25 results on '"Rohr, Ulrich‐P."'
Search Results
2. Girdin (GIV) Expression as a Prognostic Marker of Recurrence in Mismatch Repair–Proficient Stage II Colon Cancer
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Ghosh, Pradipta, Tie, Jeanne, Muranyi, Andrea, Singh, Shalini, Brunhoeber, Patrick, Leith, Katherine, Bowermaster, Rebecca, Liao, Zhiming, Zhu, Yifei, LaFleur, Bonnie, Tran, Ben, Desai, Jayesh, Jones, Ian, Croxford, Matthew, Jover, Rodrigo, Goel, Ajay, Waring, Paul, Hu, Song, Teichgraber, Volker, Rohr, Ulrich-Peter, Ridder, Ruediger, Shanmugam, Kandavel, and Gibbs, Peter
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Colo-Rectal Cancer ,Cancer ,Digestive Diseases ,Detection ,screening and diagnosis ,4.2 Evaluation of markers and technologies ,Aged ,Biomarkers ,Tumor ,Chemotherapy ,Adjuvant ,Colonic Neoplasms ,DNA Mismatch Repair ,Disease-Free Survival ,Female ,Humans ,Male ,Microfilament Proteins ,Neoplasm Invasiveness ,Neoplasm Recurrence ,Local ,Neoplasm Staging ,Prognosis ,Vesicular Transport Proteins ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposePrognostic markers that identify patients with stage II colon cancers who are at the risk of recurrence are essential to personalize therapy. We evaluated the potential of GIV/Girdin as a predictor of recurrence risk in such patients.Experimental designExpression of full-length GIV was evaluated by IHC using a newly developed mAb together with a mismatch repair (MMR)-specific antibody panel in three stage II colon cancer patient cohorts, that is, a training (n = 192), test (n = 317), and validation (n = 181) cohort, with clinical follow-up data. Recurrence risk stratification models were established in the training cohort of T3, proficient MMR (pMMR) patients without chemotherapy and subsequently validated.ResultsFor T3 pMMR tumors, GIV expression and the presence of lymphovascular invasion (LVI) were the only factors predicting recurrence in both training (GIV: HR, 2.78, P = 0.013; LVI: HR, 2.54, P = 0.025) and combined test and validation (pooled) cohorts (GIV: HR, 1.85, P = 0.019; LVI: HR, 2.52, P = 0.0004). A risk model based on GIV expression and LVI status classified patients into high- or low-risk groups; 3-year recurrence-free survival was significantly lower in the high-risk versus low-risk group across all cohorts [Training: 52.3% vs. 84.8%; HR, 3.74, 95% confidence interval (CI), 1.50-9.32; Test: 85.9% vs. 97.9%, HR, 7.83, 95% CI, 1.03-59.54; validation: 59.4% vs. 84.4%, HR, 3.71, 95% CI, 1.24-11.12].ConclusionsGIV expression status predicts recurrence risk in patients with T3 pMMR stage II colon cancer. A risk model combining GIV expression and LVI status information further enhances prediction of recurrence. Further validation studies are warranted before GIV status can be routinely included in patient management algorithms. Clin Cancer Res; 22(14); 3488-98. ©2016 AACR.
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- 2016
3. Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies
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Cassidy, James, Saltz, Leonard B., Giantonio, Bruce J., Kabbinavar, Fairooz F., Hurwitz, Herbert I., and Rohr, Ulrich-Peter
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Medicine & Public Health ,Hematology ,Internal Medicine ,Cancer Research ,Oncology ,Bevacizumab ,Chemotherapy ,Metastatic colorectal cancer ,Older patients ,Pooled analysis - Abstract
Bevacizumab is frequently combined with 5-fluorouracil-based chemotherapy for patients with metastatic colorectal cancer (mCRC). The relative benefit of bevacizumab in older patients has not been widely studied and is of interest.This retrospective analysis used data from three first-line randomized controlled studies and one second-line randomized controlled study of bevacizumab plus chemotherapy in medically fit (Eastern Cooperative Oncology Group performance status 0 or 1) patients with mCRC. Overall survival (OS) and on-treatment progression-free survival (PFS) were assessed in patients aged
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- 2010
4. Regulatory Challenges: Is a Surrogate End Point Instead of Overall Survival Enough for Regulatory Approval of (Neo)Adjuvant Cancer Treatment? The Swissmedic Perspective.
