25 results on '"Feger, D."'
Search Results
2. The Development of a 10 K Closed Cycle Stirling Cooler for Space Use
- Author
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Baker, G., Féger, D., Little, A., Orlowska, A. H., Bradshaw, T. W., Crook, M., Tomlinson, B. J., Sargeant, A., and Ross, R. G., Jr., editor
- Published
- 2002
- Full Text
- View/download PDF
3. Rehabilitation nach Mammakarzinom: Zukünftige Aufgaben und Betreuungskonzepte
- Author
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Feger, D. and Thomeit, W.
- Published
- 2003
- Full Text
- View/download PDF
4. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells
- Author
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Mathew, N.R., Baumgartner, F., Braun, L., O'Sullivan, D., Thomas, S., Waterhouse, M., Muller, T.A., Hanke, K., Taromi, S., Apostolova, P., Illert, A.L., Melchinger, W., Duquesne, S., Schmitt-Graeff, A., Osswald, L., Yan, K.L., Weber, A, Tugues, S., Spath, S., Pfeifer, D., Follo, M., Claus, R., Lubbert, M., Rummelt, C., Bertz, H., Wasch, R., Haag, J., Schmidts, A., Schultheiss, M., Bettinger, D., Thimme, R., Ullrich, E., Tanriver, Y., Vuong, G.L., Arnold, R., Hemmati, P., Wolf, D., Ditschkowski, M., Jilg, C., Wilhelm, K., Leiber, C., Gerull, S., Halter, J., Lengerke, C., Pabst, T., Schroeder, T., Kobbe, G., Rosler, W., Doostkam, S., Meckel, S., Stabla, K., Metzelder, S.K., Halbach, S., Brummer, T., Hu, Z, Dengjel, J., Hackanson, B., Schmid, C., Holtick, U., Scheid, C., Spyridonidis, A., Stolzel, F., Ordemann, R., Muller, L.P., Sicre-de-Fontbrune, F., Ihorst, G., Kuball, J., Ehlert, J.E., Feger, D., Wagner, E.M., Cahn, J.Y., Schnell, J., Kuchenbauer, F., Bunjes, D., Chakraverty, R., Richardson, S., Gill, S., Kroger, N., Ayuk, F., Vago, L., Ciceri, F., Muller, A.M., Kondo, T., Teshima, T., Klaeger, S., Kuster, B., Kim, D.D.H., Weisdorf, D., Velden, W.J. van der, Dorfel, D., Bethge, W., Hilgendorf, I., Hochhaus, A., Andrieux, G., Borries, M., Busch, H., Magenau, J., Reddy, P., Labopin, M., Antin, J.H., et al., Mathew, N.R., Baumgartner, F., Braun, L., O'Sullivan, D., Thomas, S., Waterhouse, M., Muller, T.A., Hanke, K., Taromi, S., Apostolova, P., Illert, A.L., Melchinger, W., Duquesne, S., Schmitt-Graeff, A., Osswald, L., Yan, K.L., Weber, A, Tugues, S., Spath, S., Pfeifer, D., Follo, M., Claus, R., Lubbert, M., Rummelt, C., Bertz, H., Wasch, R., Haag, J., Schmidts, A., Schultheiss, M., Bettinger, D., Thimme, R., Ullrich, E., Tanriver, Y., Vuong, G.L., Arnold, R., Hemmati, P., Wolf, D., Ditschkowski, M., Jilg, C., Wilhelm, K., Leiber, C., Gerull, S., Halter, J., Lengerke, C., Pabst, T., Schroeder, T., Kobbe, G., Rosler, W., Doostkam, S., Meckel, S., Stabla, K., Metzelder, S.K., Halbach, S., Brummer, T., Hu, Z, Dengjel, J., Hackanson, B., Schmid, C., Holtick, U., Scheid, C., Spyridonidis, A., Stolzel, F., Ordemann, R., Muller, L.P., Sicre-de-Fontbrune, F., Ihorst, G., Kuball, J., Ehlert, J.E., Feger, D., Wagner, E.M., Cahn, J.Y., Schnell, J., Kuchenbauer, F., Bunjes, D., Chakraverty, R., Richardson, S., Gill, S., Kroger, N., Ayuk, F., Vago, L., Ciceri, F., Muller, A.M., Kondo, T., Teshima, T., Klaeger, S., Kuster, B., Kim, D.D.H., Weisdorf, D., Velden, W.J. van der, Dorfel, D., Bethge, W., Hilgendorf, I., Hochhaus, A., Andrieux, G., Borries, M., Busch, H., Magenau, J., Reddy, P., Labopin, M., and Antin, J.H., et al.
