Dagmar Beier

University Hospital RWTH Aachen, Aachen, North Rhine-Westphalia, Germany

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Publications (66)227.79 Total impact

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    ABSTRACT: Glioblastoma remains a tumor with a dismal prognosis because of failure of current treatment. Glioblastoma cells with stem cell (GSC) properties survive chemotherapy and give rise to tumor recurrences that invariably result in the death of the patients. Here we summarize the current knowledge on chemoresistance of malignant glioma with a strong focus on GSC. Chemoresistant GSC are the most likely cause of tumor recurrence, but it remains controversial if GSC and under which conditions GSC are more chemoresistant than non-GSC within the tumor. Regardless of this uncertainty, the chemoresistance varies and it is mainly mediated by intrinsic factors. O6-methyl-guanidine methyltransferase (MGMT) remains the most potent mediator of chemoresistance, but disturbed mismatch repair system and multidrug resistance proteins contribute substantially. However, the intrinsic resistance by MGMT expression is regulated by extrinsic factors like hypoxia increasing MGMT expression and thereby resistance to alkylating chemotherapy. The search of new biomarkers helping to predict the tumor response to chemotherapy is ongoing and will complement the already known markers like MGMT.
    Advances in Experimental Medicine and Biology 01/2015; 853:111-38. DOI:10.1007/978-3-319-16537-0_7 · 2.01 Impact Factor
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    ABSTRACT: Phase variation of hypermutable simple sequence repeats (SSRs) is a widespread and stochastic mechanism to generate phenotypic variation within a population and thereby contributes to host adaptation of bacterial pathogens. Although several examples of SSRs that affect transcription or coding potential have been reported, we now show that a SSR also impacts small RNA-mediated posttranscriptional regulation. Based on in vitro and in vivo analyses, we demonstrate that a variable homopolymeric G-repeat in the leader of the TlpB chemotaxis receptor mRNA of the human pathogen Helicobacter pylori is directly targeted by a small RNA (sRNA), RepG (Regulator of polymeric G-repeats). Whereas RepG sRNA is highly conserved, the tlpB G-repeat length varies among diverse H. pylori strains, resulting in strain-specific RepG-mediated tlpB regulation. Based on modification of the G-repeat length within one strain, we demonstrate that the G-repeat length determines posttranscriptional regulation and can mediate both repression and activation of tlpB through RepG. In vitro translation assays show that this regulation occurs at the translational level and that RepG influences tlpB translation dependent on the G-repeat length. In contrast to the digital ON-OFF switches through frame-shift mutations within coding sequences, such modulation of posttranscriptional regulation allows for a gradual control of gene expression. This connection to sRNA-mediated posttranscriptional regulation might also apply to other genes with SSRs, which could be targeting sites of cis- or trans-encoded sRNAs, and thereby could facilitate host adaptation through sRNA-mediated fine-tuning of virulence gene expression.
    Proceedings of the National Academy of Sciences 01/2014; 111(4):E501-10. DOI:10.1073/pnas.1315152111 · 9.81 Impact Factor
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    ABSTRACT: The brain cancer stem cell (CSC) model describes a small subset of glioma cells as being responsible for tumor initiation, conferring therapy resistance and tumor recurrence. In brain CSC, the PI3-K/AKT and the RAS/mitogen activated protein kinase (MAPK) pathways are found to be activated. In consequence, the human transcription factor YB-1, knowing to be responsible for the emergence of drug resistance and driving adenoviral replication, is phosphorylated and activated. With this knowledge, YB-1 was established in the past as a biomarker for disease progression and prognosis. This study determines the expression of YB-1 in glioblastoma (GBM) specimen in vivo and in brain CSC lines. In addition, the capacity of Ad-Delo3-RGD, an YB-1 dependent oncolytic adenovirus, to eradicate CSC was evaluated both in vitro and in vivo. YB-1 expression was investigated by immunoblot and immuno-histochemistry. In vitro, viral replication as well as the capacity of Ad-Delo3-RGD to replicate in and, in consequence, to kill CSC was determined by real-time PCR and clonogenic dilution assays. In vivo, Ad-Delo3-RGD-mediated tumor growth inhibition was evaluated in an orthotopic mouse GBM model. Safety and specificity of Ad-Delo3-RGD were investigated in immortalized human astrocytes and by siRNA-mediated downregulation of YB-1. YB-1 is highly expressed in brain CSC lines and in GBM specimen. Efficient viral replication in and virus-mediated lysis of CSC was observed in vitro. Experiments addressing safety aspects of Ad-Delo3-RGD showed that (i) virus production in human astrocytes was significantly reduced compared to wild type adenovirus (Ad-WT) and (ii) knockdown of YB-1 significantly reduced virus replication. Mice harboring othotopic GBM developed from a temozolomide (TMZ)-resistant GBM derived CSC line which was intratumorally injected with Ad-Delo3-RGD survived significantly longer than mice receiving PBS-injections or TMZ treatment. The results of this study supported YB-1 based virotherapy as an attractive therapeutic strategy for GBM treatment which will be exploited further in multimodal treatment concepts.