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Pavic, Matea, Wolfer, Anita, Li, Qiyu, Gircys, Arunas, Juritz, Stephanie, Wicki, Andreas, Cerny, Thomas, and Rohr, Ulrich-Peter
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- 2023
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5. A decade comparison of regulatory decision patterns for oncology products to all other non‐oncology products among Swissmedic, European Medicines Agency, and US Food and Drug Administration.
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Rohr, Ulrich‐P., Iovino, Mario, Rudofsky, Leonie, Li, Qiyu, Juritz, Stephanie, Gircys, Arunas, Wildner, Oliver, Bujar, Magda, Bolte, Claus, Dalla Torre di Sanguinetto, Simon, and Wolfer, Anita
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PUBLIC opinion , *ONCOLOGY , *DRUGS - Abstract
Consensus of regulatory decisions on the same Marketing Authorization Application (MAA) are critical for stakeholders. In this context, regulatory decision patterns from the Swissmedic (SMC), the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) were analyzed for hemato‐oncology products (OP) and non‐oncology products (NOP). We compared 336 SMC regulatory decisions between 2009 and 2018 on new active substances with the EMA and the FDA for OP (n = 77) and NOP (n = 259) regarding approval rates, consensus, and divergent decisions. For OP MAA, we analyzed the underlying reasons for divergent decisions; for consensus decisions, the similarity and strictness of labeling. For OP, the approval rate for the SMC was 88.4%, the EMA 91.3%, and the FDA 95.7%. For NOP, the SMC had an approval rate of 86.2%, the EMA of 93.8%, and the FDA of 88.8%. The consensus decision rate among agencies was 88.4% for OP and 84.4% for NOP. The main clinical driver for divergent decisions for OP was nonrandomized trial design and low patient numbers. Comparing the approved indication wordings, the highest similarity was between the SMC and the EMA, and lowest for the FDA and the EMA. Investigating label strictness, the FDA numerically had the highest but not‐statistically significant number of strict labels. The approval rate stratified by disease area (OP and NOP) differed among the SMC, the EMA, and the FDA. High concordance in regulatory decisions was observed between agencies for OP as well as NOP. Reasons for divergent decisions regarding OP were mainly due to scientific uncertainties. Comparing strictness of indications, numerical but no statistically significant differences were observed between agencies. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Use of RNA interference to inhibit integrin subunit αV-mediated angiogenesis
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Graef, Thorsten, Steidl, Ulrich, Nedbal, Wolfgang, Rohr, Ulrich, Fenk, Roland, Haas, Rainer, and Kronenwett, Ralf
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- 2006
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7. Non-small lung cancer cells are prime targets for p53 gene transfer mediated by a recombinant adeno-associated virus type-2 vector
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Rohr, Ulrich-Peter, Wulf, Marc-Andre, Stahn, Susanne, Heyd, Florian, Steidl, Ulrich, Fenk, Roland, Opalka, Bertram, Pitschke, Gerald, Prisack, Hans-Bernd, Bojar, Hans, Haas, Rainer, and Kronenwett, Ralf
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- 2003
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8. Inhibition of angiogenesis in vitro by αv integrin–directed antisense oligonucleotides
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Kronenwett, Ralf, Gräf, Thorsten, Nedbal, Wolfgang, Weber, Markus, Steidl, Ulrich, Rohr, Ulrich-Peter, Möhler, Thomas, and Haas, Rainer
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- 2002
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9. Aberrant promoter methylation of p16INK4a, RARB2 and SEMA3B in bronchial aspirates from patients with suspected lung cancer
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Grote, Hans J., Schmiemann, Viola, Geddert, Helene, Rohr, Ulrich P., Kappes, Rainer, Gabbert, Helmut E., and Böcking, Alfred
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- 2005
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10. Distinct Gene Expression Pattern of Malignant Hematopoietic Stem and Progenitor Cells in Polycythemia Vera
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STEIDL, ULRICH, SCHROEDER, THOMAS, STEIDL, CHRISTIAN, KOBBE, GUIDO, GRAEF, THORSTEN, BORK, SIMONE, PECHTEL, SABRINA, KLISZEWSKI, SLAWOMIR, KUENDGEN, ANDREA, ROHR, ULRICH P., FENK, ROLAND, SCHROEDER, MICHAEL, HAASE, DETLEF, HAAS, RAINER, and KRONENWETT, RALF