- Abstract
Contains fulltext : 190745.pdf (publisher's version ) (Closed access), Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD(+) leukemia cells. This synergized with the allogeneic CD8(+) T cell response, leading to long-term survival in six mouse models of FLT3-ITD(+) AML. Sorafenib-related IL-15 production caused an increase in CD8(+)CD107a(+)IFN-gamma(+) T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD(+) AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8(+) T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.
- Published
- 2018
5. Analysis of the combinatorial effect of cisplatin and VE-821 on a large panel of tumor cell lines
- Author
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Chakrabarti, A., primary, Feger, D., additional, Boehmer, K., additional, Umber, S., additional, Birkle, M., additional, Siedentopf, O., additional, and Ehlert, J., additional
- Published
- 2016
- Full Text
- View/download PDF
6. COMORBIDITIES AND SAFETY EVENTS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS.
- Author
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Krueger, W., Feger, D., Friedman, A., Doan, T., and D'silva, K.
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- 2023
- Full Text
- View/download PDF
7. 144 - Analysis of the combinatorial effect of cisplatin and VE-821 on a large panel of tumor cell lines
- Author
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Chakrabarti, A., Feger, D., Boehmer, K., Umber, S., Birkle, M., Siedentopf, O., and Ehlert, J.
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- 2016
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8. 173 Analysis of Cellular Kinase Activity of Resistance-related EGFR Mutants Using Transmembrane-Domain (TMD) Activated Kinase Variants
- Author
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Weber, H., primary, Müller, D., additional, Totzke, F., additional, Müller, M., additional, Siedentopf, O., additional, Kubbutat, M.H.G., additional, Graeser, R., additional, Feger, D., additional, Schaechtele, C., additional, and Ehlert, J.E., additional
- Published
- 2012
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9. Rehabilitation nach Mammakarzinom
- Author
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Feger, D., primary and Thomeit, W., additional
- Published
- 2003
- Full Text
- View/download PDF
10. A simple and efficient thermal link assembly for cryocoolers
- Author
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Ravex, A, primary, Feger, D, additional, and Duband, L, additional
- Published
- 1999
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11. Der Besitz der Urklöster am Dinkelberg
- Author
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Feger, D.
- Published
- 1938
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12. The Bissell Truck. MEMPHIS AND CHARLESTON RAILROAD OFFICE, MEMPHIS, July 17th, 1860.
- Author
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FEGER, D. H.
- Published
- 1860
13. Liquid Mixing on Falling Films: Marker-Free, Molecule-Sensitive 3D Mapping Using Raman Imaging.
- Author
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Nachtmann M, Feger D, Wühler F, Rädle M, and Scholl S
- Subjects
- Diagnostic Imaging, Motion Pictures
- Abstract
Following up on a proof of concept, this publication presents a new method for mixing mapping on falling liquid films. On falling liquid films, different surfaces, plain or structured, are common. Regarding mixing of different components, the surface has a significant effect on its capabilities and performance. The presented approach combines marker-free and molecule-sensitive measurements with cross-section mapping to emphasize the mixing capabilities of different surfaces. As an example of the mixing capabilities on falling films, the mixing of sodium sulfate with tap water is presented, followed by a comparison between a plain surface and a pillow plate. The method relies upon point-by-point Raman imaging with a custom-built high-working-distance, low-depth-of-focus probe. To compensate for the long-time measurements, the continuous plant is in its steady state, which means the local mixing state is constant, and the differences are based on the liquids' position on the falling film, not on time. Starting with two separate streams, the mixing progresses by falling down the surface. In conclusion, Raman imaging is capable of monitoring mixing without any film disturbance and provides detailed information on liquid flow in falling films.
- Published
- 2023
- Full Text
- View/download PDF
14. Associations between circulating cell-free mitochondrial DNA, inflammatory markers, and cognitive and physical outcomes in community dwelling older adults.
