrice, Pühler, Alfred, Poirel, Laurent, and Schlüter, Andreas

Abstract

The species Acinetobacter baumannii is one of the most important multidrug-resistant human pathogens. To determine its virulence and antibiotic resistance determinants, the genome of the nosocomial blaNDM-1-positive A. baumannii strain R2090 originating from Egypt was completely sequenced. Genome analysis revealed that strain R2090 is highly related to the community-acquired Australian A. baumannii strain D1279779. The two strains belong to sequence type 267 (ST267). Isolate R2090 harbored the chromosomally integrated transposon Tn125 carrying the carbapenemase gene blaNDM- 1 that is not present in the D1279779 genome. To test the transferability of the metallo-β-lactamase (MBL) gene region, the clinical isolate R2090 was mated with the susceptible A. baumannii recipient CIP 70.10, and the carbapenem-resistant derivative R2091 was obtained. Genome sequencing of the R2091 derivative revealed that it had received an approximately 66-kb region comprising the transposon Tn125 embedding the blaNDM-1 gene. This region had integrated into the chromosome of the recipient strain CIP 70.10. From the four known mechanisms for horizontal gene transfer (conjugation, outer membrane vesicle- mediated transfer, transformation, and transduction), conjugation could be ruled out, since strain R2090 lacks any plasmid, and a type IV secretion system is not encoded in its chromosome. However, strain R2090 possesses three putative prophages, two of which were predicted to be complete and therefore functional. Accordingly, it was supposed that the transfer of the resistance gene region from the clinical isolate R2090 to the recipient occurred by general transduction facilitated by one of the prophages present in the R2090 genome. Hence, phage-mediated transduction has to be taken into account for the dissemination of antibiotic resistance genes within the species A. baumannii.

Published
2016

56. Isolation of circulating tumor cells from pancreatic cancer by automated filtration

Author

Brychta, Nora, primary, Drosch, Michael, additional, Driemel, Christiane, additional, Fischer, Johannes C., additional, Neves, Rui P., additional, Esposito, Irene, additional, Knoefel, Wolfram, additional, Möhlendick, Birte, additional, Hille, Claudia, additional, Stresemann, Antje, additional, Krahn, Thomas, additional, Kassack, Matthias U., additional, Stoecklein, Nikolas H., additional, and von Ahsen, Oliver, additional

Published
2017
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57. In situ analysis of FGFR2 mRNA and comparison with FGFR2 gene copy number by dual-color in situ hybridization in a large cohort of gastric cancer patients

Author

Kuboki, Yasutoshi, primary, Schatz, Christoph A., additional, Koechert, Karl, additional, Schubert, Sabine, additional, Feng, Janine, additional, Wittemer-Rump, Sabine, additional, Ziegelbauer, Karl, additional, Krahn, Thomas, additional, Nagatsuma, Akiko Kawano, additional, and Ochiai, Atsushi, additional

Published
2017
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59. Abstract 3786: Multicenter evaluation of technology platforms for the enumeration of circulating tumor cells

Author

Bender, Sebastian, primary, Lütke-Eversloh, Merlin V., additional, Neves, Rui P., additional, Stoecklein, NNikolas H., additional, Terstappen, Leon W., additional, Baggiani, Barbara, additional, Neumann, Martin H., additional, Krahn, Thomas, additional, Pantel, Klaus, additional, Schlange, Thomas, additional, and Zeune, Leonie L., additional

Published
2017
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60. Reliability of peripheral arterial tonometry in patients with heart failure, diabetic nephropathy and arterial hypertension

Author

Weisrock, Fabian, primary, Fritschka, Max, additional, Beckmann, Sebastian, additional, Litmeier, Simon, additional, Wagner, Josephine, additional, Tahirovic, Elvis, additional, Radenovic, Sara, additional, Zelenak, Christine, additional, Hashemi, Djawid, additional, Busjahn, Andreas, additional, Krahn, Thomas, additional, Pieske, Burkert, additional, Dinh, Wilfried, additional, and Düngen, Hans-Dirk, additional

Published
2017
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62. Complete Genome Sequence of the Clinical Strain Acinetobacter baumannii R2090 Carrying the Chromosomally Encoded Metallo-β-Lactamase GeneblaNDM-1

Author

Krahn, Thomas, Wibberg, Daniel, Maus, Irena, Winkler, Anika, Nordmann, Patrice, Pühler, Alfred, Poirel, Laurent, and Schlüter, Andreas

Subjects
polycyclic compounds, bacteria, Prokaryotes, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses
Abstract

Acinetobacter baumannii is an emerging human pathogen causing nosocomial and community-acquired infections. Here, we present the complete genome sequence of the clinical A. baumannii strain R2090 carrying the metallo-β-lactamase gene blaNDM-1 in its chromosome within the transposon Tn125.