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- 2005
11. Gene expression profiling for molecular distinction and characterization of laser captured primary lung cancers
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Schott Matthias, Pitschke Gerald, von Haeseler Arndt, Gabbert Helmut E, Schwalen Andreas, Geddert Helene, Pardillos Guillermo G, Rosskopf Michael, Neukirchen Judith, Rohrbeck Astrid, Kronenwett Ralf, Haas Rainer, and Rohr Ulrich-Peter
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Medicine - Abstract
Abstract Methods We examined gene expression profiles of tumor cells from 29 untreated patients with lung cancer (10 adenocarcinomas (AC), 10 squamous cell carcinomas (SCC), and 9 small cell lung cancer (SCLC)) in comparison to 5 samples of normal lung tissue (NT). The European and American methodological quality guidelines for microarray experiments were followed, including the stipulated use of laser capture microdissection for separation and purification of the lung cancer tumor cells from surrounding tissue. Results Based on differentially expressed genes, different lung cancer samples could be distinguished from each other and from normal lung tissue using hierarchical clustering. Comparing AC, SCC and SCLC with NT, we found 205, 335 and 404 genes, respectively, that were at least 2-fold differentially expressed (estimated false discovery rate: < 2.6%). Different lung cancer subtypes had distinct molecular phenotypes, which also reflected their biological characteristics. Differentially expressed genes in human lung tumors which may be of relevance in the respective lung cancer subtypes were corroborated by quantitative real-time PCR. Genetic programming (GP) was performed to construct a classifier for distinguishing between AC, SCC, SCLC, and NT. Forty genes, that could be used to correctly classify the tumor or NT samples, have been identified. In addition, all samples from an independent test set of 13 further tumors (AC or SCC) were also correctly classified. Conclusion The data from this research identified potential candidate genes which could be used as the basis for the development of diagnostic tools and lung tumor type-specific targeted therapies.
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- 2008
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12. Medical Value as a New Strategy to Increase Corporate Viability: Market Chances and Limitations in the Diagnostic Industry
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Maitland Roger, Laubender Ruediger P, Dieterle Thomas, Schäfer H Hendrik, Zaugg Christian E, Filser Ludwig, and Rohr Ulrich P
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Standardization ,business.industry ,media_common.quotation_subject ,Comparability ,Product (business) ,Excellence ,Sustainable business ,Health care ,Economics ,Marketing ,business ,Emerging markets ,health care economics and organizations ,media_common ,Multiple choice - Abstract
Study background: While the strategic advantage of Medical Value (MV) products is widely accepted in developed markets, it remains unclear if varying societal wealth influences the perception of customers on MV products. Methods: 231 of 240 Internal Medicine physicians from 8 countries participated in a survey with 5 multiple choice questions on MV. Responses from countries have been allocated to income levels according to world-bank data. Three groups have been defined (high-income countries: Canada, Norway and Switzerland=developed markets, upper-mid income markets: Argentina, China, Mexico and Turkey, lower-mid income counties: India=emerging markets). Answers have been statistically analyzed in subgroups (emerging markets vs. developed markets). Results: The majority of physicians believed that reliable and clinically validated treatment algorithms should accompany a product qualifying for MV. Algorithms should be created, predominantly for existing markers. Emphasis has been given to the discovery of better markers for well-known diseases in developed markets. Physicians` answers on pivotal factors for MV products yielded highest emphasis for generalizability (global technical standardization and data comparability). Technical excellence was given lower priority in developed markets comparing to emerging markets. Cost control was emphasized mainly in high-income markets. Conclusion: Both developed and emerging markets demand more clinical trials to establish algorithms for diagnostic tests. The prove of clinical utility is a pivotal factor for sustainable business success.