- Author
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Nidadavolu LS, Feger D, Chen D, Wu Y, Grodstein F, Gross AL, Bennett DA, Walston JD, Oh ES, and Abadir PM
- Abstract
Background: Dementia and frailty are common age-related syndromes often linked to chronic inflammation. Identifying the biological factors and pathways that contribute to chronic inflammation is crucial for developing new therapeutic targets. Circulating cell-free mitochondrial DNA (ccf-mtDNA) has been proposed as an immune stimulator and potential predictor of mortality in acute illnesses. Dementia and frailty are both associated with mitochondrial dysfunction, impaired cellular energetics, and cell death. The size and abundance of ccf-mtDNA fragments may indicate the mechanism of cell death: long fragments typically result from necrosis, while short fragments arise from apoptosis. We hypothesize that increased levels of necrosis-associated long ccf-mtDNA fragments and inflammatory markers in serum are linked to declines in cognitive and physical function, as well as increased mortality risk., Results: Our study of 672 community-dwelling older adults revealed that inflammatory markers (C-Reactive Protein, soluble tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 [sTNFR1], and interleukin-6 [IL-6]) positively correlated with ccf-mtDNA levels in serum. Although cross-sectional analysis revealed no significant associations between short and long ccf-mtDNA fragments, longitudinal analysis demonstrated a connection between higher long ccf-mtDNA fragments (necrosis-associated) and worsening composite gait scores over time. Additionally, increased mortality risk was observed only in individuals with elevated sTNFR1 levels., Conclusion: In a community dwelling cohort of older adults, there are cross-sectional and longitudinal associations between ccf-mtDNA and sTNFR1 with impaired physical and cognitive function and increased hazard of death. This work suggests a role for long ccf-mtDNA as a blood-based marker predictive of future physical decline., (© 2023. The Author(s).)
- Published
- 2023
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15. Markedly divergent effects of Ouabain on a Temozolomide-resistant (T98G) vs. a Temozolomide-sensitive (LN229) Glioblastoma cell line.
- Author
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Weidemann H, Feger D, Ehlert JE, Menger MM, and Krempien RC
- Abstract
Background: Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor prognosis. GMB are highly recurrent mainly because of radio- and chemoresistance. Radiotherapy with Temozolomide (TMZ) is until today the golden standard adjuvant therapy, however, the optimal treatment of recurrent glioblastoma remains controversial. Ouabain belongs to the Cardiotonic Steroids (CTS) the natural ligands of the Na/K-ATPase (NKA). It is established that the NKA represents a signal transducer with either stimulating or inhibiting cell growth, apoptosis, migration and angiogenesis. Over the last decade evidence grew that CTS have anti-tumor properties especially in GBM., Aim: Proceeding from recent studies we wanted to further demonstrate a divergent effect of Ouabain on a TMZ-resistant (T98G) as compared to a TMZ-sensitive (LN229) GBM cell line., Methods: We analyzed the effect of Ouabain on cell migration and plasma cell membrane potential (PCMP) in the LN229 and T98G GBM cell line as well as underlying mechanisms (Bcl-2 and p-Akt/pan-Akt expression). Moreover, we analyzed the anti-angiogenic effect of Ouabain on human umbilical vein endothelial cells (HUVECs)., Results: T98G cells showed a significant inhibition of cell migration and a significant depolarization of the PCMP at similar Ouabain concentrations (IC50 = 1.67 × 10
-7 M) resp. (IC50 = 2.72 × 10-7 M) with a strong inverse correlation (R2 = 0.95). In contrast, LN229 cells did not respond to Ouabain in these assays at all. Similarly, only T98G but not LN229 cells revealed Bcl-2 down-regulation at nanomolar Ouabain concentrations. This unique response to Ouabain is associated with a down-regulation of pan-Akt in T98G cells 24 h after Ouabain (1.0 × 10-6 M) treatment. For the first time, the anti-angiogenic effect of Ouabain on HUVEC cells (IC50 = 5.49 × 10-8 M) was demonstrated which correlated strongly with the anti-migratory effect (R2 = 0.85)., Conclusion: The TMZ-resistant T98G cell line as compared to the TMZ-sensitive LN229 cell line shows a high sensitivity towards Ouabain. We consider it as a promising new compound especially in recurrent GBM to overcome the resistance to TMZ and irradiation., (© 2023. The Author(s).)- Published