Published
2015

63. Multicenter Evaluation of Circulating Plasma MicroRNA Extraction Technologies for the Development of Clinically Feasible Reverse Transcription Quantitative PCR and Next-Generation Sequencing Analytical Work Flows.

Author

Kloten, Vera, Neumann, Martin H. D., Di Pasquale, Francesca, Sprenger-Haussels, Markus, Shaffer, Jonathan M., Schlumpberger, Martin, Herdean, Andrei, Betsou, Fay, Ammerlaan, Wim, af Hällström, Taija, Serkkola, Elina, Forsman, Tarja, Lianidou, Evi, Sjöback, Robert, Kubista, Mikael, Bender, Sebastian, Lampignano, Rita, Krahn, Thomas, and Schlange, Thomas

Published
2019
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68. Abstract 4933: In Situ analysis of FGFR2 RNA and comparison with FGFR2 gene copy number by dual-color in situ hybridization in a large cohort of gastric cancer patients

Author

Kuboki, Yasutoshi, primary, Schatz, Christoph A., additional, Jabusch, Sabine, additional, Koechert, Karl, additional, Feng, Janine, additional, Wittemer-Rump, Sabine, additional, Ziegelbauer, Karl, additional, Krahn, Thomas, additional, Nagatsuma, Akiko, additional, and Ochiai, Atsushi, additional

Published
2016
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69. Abstract 513: Standardization of technologies for CTC, ctDNA and miRNA enrichment, isolation and analysis for liquid biopsies during the first year of IMI's CANCER-ID

Author

Schlange, Thomas, primary, Stoecklein, Nikolas, additional, Neves, Rui P., additional, Pleier, Sabrina, additional, Bender, Sebastian, additional, Brychta, Nora, additional, Luetke-Eversloh, Merlin V., additional, Andree, Kiki, additional, Terstappen, Leon, additional, and Krahn, Thomas, additional

Published
2016
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70. Developing New Treatments for Heart Failure

Author

Gheorghiade, Mihai, primary, Larson, Christopher J., additional, Shah, Sanjiv J., additional, Greene, Stephen J., additional, Cleland, John G.F., additional, Colucci, Wilson S., additional, Dunnmon, Preston, additional, Epstein, Stephen E., additional, Kim, Raymond J., additional, Parsey, Ramin V., additional, Stockbridge, Norman, additional, Carr, James, additional, Dinh, Wilfried, additional, Krahn, Thomas, additional, Kramer, Frank, additional, Wahlander, Karin, additional, Deckelbaum, Lawrence I., additional, Crandall, David, additional, Okada, Shunichiro, additional, Senni, Michele, additional, Sikora, Sergey, additional, Sabbah, Hani N., additional, and Butler, Javed, additional

Published
2016
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71. Enumeration and Molecular Characterization of Tumor Cells in Lung Cancer Patients Using a Novel In Vivo Device for Capturing Circulating Tumor Cells

Author

Gorges, Tobias M., primary, Penkalla, Nicole, additional, Schalk, Thomas, additional, Joosse, Simon A., additional, Riethdorf, Sabine, additional, Tucholski, Johannes, additional, Lücke, Klaus, additional, Wikman, Harriet, additional, Jackson, Stephen, additional, Brychta, Nora, additional, von Ahsen, Oliver, additional, Schumann, Christian, additional, Krahn, Thomas, additional, and Pantel, Klaus, additional

Published
2016
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73. In situ analysis of FGFR2 mRNA and comparison with <italic>FGFR2</italic> gene copy number by dual-color in situ hybridization in a large cohort of gastric cancer patients.

