10 results on '"Stückrath I"'
Search Results
2. Characterization of null mutants of the glyoxylate cycle and gluconeogenic enzymes in S. cerevisiae through metabolic network modeling verified by chemostat cultivation.
- Author
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Stückrath, I., Lange, H. C., Kötter, P., van Gulik, W. M., Entian, K.-D., and Heijnen, J. J.
- Published
- 2002
- Full Text
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3. Characterization of null mutants of the glyoxylate cycle and gluconeogenic enzymes in <TOGGLE>S. cerevisiae</TOGGLE> through metabolic network modeling verified by chemostat cultivation
- Author
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Stückrath, I., Lange, H. C., Kötter, P., Gulik, W. M. van, Entian, K.-D., and Heijnen, J. J.
- Abstract
Biomass yields for several null mutants in
Saccharomyces cerevisiae were successfully predicted with a metabolic network model. Energetic parameters of the model were obtained from growth data in C-limited aerobic chemostat cultures of the corresponding wild-type strain, which exhibited aP/O ratio of 1.46, a non-growth-related maintenance of 56 mmol ATP/C-mol biomass/h, and a growth-related requirement of 655 mmol ATP/C-mol biomass. Biomass yields and carbon uptake rates were modeled for different mutants incapacitated in their glyoxylate cycle and their gluconeogenesis. Biomass yields were calculated for different feed ratios of glucose to ethanol, and decreases for higher ethanol fractions were correctly predicted for mutants with deletions of the malate synthase, the isocitrate lyase, or the phosphoenolpyruvate carboxykinase. The growth of the fructose- 1,6-bisphosphatase deletion mutant was anticipated less accurate, but the tendency was modeled correctly. © 2002 John Wiley & Sons, Inc. Biotechnol Bioeng 77: 6172, 2002.- Published
- 2002
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4. Aberrant plasma levels of circulating miR-16, miR-107, miR-130a and miR-146a are associated with lymph node metastasis and receptor status of breast cancer patients.
- Author
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Stückrath I, Rack B, Janni W, Jäger B, Pantel K, and Schwarzenbach H
- Subjects
- Adult, Aged, Breast Neoplasms blood, Breast Neoplasms metabolism, Disease Progression, Female, Humans, Lymphatic Metastasis, Middle Aged, Real-Time Polymerase Chain Reaction, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Breast Neoplasms pathology, MicroRNAs blood
- Abstract
Within the multicenter SUCCESS trial, we investigated the association of plasma microRNAs with different subtypes of invasive breast cancer.Six miRs (miR-16, miR-27a, miR-107, miR-130a, miR-132 and miR-146a) were selected from microarray profiling and further validated in plasma of 111 breast cancer patients before and after chemotherapy and 46 healthy women by quantitative real-time PCR.Plasma levels of miR-16 (p = 0.0001), miR-27a (p = 0.039) and miR-132 (p = 0.020) were higher in breast cancer patients before chemotherapy than healthy women. With the exception of miR-16, the increased levels of miR-27a (p = 0.035) and miR-132 (p = 0.025) decreased after chemotherapy to those observed in healthy women. Levels of miR-16 (p = 0.019), miR-107 (p = 0.036), miR-130a (p = 0.027) and miR-146a (p = 0.047) were different between lymph node -positive and -negative patients, while the levels of miR-130a (p = 0.001) and miR-146a (p = 0.025) also differed between HER2-positive and -negative status. Estrogen-receptor negative tumors displayed higher concentrations of circulating miR-107 than their counterparts (p = 0.035). However, overexpression of miR-107 in MCF-7 cells did not downregulate estrogen receptor protein. Altered expression levels of miR-107 influenced the migration and invasion behavior of MCF-7 and MDA-MB-231 cells.Our data indicate differential concentrations of plasma miR-16, miR-107, miR-130a and miR-146a in different breast cancer subtypes, suggesting a potential role of these miRs in breast cancer biology and tumor progression.
- Published
- 2015
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5. Increased serum levels of circulating exosomal microRNA-373 in receptor-negative breast cancer patients.