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- 2013
13. Medical Value as a New Strategy to Increase Corporate Viability: Market Chances and Limitations in the Diagnostic Industry
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Rohr Ulrich P, Filser Ludwig, primary
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- 2013
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14. Aberrant promoter methylation ofp16INK4a,RARB2 andSEMA3B in bronchial aspirates from patients with suspected lung cancer
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Grote, Hans J., primary, Schmiemann, Viola, additional, Geddert, Helene, additional, Rohr, Ulrich P., additional, Kappes, Rainer, additional, Gabbert, Helmut E., additional, and Böcking, Alfred, additional
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- 2005
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15. Primary human CD34+ hematopoietic stem and progenitor cells express functionally active receptors of neuromediators
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Steidl, Ulrich, Bork, Simone, Schaub, Sebastian, Selbach, Oliver, Seres, Janette, Aivado, Manuel, Schroeder, Thomas, Rohr, Ulrich-Peter, Fenk, Roland, Kliszewski, Slawomir, Maercker, Christian, Neubert, Peter, Bornstein, Stefan R., Haas, Helmut L., Kobbe, Guido, Tenen, Daniel G., Haas, Rainer, and Kronenwett, Ralf
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Recently, overlapping molecular phenotypes of hematopoietic and neuropoietic cells were described in mice. Here, we examined primary human CD34+ hematopoietic stem and progenitor cells applying specialized cDNA arrays, real-time reverse-transcriptase–polymerase chain reaction (RT-PCR), and fluorescent-activated cell sorter (FACS) analysis focusing on genes involved in neurobiologic functions. We found expression of vesicle fusion and motility genes, ligand- and voltage-gated ion channels, receptor kinases and phosphatases, and, most interestingly, mRNA as well as protein expression of G protein–coupled receptors of neuromediators (corticotropin-releasing hormone 1 [CRH 1] and CRH 2 receptors, orexin/hypocretin 1 and 2 receptors, GABAB receptor, adenosine A2B receptor, opioid κ1 and μ1 receptors, and 5-HT 1F receptor). As shown by 2-color immunofluorescence, the protein expression of these receptors was higher in the more immature CD38dim than in the CD38bright subset within the CD34+ population, and completely absent in fully differentiated blood cells, suggesting that those receptors play a role in developmentally early CD34+ stem and progenitor cells. The intracellular concentration of cyclic adenosine monophosphate (cAMP) in CD34+ cells was diminished significantly upon stimulation of either CRH or orexin receptors, indicating that those are functionally active and coupled to inhibitory G proteins in human hematopoietic cells. In conclusion, these findings suggest a molecular interrelation of neuronal and hematopoietic signaling mechanisms in humans.
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- 2004
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16. Primary human CD34+hematopoietic stem and progenitor cells express functionally active receptors of neuromediators
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Steidl, Ulrich, Bork, Simone, Schaub, Sebastian, Selbach, Oliver, Seres, Janette, Aivado, Manuel, Schroeder, Thomas, Rohr, Ulrich-Peter, Fenk, Roland, Kliszewski, Slawomir, Maercker, Christian, Neubert, Peter, Bornstein, Stefan R., Haas, Helmut L., Kobbe, Guido, Tenen, Daniel G., Haas, Rainer, and Kronenwett, Ralf
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Recently, overlapping molecular phenotypes of hematopoietic and neuropoietic cells were described in mice. Here, we examined primary human CD34+hematopoietic stem and progenitor cells applying specialized cDNA arrays, real-time reverse-transcriptase–polymerase chain reaction (RT-PCR), and fluorescent-activated cell sorter (FACS) analysis focusing on genes involved in neurobiologic functions. We found expression of vesicle fusion and motility genes, ligand- and voltage-gated ion channels, receptor kinases and phosphatases, and, most interestingly, mRNA as well as protein expression of G protein–coupled receptors of neuromediators (corticotropin-releasing hormone 1 [CRH 1] and CRH 2 receptors, orexin/hypocretin 1 and 2 receptors, GABAB receptor, adenosine A2B receptor, opioid κ1 and μ1 receptors, and 5-HT 1F receptor). As shown by 2-color immunofluorescence, the protein expression of these receptors was higher in the more immature CD38dimthan in the CD38brightsubset within the CD34+population, and completely absent in fully differentiated blood cells, suggesting that those receptors play a role in developmentally early CD34+stem and progenitor cells. The intracellular concentration of cyclic adenosine monophosphate (cAMP) in CD34+cells was diminished significantly upon stimulation of either CRH or orexin receptors, indicating that those are functionally active and coupled to inhibitory G proteins in human hematopoietic cells. In conclusion, these findings suggest a molecular interrelation of neuronal and hematopoietic signaling mechanisms in humans.