Author

Kuboki, Yasutoshi, Schatz, Christoph A., Koechert, Karl, Schubert, Sabine, Feng, Janine, Wittemer-Rump, Sabine, Ziegelbauer, Karl, Krahn, Thomas, Nagatsuma, Akiko Kawano, and Ochiai, Atsushi

Subjects
STOMACH cancer, FIBROBLAST growth factor receptors, MESSENGER RNA, GENE amplification, CANCER patients
Abstract

Background: Fibroblast growth factor receptor (FGFR2) has been proposed as a target in gastric cancer. However, appropriate methods to select patients for anti-FGFR2 therapies have not yet been established.Methods: We used in situ techniques to investigate FGFR2 mRNA expression and gene amplification in a large cohort of 1036 Japanese gastric cancer patients. FGFR2 mRNA expression was determined by RNAscope. FGFR2 gene amplification was determined by dual-color in situ hybridization (DISH).Results: We successfully analyzed 578 and 718 samples by DISH and RNAscope, respectively; 2% (12/578) showed strong FGFR2 gene amplification (FGFR2:CEN10 >10); moderate FGFR2 gene amplification (FGFR2:CEN10 <10; ≥2) was detected in 8% (47/578); and high FGFR2 mRNA expression of score 4 (>10 dots/cell and >10% of positive cells with dot clusters under a 20× objective) was seen in 4% (29/718). For 468 samples, both mRNA and DISH data were available. FGFR2 mRNA expression levels were associated with gene amplification; FGFR2 mRNA levels were highest in the highly amplified samples (n = 12). All highly amplified samples showed very strong FGFR2 mRNA expression (dense clusters of the signal visible under a 1× objective). Patients with very strong FGFR2 mRNA expression showed more homogeneous FGFR2 mRNA expression compared to patients with lower FGFGR2 mRNA expression. Gastric cancer patients with tumors that had an FGFR2 mRNA expression score of 4 had shorter RFS compared with score 0-3 patients.Conclusion: RNAscope and DISH are suitable methods to evaluate FGFR2 status in gastric cancer. Formalin-fixed paraffin-embedded (FFPE) tissue slides allowed evaluation of the intratumor heterogeneity of these FGFR2 biomarkers. [ABSTRACT FROM AUTHOR]

Published
2018
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77. Abstract 1583: Circulating tumor cells isolated from non-small cell lung cancer patients using the in vivo CellCollector Technology

Author

Krahn, Thomas, primary, Gasiorowski, Lukasz, additional, Dyszkiewicz, Wojciech, additional, Dworacki, Grzegorz, additional, Zabel, Maciej, additional, Hoon, Dave S., additional, Herold, Stefanie, additional, Nowack, Bjoern, additional, Tucholsky, Johannes, additional, Schumann, Christian, additional, and Lücke, Klaus, additional

Published
2015
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83. Abstract 2836: Development of a companion diagnostic IHC assay for the biomarker-driven selection of C4.4a positive patients

Author

Schneider, Claudia, primary, Couto, Joseph, additional, Zhu, Yifei, additional, Liao, Zhiming, additional, Pytela, Robert, additional, Hiscox, Alton, additional, Wittemer-Rump, Sabine, additional, Forssmann, Ulf, additional, Linden, Lars, additional, Willuda, Joerg, additional, Forler, Daniel, additional, Nelson, Matthew, additional, Finnern, Ricarda, additional, Krahn, Thomas, additional, and Asadullah, Khusru, additional

Published
2014
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86. Functional and RNA expression profile of adenosine receptor subtypes in mouse mesenteric arteries

Author

Teng, Bunyen, Fil, Daniel, Tilley, Stephen S.L., Ledent, Catherine, Krahn, Thomas, Mustafa, Jamal S.J., Teng, Bunyen, Fil, Daniel, Tilley, Stephen S.L., Ledent, Catherine, Krahn, Thomas, and Mustafa, Jamal S.J.