- 2023
- Full Text
- View/download PDF
16. Marker-Free, Molecule Sensitive Mapping of Disturbed Falling Fluid Films Using Raman Imaging.
- Author
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Nachtmann M, Feger D, Sold S, Wühler F, Scholl S, and Rädle M
- Subjects
- Film Dosimetry, Molecular Structure, Diagnostic Imaging, Spectrum Analysis, Raman
- Abstract
Technical liquid flow films are the basic arrangement for gas fluid transitions of all kinds and are the basis of many chemical processes, such as columns, evaporators, dryers, and different other kinds of fluid/fluid separation units. This publication presents a new method for molecule sensitive, non-contact, and marker-free localized concentration mapping in vertical falling films. Using Raman spectroscopy, no label or marker is needed for the detection of the local composition in liquid mixtures. In the presented cases, the film mapping of sodium sulfate in water on a plain surface as well as an added artificial streaming disruptor with the shape of a small pyramid is scanned in three dimensions. The results show, as a prove of concept, a clear detectable spectroscopic difference between air, back plate, and sodium sulfate for every local point in all three dimensions. In conclusion, contactless Raman scanning on falling films for liquid mapping is realizable without any mechanical film interaction caused by the measuring probe. Surface gloss or optical reflections from a metallic back plate are suppressed by using only inelastic light scattering and the mathematical removal of background noise.
- Published
- 2022
- Full Text
- View/download PDF
17. Circulating Cell-Free Genomic DNA Is Associated with an Increased Risk of Dementia and with Change in Cognitive and Physical Function.
- Author
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Nidadavolu LS, Feger D, Wu Y, Grodstein F, Gross AL, Bennett DA, Walston JD, Oh ES, and Abadir PM
- Subjects
- Aged, Cognition physiology, Genomics, Humans, Cell-Free Nucleic Acids, Cognitive Dysfunction epidemiology, Cognitive Dysfunction genetics, Dementia epidemiology, Dementia genetics, Frailty psychology
- Abstract
Background: Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA)., Objective: The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) is associated with physical and cognitive decline in older adults., Methods: We used serum from 631 community-dwelling individuals from the Religious Orders Study or Rush Memory and Aging Project who were without cognitive impairment at baseline. ccf-gDNA fragments in serum were quantified using digital PCR. An array of cognitive and physical traits, risk of dementia, global cognition, and frailty at or nearest the time of blood draw were regressed on ccf-DNA, with adjustment for age, sex, race, and education., Results: Cross-sectionally, higher ccf-gDNA levels were associated with lower global cognition score and slower gait speed at the evaluation nearest to blood draw. Higher ccf-gDNA levels were associated with increased odds of incident dementia (OR 1.27, 95% CI 1.05, 1.54). Longitudinally, higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty over eight years of follow up., Conclusion: This study demonstrates that ccf-gDNA fragments have utility for identifying persons at higher risk of developing dementia and worsening cognition and frailty.
- Published
- 2022
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18. Novel SAR for quinazoline inhibitors of EHMT1 and EHMT2.
- Author
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Leenders R, Zijlmans R, van Bree B, van de Sande M, Trivarelli F, Damen E, Wegert A, Müller D, Ehlert JE, Feger D, Heidemann-Dinger C, Kubbutat M, Schächtele C, Lenstra DC, Mecinović J, and Müller G
- Subjects
- Binding Sites, Cell Line, Tumor, Drug Design, Enzyme Inhibitors metabolism, Histocompatibility Antigens genetics, Histocompatibility Antigens metabolism, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Histones metabolism, Humans, Inhibitory Concentration 50, Lysine chemistry, Molecular Docking Simulation, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Point Mutation, Quinazolines chemistry, Quinazolines metabolism, Structure-Activity Relationship, Enzyme Inhibitors chemistry, Histone-Lysine N-Methyltransferase antagonists & inhibitors
- Abstract
Detailed structure activity relationship of two series of quinazoline EHMT1/EHMT2 inhibitors (UNC0224 and UNC0638) have been elaborated. New and active alternatives are presented for the ubiquitous substitution patterns found in literature for the linker to the lysine mimicking region and the lysine mimic itself. These findings could allow for advancing EHMT1/EHMT2 inhibitors of that type beyond tool compounds by fine-tuning physicochemical properties making these inhibitors more drug-like. ., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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19. Erratum: Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.