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- 2004
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17. Gene expression profiling identifies significant differences between the molecular phenotypes of bone marrow–derived and circulating human CD34+ hematopoietic stem cells
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Steidl, Ulrich, Kronenwett, Ralf, Rohr, Ulrich-Peter, Fenk, Roland, Kliszewski, Slawomir, Maercker, Christian, Neubert, Peter, Aivado, Manuel, Koch, Judith, Modlich, Olga, Bojar, Hans, Gattermann, Norbert, and Haas, Rainer
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CD34+ hematopoietic stem cells are used clinically to support cytotoxic therapy, and recent studies raised hope that they could even serve as a cellular source for nonhematopoietic tissue engineering. Here, we examined in 18 volunteers the gene expressions of 1185 genes in highly enriched bone marrow CD34+(BM-CD34+) or granulocyte–colony-stimulating factor–mobilized peripheral blood CD34+(PB-CD34+) cells by means of cDNA array technology to identify molecular causes underlying the functional differences between circulating and sedentary hematopoietic stem and progenitor cells. In total, 65 genes were significantly differentially expressed. Greater cell cycle and DNA synthesis activity of BM-CD34+ than PB-CD34+ cells were reflected by the 2- to 5-fold higher expression of 9 genes involved in cell cycle progression, 11 genes regulating DNA synthesis, and cell cycle–initiating transcription factor E2F-1. Conversely, 9 other transcription factors, including the differentiation blocking GATA2 and N-myc, were expressed 2 to 3 times higher in PB-CD34+ cells than in BM-CD34+cells. Expression of 5 apoptosis driving genes was also 2 to 3 times greater in PB-CD34+ cells, reflecting a higher apoptotic activity. In summary, our study provides a gene expression profile of primary human CD34+ hematopoietic cells of the blood and marrow. Our data molecularly confirm and explain the finding that CD34+ cells residing in the bone marrow cycle more rapidly, whereas circulating CD34+ cells consist of a higher number of quiescent stem and progenitor cells. Moreover, our data provide novel molecular insight into stem cell physiology.
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- 2002
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18. Gene expression profiling identifies significant differences between the molecular phenotypes of bone marrow–derived and circulating human CD34+hematopoietic stem cells
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Steidl, Ulrich, Kronenwett, Ralf, Rohr, Ulrich-Peter, Fenk, Roland, Kliszewski, Slawomir, Maercker, Christian, Neubert, Peter, Aivado, Manuel, Koch, Judith, Modlich, Olga, Bojar, Hans, Gattermann, Norbert, and Haas, Rainer
- Abstract
CD34+hematopoietic stem cells are used clinically to support cytotoxic therapy, and recent studies raised hope that they could even serve as a cellular source for nonhematopoietic tissue engineering. Here, we examined in 18 volunteers the gene expressions of 1185 genes in highly enriched bone marrow CD34+(BM-CD34+) or granulocyte–colony-stimulating factor–mobilized peripheral blood CD34+(PB-CD34+) cells by means of cDNA array technology to identify molecular causes underlying the functional differences between circulating and sedentary hematopoietic stem and progenitor cells. In total, 65 genes were significantly differentially expressed. Greater cell cycle and DNA synthesis activity of BM-CD34+than PB-CD34+cells were reflected by the 2- to 5-fold higher expression of 9 genes involved in cell cycle progression, 11 genes regulating DNA synthesis, and cell cycle–initiating transcription factor E2F-1. Conversely, 9 other transcription factors, including the differentiation blocking GATA2 and N-myc, were expressed 2 to 3 times higher in PB-CD34+cells than in BM-CD34+cells. Expression of 5 apoptosis driving genes was also 2 to 3 times greater in PB-CD34+cells, reflecting a higher apoptotic activity. In summary, our study provides a gene expression profile of primary human CD34+hematopoietic cells of the blood and marrow. Our data molecularly confirm and explain the finding that CD34+cells residing in the bone marrow cycle more rapidly, whereas circulating CD34+cells consist of a higher number of quiescent stem and progenitor cells. Moreover, our data provide novel molecular insight into stem cell physiology.
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- 2002
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19. Ein Spektrometer für schnelle Neutronen und das Neutronenspektrum von Ra α + Be
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Schmidt-Rohr, Ulrich
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Es wird ein Spektrometer für Neutronen von 2—25 MeV beschrieben. Es besteht aus einem mit Wasserstoff oder Methan gefüllten Ionisationskammer-Teleskop. Die Energieverteilung der im Gas in Primärrichtung ausgelösten Rückstoßprotonen wird durch ein Koinzidenz-Antikoinzidenz-System ermittelt und durch einen Impulsspektrographen photographisch aufgenommen. Durch Ausphotometrieren kann man die Neutronenspektren auch in Form von kontinuierlichen Differentialkurven erhalten. Das Gerät registriert gleichzeitig alle Energien innerhalb eines gewissen Energiebereiches, der durch den Druck in der Kammer eingestellt werden kann. Daher werden die Spektren durch Intensitätsschwankungen der Neutronenquellen nicht beeinflußt.
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- 1953
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20. Controversial Role of Bevacizumab in the Development of Venous Thromboembolic Events.