Abstract

Concentration-response curves (CRCs) of adenosine receptor (AR) agonists, NECA (nonspecific), CCPA (A1 specific), CGS-216870 (A2A specific), BAY 60-6583 (A2B specific), and Cl-IB-MECA (A3 specific) for mesenteric arteries (MAs) from 4 AR knockout (KO) mice (A1, A2A, A2B, and A3) and their wild type (WT) were constructed. The messenger RNA expression of MAs from KO mice and WT were also studied. Adenosine (10 to 10 M) and NECA (10 to 10 M) induced relaxation in all mice except A2B KO mice, which only showed constriction by adenosine at 10 to 10 and NECA at 10 to 10 M. The CCPA induced a significant constriction at 10 and 10 M in all mice, except A1KO. BAY 60-6583 induced relaxation (10 to 10 M) in WT and no response in A2BKO except at 10 M. The CRCs for BAY 60-6583 in A1, A2A, and A3 KO mice shifted to the left when compared with WT mice, suggesting an upregulation of A2B AR. No responses were noted to CGS-21680 in all mice. Cl-IB-MECA only induced relaxation at concentration greater than 10 M, and no differences were found between different KO mice. The CRC for Bay 60-6583 was not significantly changed in the presence of 10 M of L-NAME, 10 M of indomethacin, or both. Our data suggest that A2B AR is the predominant AR subtype and the effect may be endothelial independent, whereas A1 AR plays a significant modulatory role in mouse MAs. © 2013 by Lippincott Williams & Wilkins., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2013

87. Chromosomal Determinants of Aminoglycoside Resistance in Pseudomonas aeruginosa

Author

Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)), Krahn, Thomas, Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)), and Krahn, Thomas

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen found in soil and aquatic environments that possesses a broad range of intrinsic antibiotic resistance mechanisms, including a highly impermeable outer membrane and several RND-type efflux pumps that export a number of clinically relevant antibiotic classes. Chronic P. aeruginosa infections in cystic fibrosis (CF) patients gradually develop high levels of resistance to antimicrobial therapy due to conditions that favour the acquisition and selection of numerous chromosomal mutations, the nature of which are poorly understood. To identify chromosomal contributors to aminoglycoside resistance a P. aeruginosa transposon mutant library was screened for increases in aminoglycoside susceptibility. Six genes of interest (pstB, lptA, faoA, amgR, PA0392, and PA2798) were identified, the deletion of which meaningfully decreased aminoglycoside minimum inhibitory concentrations in wild-type P. aeruginosa. Combinations of gene deletions were constructed to determine if any of these genes contributed to aminoglycoside resistance via a common mechanism or whether they operated independently to promote intrinsic aminoglycoside resistance. In all cases, double deletion had an additive impact on aminoglycoside susceptibility, suggesting that each gene of interest contributes to resistance through an independent mechanism. Deletions in pstB, lptA, faoA, amgR, PA0392, and PA2798 were introduced into pan-aminoglycoside-resistant CF-lung isolates where they dramatically compromised aminoglycoside resistance, indicating that these genes also contribute to acquired aminoglycoside resistance in chronic P. aeruginosa infections. A fluorimetric assay was developed to measure aminoglycoside-induced membrane depolarization using the voltage sensitive probe DIBAC4(3). Gentamicin-induced membrane depolarization was found to be substantially increased in the amgR, pstB, and PA0392 mutant strains when compared to wild-type P. aeruginosa. These inc, Thesis (Master, Microbiology & Immunology) -- Queen's University, 2012-09-21 21:27:23.303

Published
2012

88. Contributions of A2A and A2B adenosine receptors in coronary flow responses in relation to the KATP channel using A2B and A2A/2B double-knockout mice

Author

Sanjani, Maryam Sharifi, Teng, Bunyen, Krahn, Thomas, Tilley, Stephen S.L., Ledent, Catherine, Mustafa, Jamal S.J., Sanjani, Maryam Sharifi, Teng, Bunyen, Krahn, Thomas, Tilley, Stephen S.L., Ledent, Catherine, and Mustafa, Jamal S.J.