- Author
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Mathew NR, Baumgartner F, Braun L, O'Sullivan D, Thomas S, Waterhouse M, Müller TA, Hanke K, Taromi S, Apostolova P, Illert AL, Melchinger W, Duquesne S, Schmitt-Graeff A, Osswald L, Yan KL, Weber A, Tugues S, Spath S, Pfeifer D, Follo M, Claus R, Lübbert M, Rummelt C, Bertz H, Wäsch R, Haag J, Schmidts A, Schultheiss M, Bettinger D, Thimme R, Ullrich E, Tanriver Y, Vuong GL, Arnold R, Hemmati P, Wolf D, Ditschkowski M, Jilg C, Wilhelm K, Leiber C, Gerull S, Halter J, Lengerke C, Pabst T, Schroeder T, Kobbe G, Rösler W, Doostkam S, Meckel S, Stabla K, Metzelder SK, Halbach S, Brummer T, Hu Z, Dengjel J, Hackanson B, Schmid C, Holtick U, Scheid C, Spyridonidis A, Stölzel F, Ordemann R, Müller LP, Sicre-de-Fontbrune F, Ihorst G, Kuball J, Ehlert JE, Feger D, Wagner EM, Cahn JY, Schnell J, Kuchenbauer F, Bunjes D, Chakraverty R, Richardson S, Gill S, Kröger N, Ayuk F, Vago L, Ciceri F, Müller AM, Kondo T, Teshima T, Klaeger S, Kuster B, Kim DDH, Weisdorf D, van der Velden W, Dörfel D, Bethge W, Hilgendorf I, Hochhaus A, Andrieux G, Börries M, Busch H, Magenau J, Reddy P, Labopin M, Antin JH, Henden AS, Hill GR, Kennedy GA, Bar M, Sarma A, McLornan D, Mufti G, Oran B, Rezvani K, Shah O, Negrin RS, Nagler A, Prinz M, Burchert A, Neubauer A, Beelen D, Mackensen A, von Bubnoff N, Herr W, Becher B, Socié G, Caligiuri MA, Ruggiero E, Bonini C, Häcker G, Duyster J, Finke J, Pearce E, Blazar BR, and Zeiser R
- Abstract
This corrects the article DOI: 10.1038/nm.4484.
- Published
- 2018
- Full Text
- View/download PDF
20. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.
- Author
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Mathew NR, Baumgartner F, Braun L, O'Sullivan D, Thomas S, Waterhouse M, Müller TA, Hanke K, Taromi S, Apostolova P, Illert AL, Melchinger W, Duquesne S, Schmitt-Graeff A, Osswald L, Yan KL, Weber A, Tugues S, Spath S, Pfeifer D, Follo M, Claus R, Lübbert M, Rummelt C, Bertz H, Wäsch R, Haag J, Schmidts A, Schultheiss M, Bettinger D, Thimme R, Ullrich E, Tanriver Y, Vuong GL, Arnold R, Hemmati P, Wolf D, Ditschkowski M, Jilg C, Wilhelm K, Leiber C, Gerull S, Halter J, Lengerke C, Pabst T, Schroeder T, Kobbe G, Rösler W, Doostkam S, Meckel S, Stabla K, Metzelder SK, Halbach S, Brummer T, Hu Z, Dengjel J, Hackanson B, Schmid C, Holtick U, Scheid C, Spyridonidis A, Stölzel F, Ordemann R, Müller LP, Sicre-de-Fontbrune F, Ihorst G, Kuball J, Ehlert JE, Feger D, Wagner EM, Cahn JY, Schnell J, Kuchenbauer F, Bunjes D, Chakraverty R, Richardson S, Gill S, Kröger N, Ayuk F, Vago L, Ciceri F, Müller AM, Kondo T, Teshima T, Klaeger S, Kuster B, Kim DDH, Weisdorf D, van der Velden W, Dörfel D, Bethge W, Hilgendorf I, Hochhaus A, Andrieux G, Börries M, Busch H, Magenau J, Reddy P, Labopin M, Antin JH, Henden AS, Hill GR, Kennedy GA, Bar M, Sarma A, McLornan D, Mufti G, Oran B, Rezvani K, Shah O, Negrin RS, Nagler A, Prinz M, Burchert A, Neubauer A, Beelen D, Mackensen A, von Bubnoff N, Herr W, Becher B, Socié G, Caligiuri MA, Ruggiero E, Bonini C, Häcker G, Duyster J, Finke J, Pearce E, Blazar BR, and Zeiser R
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, Cellular Reprogramming genetics, Gene Expression Regulation, Neoplastic drug effects, Graft vs Host Disease drug therapy, Graft vs Host Disease genetics, Graft vs Host Disease pathology, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Mice, Sorafenib administration & dosage, Sorafenib adverse effects, Tandem Repeat Sequences genetics, Transplantation, Homologous adverse effects, Activating Transcription Factor 4 genetics, Interferon Regulatory Factor-7 genetics, Interleukin-15 genetics, Leukemia, Myeloid, Acute drug therapy, fms-Like Tyrosine Kinase 3 genetics