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Hapani, Sanjaykumar, Shenhong Wu, Lyman, Gary H., Hurwitz, Herbert I., Sirzén, Florin, and Rohr, Ulrich-Peter
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- 2011
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21. Developing companion diagnostics for delivering personalised medicine: opportunities and challenges.
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Desiere, Frank, Gutjahr, Thorsten S., and Rohr, Ulrich-Peter
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DRUG development ,TARGETED drug delivery ,PATHOLOGICAL physiology ,BIOLOGICAL tags ,INDIVIDUALIZED medicine - Abstract
A greater understanding of disease biology processes, the opportunity to develop targeted drugs leading to further improved patient outcomes and technology advances, as well as increasing pressure on healthcare budgets have led to a shift towards personalised healthcare solutions. Personalised medicine has tremendous potential benefits for patients and healthcare providers, as well as for regulatory agencies and pharmaceutical and diagnostic companies, but the advancement of this innovative therapeutic strategy depends on identifying biomarkers functioning as companion diagnostics for the targeted drug. However, considerable practical, methodological, regulatory and economic issues must be addressed to fully realise the potential of this approach. [ABSTRACT FROM AUTHOR]
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- 2013
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22. Pegylated G-CSF Mobilizes CD34+ Cells with Different Stem and Progenitor Cell Subsets and Distinct Functional Properties in Comparison with Unconjugated G-CSF.
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Bruns, Ingmar, Steidl, Ulrich, Fischer, Johannes C., Raschke, Sascha, Kobbe, Guido, Fenk, Roland, Rosskopf, Michael, Pechtel, Sabrina, Rohr, Ulrich-Peter, von Haeseler, Arndt, Wernet, Peter, Tenen, Daniel, Haas, Rainer, and Kronenwett, Ralf
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Current regimens for peripheral blood stem cell (PBSC) mobilization in patients with multiple myeloma are based on daily subcutaneous injections of G-CSF starting shortly after cytotoxic therapy. Recently a polyethylenglycole (PEG)-conjugated G-CSF has been introduced which has a substantially longer half-life than the original formula and therefore provides the basis for long-lasting G-CSF serum-levels after a single injection. In this study, we compared gene expression patterns, subset composition and functional properties of CD34+ cells and highly purified HSC mobilized with cyclophosphamide and either Peg-G-CSF or G-CSF. Cells were derived from peripheral blood of patients with multiple myeloma. After the end of chemotherapy, 7 patients got a single injection of Peg-G-CSF whereas 9 patients received daily G-CSF resulting in an equal cumulative dose. Gene expression analysis was performed using Affymetrix HG Focus GeneChips. Key functional genes were verified by RT-PCR. Subset analysis and fluorescence based cell sorting has been conducted to assess the effects of stimulation with either pegylated or unconjugated G-CSF on CD34+ subset composition and to obtain HSCs. Cell cycle and apoptosis assays as well as clonogenic assays were for functional corroboration. The same patients with multiple myeloma who had donated CD34+ cells for the molecular and biological studies were transplantated with Peg-G-CSF- or G-CSF-mobilized PBSC. Peg-G-CSF-mobilized cells showed lower expression of genes characteristic for erythroid and later stages of myeloid differentiation as well as a lower BFU-E/CFU-GM ratio compared to G-CSF-mobilized cells. In turn, we found higher expression levels of genes indicative of early hematopoiesis including HOXA9, MEIS1, MLL and GATA3. Subset analyses revealed a greater number of HSC and CMP (common myeloid progenitors) and a lower number of MEP (megakaryocyte-erthrocyte progenitors) in Peg-G-CSF-mobilized CD34+ cells. Cell cycle-promoting genes including cyclins and kinases were higher expressed in Peg-G-CSF-mobilized cells. On the other hand human HTm4, which causes cell cycle arrest in hematopoietic cells, was lower expressed compared to G-CSF-mobilized cells. This is emphasized by a significant higher proportion of actively cycling CD34+ cells after pegfilgrastim-mobilization. Higher gene expression levels of HOXA9, MEIS1 and GATA3 were also found in sorted Peg-G-CSF-mobilized HSC in comparison to G-CSF-mobilized HSC. Moreover, Peg-G-CSF-mobilized HSC showed a lower apoptosis rate and a greater proportion of cells in S- and G2/M phase of cell cycle. After transplantation of Peg-G-CSF-mobilized stem- and progenitor cells we observed earlier leukocyte recovery compared to G-CSF-mobilized transplants. Our data demonstrate that Peg-G-CSF and G-CSF stimulation differentially affects the expression of key regulatory genes and functional properties of mobilized HSC as well as their progeny, which might be important for their application in stem cell transplantation.