- Author
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Eichelser C, Stückrath I, Müller V, Milde-Langosch K, Wikman H, Pantel K, and Schwarzenbach H
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- Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Phytogenic antagonists & inhibitors, Antineoplastic Agents, Phytogenic pharmacology, Apoptosis drug effects, Apoptosis genetics, Biomarkers, Tumor blood, Biomarkers, Tumor genetics, Breast Diseases blood, Breast Diseases genetics, Camptothecin antagonists & inhibitors, Camptothecin pharmacology, Case-Control Studies, Cell Line, Tumor, Cell Movement, Cohort Studies, Exosomes genetics, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, MCF-7 Cells, Middle Aged, Receptors, Estrogen biosynthesis, Receptors, Estrogen genetics, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology, Exosomes metabolism, MicroRNAs blood, Triple Negative Breast Neoplasms blood
- Abstract
In this study, we compared the blood serum levels of circulating cell-free and exosomal microRNAs, and their involvement in the molecular subtypes of breast cancer patients. Our analyses on cell-free miR-101, miR-372 and miR-373 were performed in preoperative blood serum of 168 patients with invasive breast cancer, 19 patients with benign breast diseases and 28 healthy women. MicroRNAs were additionally quantified in exosomes of 50 cancer patients and 12 healthy women from the same cohort. Relative concentrations were measured by quantitative TaqMan MicroRNA assays and correlated to clinicopathological risk factors. The concentrations of cell-free miR-101 (p=0.013) and miR-373 (p=0.024) were significantly different between patients with breast cancer and benign tumors. A prevalence of miR-101, miR-372 and miR-373 were found in exosomes. The levels of circulating exosomal (but not cell-free) miR-373 were higher in triple negative than luminal carcinomas (p=0.027). Also, estrogen-negative (p=0.021) and progesterone-negative (p=0.01) tumors displayed higher concentrations of exosomal miR-373 than patients with hormone-receptor positive tumors. Overexpression of miR-373 by transfection of MCF-7 cells showed downregulated protein expression of the estrogen receptor, and inhibition of apoptosis induced by camptothecin. Our data indicate that serum levels of exosomal miR-373 are linked to triple negative and more aggressive breast carcinomas.
- Published
- 2014
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6. Low levels of cell-free circulating miR-361-3p and miR-625* as blood-based markers for discriminating malignant from benign lung tumors.
- Author
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Roth C, Stückrath I, Pantel K, Izbicki JR, Tachezy M, and Schwarzenbach H
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung surgery, Cell-Free System, Cohort Studies, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Health, Humans, Lung Neoplasms genetics, Lung Neoplasms surgery, MicroRNAs genetics, MicroRNAs metabolism, Middle Aged, Oligonucleotide Array Sequence Analysis, Postoperative Care, Preoperative Care, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, Smad2 Protein metabolism, Smoking genetics, Transforming Growth Factor beta1 genetics, Transforming Growth Factor beta1 metabolism, Biomarkers, Tumor blood, Biomarkers, Tumor genetics, Lung Neoplasms blood, Lung Neoplasms diagnosis, MicroRNAs blood
- Abstract
The high mortality rate of lung cancer patients is mainly due to the late stage at which lung cancer is diagnosed. For effective cancer prevention programs and early diagnosis, better blood-based markers are needed. Hence, blood-based microarray profiling of microRNA (miR) expression was performed in preoperative serum of 21 non-small cell lung cancer (NSCLC) patients and 11 healthy individuals by microfluid biochips containing 1158 different miRs. Two out of the 30 most dysregulated miRs were further validated in serum of 97 NSCLC patients, 20 patients with benign lung diseases and 30 healthy individuals by TaqMan MicroRNA Assays. Microarray profiling showed that miR-361-3p and miR-625* were significantly down-regulated in serum of lung cancer patients. Their further evaluation by quantitative RT-PCR showed that the levels of miR-361-3p and miR-625* were lower in NSCLC than in benign disease (p = 0.0001) and healthy individuals (p = 0.0001, p = 0.0005, respectively). Moreover, the levels of miR-625* were significantly lower in patients with large cell lung cancer (LCLC, p = 0.014) and smoking patients (p = 0.030) than in patients with adenocarcinoma and non-smoking patients, respectively. A rise in the levels of both miRs was observed in the postoperative samples compared with the preoperative levels (p = 0.0001). Functional analyses showed that Smad2 and TGFß1 are not dysregulated by miR-361-3p and miR-625* in the lung cell line A549, respectively. Our present pilot study suggests that miR-361-3p and miR-625* might have a protective influence on the development of NSCLC, and the quantitative assessment of these miRs in blood serum might have diagnostic potential to detect NSCLC, in particular in smokers.
- Published
- 2012
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7. Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer.