    Journal of Translational Medicine 09/2013; 11(1):216. DOI:10.1186/1479-5876-11-216 · 3.99 Impact Factor
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    ABSTRACT: HP1043 of Helicobacter pylori is an orphan response regulator with a highly degenerate receiver sequence incapable of phosphorylation which is essential for cell viability. In contrast, the orthologous response regulator protein of Helicobacter pullorum, an enterohepatic Helicobacter species mainly isolated from poultry, harbours a consensus receiver sequence and is associated with a cognate histidine kinase. Here we show that this two-component system of H. pullorum, denoted HPMG439/HPMG440, is involved in the control of nitrogen metabolism by regulating the expression of glutamate dehydrogenase, an AmtB ammonium transporter and a PII protein. However, the role of the response regulator HPMG439 is not restricted to nitrogen regulation since, in contrast to the histidine kinase HPMG440, HPMG439 is essential for growth of H. pullorum under nutrient rich conditions.
    Microbiology 03/2013; DOI:10.1099/mic.0.066548-0 · 2.84 Impact Factor
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    ABSTRACT: Immune cell infiltration varies widely between different glioblastomas (GBMs). The underlying mechanism, however, remains unknown. Here we show that TGF-beta regulates proliferation, migration, and tumorigenicity of mesenchymal GBM cancer stem cells (CSCs) in vivo and in vitro. In contrast, proneural GBM CSCs resisted TGF-beta due to TGFR2 deficiency. In vivo, a substantially increased infiltration of immune cells was observed in mesenchymal GBMs, while immune infiltrates were rare in proneural GBMs. On a functional level, proneural CSC lines caused a significantly stronger TGF-beta-dependent suppression of NKG2D expression on CD8(+) T and NK cells in vitro providing a mechanistic explanation for the reduced immune infiltration of proneural GBMs. Thus, the molecular subtype of CSCs TGF-beta-dependently contributes to the degree of immune infiltration.
    Stem cells and development 06/2012; 21(15):2753-61. DOI:10.1089/scd.2011.0660 · 4.20 Impact Factor
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    ABSTRACT: Ten years after the first description of cancer stem cells (CSCs) in glioblastoma (GBM), the initial concept of CSC has been challenged and our understanding of cellular heterogeneity within malignant brain tumors became more complex. The increasing knowledge on CSC also influences preclinical research and clinical practice. This review therefore describes current concepts and controversies on CSC in GBM and summarizes the recent progress how the CSC hypothesis is about to translate into preclinical and clinical application.
    Cancer letters 06/2012; DOI:10.1016/j.canlet.2012.05.033 · 5.02 Impact Factor
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    ABSTRACT: The effectiveness of temozolomide (TMZ) dosing schemes and the "rechallenge" of recurrent glioblastoma (GBM) with TMZ are controversial. We therefore compared the efficacy of different TMZ dosing schemes against GBM cancer stem cell (CSC) lines in vitro. In O(6)-methyl-guanidine-methyl-transferase (MGMT)-negative CSC lines, all schedules (1 day on/27 days off, 5 days on/23 days off, 7 days on/7 days off, 21 days on/7 days off, continuous low-dose TMZ) depleted clonogenic cells. In TMZ-resistant CSC lines, the 7 days on/7 days off scheme showed higher toxicity as compared with the other schemes. However, clinically feasible concentrations remained ineffective in highly resistant CSC lines. In addition, none of the schedules induced long-term depletion of clonogenic cells even at the highest concentrations (up to 250 μM). After sublethal TMZ treatment for 5 days, TMZ rechallenge of recovering CSC lines remained effective. Our data advocate CSC lines as in vitro model to address clinical questions. Using this model, our data suggest the effectiveness of TMZ in MGMT-negative CSC lines and support the concept of TMZ rechallenge. The 7 days on/7 days off scheme consistently showed the best activity of all schedules in TMZ-resistant CSC lines.