Abstract

Adenosine plays a role in physiological and pathological conditions, and A2 adenosine receptor (AR) expression is modified in many cardiovascular disorders. In this study, we elucidated the role of the A2BAR and its relationship to the A2AAR in coronary flow (CF) changes using A2B single-knockout (KO) and A2A/2B double-KO (DKO) mice in a Langendorff setup. We used two approaches: 1) selective and nonselective AR agonists and antagonists and 2) A2AKO and A2BKO and A2A/2BDKO mice. BAY 60-6583 (a selective A2B agonist) had no effect on CF in A2BKO mice, whereas it significantly increased CF in wild-type (WT) mice (maximum of 23.3 ± 9 ml·min-1·g-1). 5'-N-ethylcarboxamido adenosine (NECA; a nonselective AR agonist) increased CF in A2BKO mice (maximum of 34.6 ± 4.7 ml·min-1·g-1) to a significantly higher degree compared with WT mice (maximum of 23.1 ± 2.1 ml·min-1·g-1). Also, CGS-21680 (a selective A2A agonist) increased CF in A2BKO mice (maximum of 29 ± 1.9 ml·min-1·g-1) to a significantly higher degree compared with WT mice (maximum of 25.1 ± 2.3 ml·min-1·g-1). SCH-58261 (an A2A-selective antagonist) inhibited the NECA-induced increase in CF to a significantly higher degree in A2BKO mice (19.3 ± 1.6 vs. 0.5 ± 0.4 ml·min-1·g-1) compared with WT mice (19 ± 3.5 vs. 3.6 ± 0.5 ml·min-1·g-1). NECA did not induce any increase in CF in A2A/2BDKO mice, whereas a significant increase was observed in WT mice (maximum of 23.1 ± 2.1 ml·min-1·g-1). Furthermore, the mitochondrial ATP-sensitive K(KATP) channel blocker 5-hydroxydecanoate had no effect on the NECAinduced increase in CF in WT mice, whereas the NECA-induced increase in CF in WT (17.6 ± 2 ml·min-1·g-1), A2AKO (12.5 ± 2.3 ml·min-1·g-1), and A2BKO (16.2 ± 0.8 ml·min-1·g-1) mice was significantly blunted by the KATP channel blocker glibenclamide (to 0.7 ± 0.7, 2.3 ± 1.1, and 0.9 ± 0.4 ml·min-1·g-1, respectively). Also, the CGS-21680-induced (22 ± 2.3 ml·min-1·g-1) and BAY 60-6583-induced (16.4 ± 1.60 ml·min-1·g-1) increase in, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2011

93. An African American Paternal Lineage Adds an Extremely Ancient Root to the Human Y Chromosome Phylogenetic Tree

Author

Mendez, Fernando L., primary, Krahn, Thomas, additional, Schrack, Bonnie, additional, Krahn, Astrid-Maria, additional, Veeramah, Krishna R., additional, Woerner, August E., additional, Fomine, Forka Leypey Mathew, additional, Bradman, Neil, additional, Thomas, Mark G., additional, Karafet, Tatiana M., additional, and Hammer, Michael F., additional

Published
2013
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96. Cardioprotection by ecto-5'-nucleotidase (CD73) and A2B adenosine receptors.

Author

Eckle, Tobias, Krahn, Thomas, Grenz, Almut, Köhler, David, Mittelbronn, Michel, Ledent, Catherine, Jacobson, Marlene A, Osswald, Hartmut, Thompson, Linda F, Unertl, Klaus, Eltzschig, Holger K, Eckle, Tobias, Krahn, Thomas, Grenz, Almut, Köhler, David, Mittelbronn, Michel, Ledent, Catherine, Jacobson, Marlene A, Osswald, Hartmut, Thompson, Linda F, Unertl, Klaus, and Eltzschig, Holger K

Abstract

BACKGROUND: Ecto-5'-nucleotidase (CD73)-dependent adenosine generation has been implicated in tissue protection during acute injury. Once generated, adenosine can activate cell-surface adenosine receptors (A1 AR, A2A AR, A2B AR, A3 AR). In the present study, we define the contribution of adenosine to cardioprotection by ischemic preconditioning. METHODS AND RESULTS: On the basis of observations of CD73 induction by ischemic preconditioning, we found that inhibition or targeted gene deletion of cd73 abolished infarct size-limiting effects. Moreover, 5'-nucleotidase treatment reconstituted cd73-/- mice and attenuated infarct sizes in wild-type mice. Transcriptional profiling of adenosine receptors suggested a contribution of A2B AR because it was selectively induced by ischemic preconditioning. Specifically, in situ ischemic preconditioning conferred cardioprotection in A1 AR-/-, A2A AR-/-, or A3 AR-/- mice but not in A2B AR-/- mice or in wild-type mice after inhibition of the A2B AR. Moreover, A2B AR agonist treatment significantly reduced infarct sizes after ischemia. CONCLUSIONS: Taken together, pharmacological and genetic evidence demonstrate the importance of CD73-dependent adenosine generation and signaling through A2B AR for cardioprotection by ischemic preconditioning and suggests 5'-nucleotidase or A2B AR agonists as therapy for myocardial ischemia., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2007

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