- Author
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Sos ML, Fischer S, Ullrich R, Peifer M, Heuckmann JM, Koker M, Heynck S, Stückrath I, Weiss J, Fischer F, Michel K, Goel A, Regales L, Politi KA, Perera S, Getlik M, Heukamp LC, Ansén S, Zander T, Beroukhim R, Kashkar H, Shokat KM, Sellers WR, Rauh D, Orr C, Hoeflich KP, Friedman L, Wong KK, Pao W, and Thomas RK
- Subjects
- Apoptosis drug effects, Cell Line, Tumor, Genotype, Humans, Neoplasms enzymology, Neoplasms pathology, Phosphoinositide-3 Kinase Inhibitors, MAP Kinase Signaling System drug effects, Neoplasms drug therapy, Neoplasms genetics, Phosphatidylinositol 3-Kinases genetics, Protein Kinase Inhibitors pharmacology
- Abstract
In cancer, genetically activated proto-oncogenes often induce "upstream" dependency on the activity of the mutant oncoprotein. Therapeutic inhibition of these activated oncoproteins can induce massive apoptosis of tumor cells, leading to sometimes dramatic tumor regressions in patients. The PI3K and MAPK signaling pathways are central regulators of oncogenic transformation and tumor maintenance. We hypothesized that upstream dependency engages either one of these pathways preferentially to induce "downstream" dependency. Therefore, we analyzed whether downstream pathway dependency segregates by genetic aberrations upstream in lung cancer cell lines. Here, we show by systematically linking drug response to genomic aberrations in non-small-cell lung cancer, as well as in cell lines of other tumor types and in a series of in vivo cancer models, that tumors with genetically activated receptor tyrosine kinases depend on PI3K signaling, whereas tumors with mutations in the RAS/RAF axis depend on MAPK signaling. However, efficacy of downstream pathway inhibition was limited by release of negative feedback loops on the reciprocal pathway. By contrast, combined blockade of both pathways was able to overcome the reciprocal pathway activation induced by inhibitor-mediated release of negative feedback loops and resulted in a significant increase in apoptosis and tumor shrinkage. Thus, by using a systematic chemo-genomics approach, we identify genetic lesions connected to PI3K and MAPK pathway activation and provide a rationale for combined inhibition of both pathways. Our findings may have implications for patient stratification in clinical trials.
- Published
- 2009
- Full Text
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8. Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions.
- Author
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Sos ML, Michel K, Zander T, Weiss J, Frommolt P, Peifer M, Li D, Ullrich R, Koker M, Fischer F, Shimamura T, Rauh D, Mermel C, Fischer S, Stückrath I, Heynck S, Beroukhim R, Lin W, Winckler W, Shah K, LaFramboise T, Moriarty WF, Hanna M, Tolosi L, Rahnenführer J, Verhaak R, Chiang D, Getz G, Hellmich M, Wolf J, Girard L, Peyton M, Weir BA, Chen TH, Greulich H, Barretina J, Shapiro GI, Garraway LA, Gazdar AF, Minna JD, Meyerson M, Wong KK, and Thomas RK
- Subjects
- Animals, Antineoplastic Agents pharmacology, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Drug Evaluation, Preclinical, ErbB Receptors chemistry, ErbB Receptors genetics, ErbB Receptors metabolism, Gene Expression Profiling, Humans, Magnetic Resonance Imaging, Mice, Models, Molecular, Mutation genetics, Phenotype, Protein Structure, Tertiary, Substrate Specificity, Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics
- Abstract
Somatic genetic alterations in cancers have been linked with response to targeted therapeutics by creation of specific dependency on activated oncogenic signaling pathways. However, no tools currently exist to systematically connect such genetic lesions to therapeutic vulnerability. We have therefore developed a genomics approach to identify lesions associated with therapeutically relevant oncogene dependency. Using integrated genomic profiling, we have demonstrated that the genomes of a large panel of human non-small cell lung cancer (NSCLC) cell lines are highly representative of those of primary NSCLC tumors. Using cell-based compound screening coupled with diverse computational approaches to integrate orthogonal genomic and biochemical data sets, we identified molecular and genomic predictors of therapeutic response to clinically relevant compounds. Using this approach, we showed that v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations confer enhanced Hsp90 dependency and validated this finding in mice with KRAS-driven lung adenocarcinoma, as these mice exhibited dramatic tumor regression when treated with an Hsp90 inhibitor. In addition, we found that cells with copy number enhancement of v-abl Abelson murine leukemia viral oncogene homolog 2 (ABL2) and ephrin receptor kinase and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) kinase family genes were exquisitely sensitive to treatment with the SRC/ABL inhibitor dasatinib, both in vitro and when it xenografted into mice. Thus, genomically annotated cell-line collections may help translate cancer genomics information into clinical practice by defining critical pathway dependencies amenable to therapeutic inhibition.