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- 2006
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23. Escalation Treatment Algorithm with Bortezomib, Dexamethasone and Bendamustine for Patients with Relapsed or Refractory Multiple Myeloma: A Singel Centre Experience.
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Fenk, Roland, Michael, Mark, Zohren, Fabian, Graef, Thorsten, Czibere, Arkosch, Balleisen, Sebastian, Neumann, Frank, Rohr, Ulrich-Peter, Steidl, Ulrich, Haas, Rainer, and Kobbe, Guido
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Bortezomib has improved the outcome of patients with multiple myeloma. Nevertheless, bortezomib monotherapy achieves responses in less than 50% of patients with advanced disease. Combination therapy can improve response rates but is associated with more adverse events such as neuropathy or myelosuppression. Therefore, we evaluated a step-wise escalation treatment algorithm for patients with relapsed or refractory myeloma. The initial treatment (step1) consisted of bortezomib monotherapy (1.3mg/m2 on day 1,4,8,11). Patients who did not show a at least 25% reduction of paraprotein at the beginning of cycle 2 received an escalated treatment (step2) with bortezomib and dexamethasone (40mg on day 1,4,8,11). The next treatment escalation (step3) was performed by addition of bendamustine (50–100mg/m2 on day 1 + 8) to bortezomib and dexamethasone. Step3 was used for patients who did respond with less than a minor response to one cycle of step2 treatment. We report on 48 patients who have been treated at our institution according to this regimen. Patients median age was 59 years with a median β2-microglobuline level of 3.8 g/dl and median albumine level of 3.7 g/dl. All patients were heavily pre-treated with in median three prior treatment regimen including high-dose therapy and thalidomide in more than 90% of patients. Escalation therapy was applied as planned to 36 (75%) patients, whereas 12 (25%) patients received step2 at the beginning of treatment due to physicians decision because of fulminant disease progression with hypercalcemia or severe tumor burden. Toxicity was as expected for bortezomib monotherapy and was manageable with escalated treatment steps. Response rates for patients in step1 were 11% nCR, 36% PR and 11% MR. In step2 (n=26) response rates were 31% PR, 15% MR and in step3 (n = 7) 43% PR and 29% MR. This results in an overall response rate of 80% for all patients. Patients with fulminant progressive disease who needed upfront treatment with step2 had an inferior overall response rate of 42% in comparison to 90% for patients who were treated according to the planned treatment schedule. With a median follow-up of 26 months the median time to progression and overall survival was 9 months and not reached for patients in the planned program and 2 and 4 months for the patients with upfront escalated therapy. Univariate analysis including several conventional prognostic parameters revealed physicians decision for upfront escalated treatment and age >60 years as the only bad prognostic factors. Interestingly, for patients within the planned treatment schedule, response to previous therapies, the extent of paraprotein reduction and the required escalation step had no impact on response duration. Another interesting observation of our single center study was that re-exposure of step3 treatment at the time of relapse (n=8) resulted in a new remission in 50% and in stable disease in 38% of patients. In conclusion, escalating therapy with bortezomib, dexamethasone and bendamustine induces durable remissions in the majority of patients, even in the presence of poor prognostic parameters. However, this treatment algorithm is not applicable for patients presenting with fulminant disease progression, as these patients need more aggressive regimens.
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- 2006
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24. Pre-Transplantation Level of Minimal Residual Disease Detected by Quantitative Real-Time IgH-PCR Is a Prognostic Parameter in Patients with Multiple Myeloma.