- Abstract
Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD
+ leukemia cells. This synergized with the allogeneic CD8+ T cell response, leading to long-term survival in six mouse models of FLT3-ITD+ AML. Sorafenib-related IL-15 production caused an increase in CD8+ CD107a+ IFN-γ+ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD+ AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8+ T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.- Published
- 2018
- Full Text
- View/download PDF
21. Cell lines expressing recombinant transmembrane domain-activated receptor kinases as tools for drug discovery.
- Author
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Weber H, Müller D, Müller M, Ortiz A, Birkle M, Umber S, Ketterer C, Siedentopf O, Feger D, Totzke F, Kubbutat M, Schaechtele C, Ballmer-Hofer K, Ehlert JE, and Graeser R
- Subjects
- Animals, Cell Line, Cell Membrane metabolism, ErbB Receptors genetics, ErbB Receptors metabolism, Humans, Molecular Targeted Therapy, Mutation, Phosphorylation, Protein Kinase Inhibitors pharmacology, Protein Structure, Tertiary, Proto-Oncogene Proteins c-kit genetics, Proto-Oncogene Proteins c-kit metabolism, Proto-Oncogene Proteins c-met antagonists & inhibitors, Proto-Oncogene Proteins c-met genetics, Proto-Oncogene Proteins c-met metabolism, Rats, Receptor Protein-Tyrosine Kinases genetics, Recombinant Proteins genetics, Transfection, Drug Discovery methods, High-Throughput Screening Assays methods, Receptor Protein-Tyrosine Kinases metabolism, Recombinant Proteins metabolism
- Abstract
Many receptor tyrosine kinases (RTKs) represent bona fide drug targets in oncology. Effective compounds are available, but treatment invariably leads to resistance, often due to RTK mutations. The discovery of second-generation inhibitors requires cellular models of resistant RTKs. An approach using artificial transmembrane domains (TMDs) to activate RTKs was explored for the rapid generation of simple, ligand-independent cellular RTK assays, including resistance mutants. The RTKs epidermal growth factor receptor (EGFR), MET, and KIT were chosen in a proof-of-concept study. Their intracellular domains were inserted into a series of expression vectors encoding artificial TMDs, and they were tested for autophosphorylation activity in transient transfection assays. Active constructs could be identified for MET and EGFR, but not for KIT. Rat1 cell pools were generated expressing the MET or EGFR constructs, and their sensitivity to reference tool compounds was compared to that of MKN-45 or A431 cells. A good correlation between natural and recombinant cells led us to build a panel of clinically relevant MET mutant cell pools, based on the wild-type construct, which were then profiled via MET autophosphorylation and soft agar assays. In summary, a platform was established that allows for the rapid generation of cellular models for RTKs and their resistance mutants., (© 2014 Society for Laboratory Automation and Screening.)
- Published
- 2014
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22. Cytotoxic and protein kinase inhibiting nakijiquinones and nakijiquinols from the sponge Dactylospongia metachromia.