- Published
- 2009
- Full Text
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9. Estimation of biomass concentrations in fermentation processes for recombinant protein production.
- Author
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Jenzsch M, Simutis R, Eisbrenner G, Stückrath I, and Lübbert A
- Subjects
- Artificial Intelligence, Cell Proliferation, Computer Simulation, Escherichia coli cytology, Escherichia coli genetics, Escherichia coli Proteins genetics, Fermentation physiology, Neural Networks, Computer, Pattern Recognition, Automated methods, Protein Engineering methods, Algorithms, Colony Count, Microbial methods, Escherichia coli growth & development, Escherichia coli metabolism, Escherichia coli Proteins metabolism, Models, Biological, Recombinant Proteins biosynthesis
- Abstract
Online biomass estimation for bioprocess supervision and control purposes is addressed. As the biomass concentration cannot be measured online during the production to sufficient accuracy, indirect measurement techniques are required. Here we compare several possibilities for the concrete case of recombinant protein production with genetically modified Escherichia coli bacteria and perform a ranking. At normal process operation, the best estimates can be obtained with artificial neural networks (ANNs). When they cannot be employed, statistical correlation techniques can be used such as multivariate regression techniques. Simple model-based techniques, e.g., those based on the Luedeking/Piret-type are not as accurate as the ANN approach; however, they are very robust. Techniques based on principal component analysis can be used to recognize abnormal cultivation behavior. For the cases investigated, a complete ranking list of the methods is given in terms of the root-mean-square error of the estimates. All techniques examined are in line with the recommendations expressed in the process analytical technology (PAT)-initiative of the FDA.
- Published
- 2006
- Full Text
- View/download PDF
10. Physiological characterisation of a pyruvate-carboxylase-negative Saccharomyces cerevisiae mutant in batch and chemostat cultures.
- Author
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de Jong-Gubbels P, Bauer J, Niederberger P, Stückrath I, Kötter P, van Dijken JP, and Pronk JT
- Subjects
- Ammonia metabolism, Aspartic Acid metabolism, Culture Media, Ethanol metabolism, Gene Expression Regulation, Fungal, Glyoxylates metabolism, Phenotype, Glucose metabolism, Mutation, Pyruvate Carboxylase genetics, Saccharomyces cerevisiae physiology
- Abstract
A prototrophic pyruvate-carboxylase-negative (Pyc-) mutant was constructed by deleting the PYC1 and PYC2 genes in a CEN.PK strain of Saccharomyces cerevisiae. Its maximum specific growth rate on ethanol was identical to that of the isogenic wild type but it was unable to grow in batch cultures in glucose-ammonia media. Consistent with earlier reports, growth on glucose could be restored by supplying aspartate as a sole nitrogen source. Ethanol could not replace aspartate as a source of oxaloacetate in batch cultures. To investigate whether alleviation of glucose repression allowed expression of alternative pathways for oxaloacetate synthesis, the Pyc- strain and an isogenic wild-type strain were grown in aerobic carbon-limited chemostat cultures at a dilution rate of 0.10 h-1 on mixtures of glucose and ethanol. In such mixed-substrate chemostat cultures of the Pyc- strain, steady-state growth could only be obtained when ethanol contributed 30% or more of the substrate carbon in the feed. Attempts to further decrease the ethanol content of the feed invariably resulted in washout. In Pyc- as well as in wild-type cultures, levels of isocitrate lyase, malate synthase and phospho-enol-pyruvate carboxykinase in cell extracts decreased with a decreasing ethanol content in the feed. Nevertheless, at the lowest ethanol fraction that supported growth of the Pyc- mutant, activities of the glyoxylate cycle enzymes in cell extracts were still sufficient to meet the requirement for C4-compounds in biomass synthesis. This suggests that factors other than glucose repression of alternative routes for oxaloacetate synthesis prevent growth of Pyc- mutants on glucose.
- Published
- 1998
- Full Text
- View/download PDF
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