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Fenk, Roland, Korthals, Mark, Kobbe, Guido, Steidl, Ulrich, Graef, Thorsten, Rohr, Ulrich-Peter, Ruf, Leilani, Hoyer, Barbara, Neumann, Frank, Haas, Rainer, and Kronenwett, Ralf
- Abstract
Background: High-dose chemotherapy with autologous stem cell transplantation has improved outcome and survival of patients with multiple myeloma. However, the majority of patients suffer from relapse. Using real-time quantitative (RQ) PCR we have shown before (Haematologica 89,2004) that the amount of residual tumor cells in the bone marrow of patients before transplantation is of prognostic relevance. In this study we evaluated in a larger group of patients with multiple myeloma whether a pre-transplantation level of clonotypic cells in the bone marrow is predictive for time-to-progression (TTP) and overall survival (OS). Further, we compared results with known prognostic factors. Patients and Methods: Bone marrow samples of 19 patients with stage II/III multiple myeloma were obtained after induction therapy but before transplantation. Immunoglobulin heavy chain (IgH) RQ-PCR using patient-specific Taqman probes was performed to quantify pre-transplantation tumor levels. The proportion of clonotypic cells was assessed as IgH/2 beta-actin ratio in percent. Medical records of patients were reviewed for prognostic factors and outcome. Results: The median level of residual tumor cells in bone marrow of all patients at the time before transplantation was 0.3 %. At 23 month median follow-up after transplantation the median TTP and OS in our study were 14 and 36 month, respectively. The threshold level of 0.03% clonotypic cells identified two prognostic groups (p<0.0001, log rank). Twelve patients in the bad prognostic group had an early relapse with a median TTP of 9 month (range: 3 – 17 month). All patients in the good prognostic group (n=7) had ongoing remissions after a median follow-up of 24 month (range: 13–44 month). Univariat analysis was performed including other prognostic factors at the time before transplantation such as cytogenetic abnormalities, beta2-microglobulin, hemoglobulin, platelet count, LDH, CRP, serum albumine and age. Besides the pre-transplant level of minimal residual disease, CRP level was predictive for TTP. In multivariat analysis using a step-wise cox regression model grouping by pre-transplantation tumor level was the only prognostic factor for TTP (p = 0.05). Moreover, low pre-transplantation tumor levels also showed a trend for a better OS, but in multivariat analysis only normal cytogenetics were predictive for a superior outcome (p = 0.03). Conclusion: Quantitative molecular assessment of pre-transplantation tumor level in the bone marrow is an independent prognostic parameter for the progression-free survival of patients with multiple myeloma and thus helps to guide therapeutic interventions
- Published
- 2004
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25. Use of RNA Interference to Inhibit Integrin Subunit alphaV-Mediated Angiogenesis.
- Author
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Graef, Thorsten T., Steidl, Ulrich U., Fenk, Roland R., Rohr, Ulrich U., Nedbal, Wolfgang W., Haas, Rainer R., and Kronenwett, Ralf R.
- Abstract
Inhibition of angiogenesis is a promising approach for the treatment of solid tumors, inflammatory diseases and different hematological malignancies such as multiple myeloma. One of the central molecules in capillary formation during angiogenesis is the integrin alphaVbeta3 (aVb3), therefore aVb3 is a potential target molecule to inhibit angiogenesis. The aim of this study was to inhibit alphaV-mediated angiogenesis in vitro using RNA interference (RNAi) technology as well as antisense oligodeoxyribonucleotides (asON). We used synthetic small interfering RNAs (siRNA) and asON directed against the alphaV chain of aVb3 to inhibit integrin expression. Five siRNAs were selected on the basis of a systematic alignment of computer-predicted secondary structures of target mRNA and on the basis of current recommendations for siRNA oligonucleotide design. In parallel, 3 asON were examined. They had the sequence of the antisense sequence of 3 of the siRNAs molecules, respectively. SiRNAs, asON and respective control sequences were transfected into human umbilical vein endothelials cells (HUVEC) using lipofection. Following stimulation by phorbol 12-myristate 13-acetate (PMA), two siRNAs showed a dose- and time dependent inhibition of PMA-induced aV-mRNA and -protein upregulation as assessed by real-time RT-PCR and flow cytometry. At a concentration of 25 nM a 100% (SD: 4.9%) inhibition of aV upregulation was observed, whereas transfection of the respective asON sequences resulted in a 63% (SD: 6.1%) inhibition of aV upregulation at 25nM. To evaluate the anti-angiogenic potential of siRNAs in comparison to asON a cell culture model of human angiogenesis based on the co-cultivation of endothelial cells and dermal fibroblasts was used. Transfection of the most efficient siRNA sequence at a concentration of 50nM resulted in an inhibition of total length of capillary-like tubules by 48.7% (SD: 3.6%) in comparison to 21.8% (SD: 9.8%) by the respective asON sequence treated cultures. In conclusion, siRNAs can successfully be selected on the basis of computer-predicted secondary structures. In comparison with asON having the same sequence as the antisense strand of the respective siRNA the siRNA-mediated inhibition of aV expression showed a stronger inhibition of capillary tube formation in an angiogenesis in vitro assay. Therefore, siRNAs are useful tools for functional aV knock-down experiments and might be a therapeutic alternative for antagonists which bind directly to the integrins aVb3 or aVb5.
- Published
- 2004
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