- Author
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Daletos G, de Voogd NJ, Müller WE, Wray V, Lin W, Feger D, Kubbutat M, Aly AH, and Proksch P
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Benzoxazoles chemistry, Benzoxazoles pharmacology, Drug Screening Assays, Antitumor, Humans, Inhibitory Concentration 50, Marine Biology, Mice, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Quinones chemistry, Quinones pharmacology, Sesquiterpenes chemistry, Sesquiterpenes pharmacology, Antineoplastic Agents isolation & purification, Benzoxazoles isolation & purification, Porifera chemistry, Protein Kinase Inhibitors isolation & purification, Quinones isolation & purification, Sesquiterpenes isolation & purification
- Abstract
Chemical investigation of the sponge Dactylospongia metachromia afforded five new sesquiterpene aminoquinones (1-5), two new sesquiterpene benzoxazoles (6 and 7), the known analogue 18-hydroxy-5-epi-hyrtiophenol (8), and a known glycerolipid. The structures of all compounds were unambiguously elucidated by one- and two-dimensional NMR and by MS analyses, as well as by comparison with the literature. Compounds 1-5 showed potent cytotoxicity against the mouse lymphoma cell line L5178Y with IC50 values ranging from 1.1 to 3.7 μM. When tested in vitro for their inhibitory potential against 16 different protein kinases, compounds 5, 6, and 8 exhibited the strongest inhibitory activity against ALK, FAK, IGF1-R, SRC, VEGF-R2, Aurora-B, MET wt, and NEK6 kinases (IC50 0.97-8.62 μM).
- Published
- 2014
- Full Text
- View/download PDF
23. Protein kinase and HDAC inhibitors from the endophytic fungus Epicoccum nigrum.
- Author
-
El Amrani M, Lai D, Debbab A, Aly AH, Siems K, Seidel C, Schnekenburger M, Gaigneaux A, Diederich M, Feger D, Lin W, and Proksch P
- Subjects
- Drug Screening Assays, Antitumor, Histone Deacetylase Inhibitors chemistry, Humans, Inhibitory Concentration 50, Molecular Structure, Morocco, Nuclear Magnetic Resonance, Biomolecular, Plant Leaves microbiology, Polyketides chemistry, Protein Kinase Inhibitors chemistry, Protein Kinases, Structure-Activity Relationship, Ascomycota chemistry, Histone Deacetylase Inhibitors isolation & purification, Histone Deacetylase Inhibitors pharmacology, Mentha microbiology, Polyketides isolation & purification, Polyketides pharmacology, Protein Kinase Inhibitors isolation & purification, Protein Kinase Inhibitors pharmacology
- Abstract
A chemical investigation of the endophytic fungus Epicoccum nigrum isolated from leaves of Mentha suaveolens collected in Morocco resulted in the isolation of five new polyketides, epicocconigrones A and B (1 and 2), 3-methoxyepicoccone B (3), 3-methoxyepicoccone (4), and 2,3,4-trihydroxy-6-(methoxymethyl)-5-methylbenzaldehyde (5), together with five known compounds (6-10). The structures of the new compounds were unambiguously determined by extensive analysis of the 1D and 2D NMR and mass spectroscopic data. Compounds 1 and 10 showed potent inhibition of at least 15 protein kinases with IC50 values ranging from 0.07 to 9.00 μM. Moreover, compounds 1 and 10 inhibited histone deacetylase (HDAC) activities with IC50 values of 9.8 and 14.2 μM, respectively. A preliminary structure-activity relationship is discussed. Interestingly, compounds 1 and 10 exert mainly cytostatic effects in human lymphoma RAJI and U-937 cell lines.
- Published
- 2014
- Full Text
- View/download PDF
24. [Treatment and rehabilitation of paraplegics].
- Author
-
Feger D
- Subjects
- Gymnastics, Humans, Rehabilitation, Vocational, Swimming, Weight Lifting, Paraplegia rehabilitation
- Published
- 1977
25. [The gymnastic treatment of post-traumatic ankylosis].
- Author
-
Feger D
- Subjects
- Ankylosis rehabilitation, Gymnastics, Humans, Ankylosis therapy, Extremities injuries
- Published
- 1970
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