    Journal of Neuro-Oncology 04/2012; 109(1):45-52. DOI:10.1007/s11060-012-0878-4 · 2.79 Impact Factor
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    ABSTRACT: The noninvasive tracking of glioblastoma cancer stem cells (CSCs) in vivo constitutes a prerequisite for the development of CSC-specific therapies. Therefore, as a pilot study to identify CSC biomarkers for clinical magnetic resonance spectroscopy, 10 CSC lines were investigated using high-resolution (1)H-nuclear magnetic resonance ((1)H-NMR) spectroscopy at 600 and 800 MHz (14.4 and 18.8 T) under reproducible in vitro conditions. The spectra were analyzed using principal component analysis (PCA), and spectral regions of high variability were evaluated regarding correlations to stem cell-related properties (clonogenic index and CD133 positivity) and cell death. PCA revealed that duplicates of CSC lines clustered together suggesting a characteristic (1)H-NMR pattern of each CSC line. PCA enabled discrimination between samples with high and low clonogenicity, that is, clustering according to one of the hallmarks of stemness in samples with high viability. High/moderate correlations to clonogenicity and CD133 were found in spectral regions with high variability. In contrast, the mobile lipid signal at 1.28 ppm correlated to cell death, but not to stemness, as published previously for neural progenitor cells. In conclusion, our exploratory study demonstrates the correlation of specific resonances within (1)H-NMR spectra with stem cell properties and advocates the use of the 1.28 ppm resonance as biomarker for cell death also in CSCs.
    Stem cells and development 12/2011; 20(12):2189-95. DOI:10.1089/scd.2010.0567 · 4.20 Impact Factor
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    ABSTRACT: Glioblastomas (GBM) are a paradigm for the investigation of cancer stem cells (CSC) in solid malignancies. The susceptibility of GBM CSC to standard chemotherapeutic drugs is controversial as the existing literature presents conflicting experimental data. Here, we summarize the experimental evidence on the resistance of GBM CSC to alkylating chemotherapeutic agents, with a special focus on temozolomide (TMZ). The data suggests that CSC are neither resistant nor susceptible to chemotherapy per se. Detoxifying proteins such as O6-methylguanine-DNA-methyltransferase (MGMT) confer a strong intrinsic resistance to CSC in all studies. Extrinsic factors may also contribute to the resistance of CSC to TMZ. These may include TMZ concentrations in the brain parenchyma, TMZ dosing schemes, hypoxic microenvironments, niche factors, and the re-acquisition of stem cell properties by non-stem cells. Thus, the interaction of CSC and chemotherapy is more complex than may be expected and it is necessary to consider these factors in order to overcome chemoresistance in the patient.
    Molecular Cancer 10/2011; 10:128. DOI:10.1186/1476-4598-10-128 · 5.40 Impact Factor
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    ABSTRACT: Cancer stem cells or cancer initiating cells are believed to contribute to cancer recurrence after therapy. MicroRNAs (miRNAs) are short RNA molecules with fundamental roles in gene regulation. The role of miRNAs in cancer stem cells is only poorly understood. Here, we report miRNA expression profiles of glioblastoma stem cell-containing CD133(+) cell populations. We find that miR-9, miR-9(*) (referred to as miR-9/9(*)), miR-17 and miR-106b are highly abundant in CD133(+) cells. Furthermore, inhibition of miR-9/9(*) or miR-17 leads to reduced neurosphere formation and stimulates cell differentiation. Calmodulin-binding transcription activator 1 (CAMTA1) is a putative transcription factor, which induces the expression of the anti-proliferative cardiac hormone natriuretic peptide A (NPPA). We identify CAMTA1 as an miR-9/9(*) and miR-17 target. CAMTA1 expression leads to reduced neurosphere formation and tumour growth in nude mice, suggesting that CAMTA1 can function as tumour suppressor. Consistently, CAMTA1 and NPPA expression correlate with patient survival. Our findings could provide a basis for novel strategies of glioblastoma therapy.
    The EMBO Journal 08/2011; 30(20):4309-22. DOI:10.1038/emboj.2011.301 · 10.75 Impact Factor
  • Christoph P Beier, Dagmar Beier
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    ABSTRACT: Glioblastomas (GBM) are paradigmatic for the investigation of cancer stem cells (CSC) in solid tumors. Recently, the discovery of CD133- CSC in addition to CD133+ CSC has substantially added to our understanding of the complexity of GBM CSC. This review gives an overview on our current knowledge on CD133- cells in GBM and describes five different hypothesizes on the nature of CD133- cells in GBM. In addition, we summarize the current knowledge on tumorigenic CD133- CSC, list available markers, describe the current controversies on the origin of CD133- CSC, and discuss how the heterogeneity of CSC may correspond to the molecular heterogeneity of GBM.
    Frontiers in bioscience (Elite edition) 01/2011; 3:701-10. DOI:10.2741/e280
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    ABSTRACT: Glioblastoma multiforme (GBM) is paradigmatic for the investigation of cancer stem cells (CSC) in solid tumors. The CSC hypothesis implies that tumors are maintained by a rare subpopulation of CSC that gives rise to rapidly proliferating progenitor cells. Although the presence of progenitor cells is crucial for the CSC hypothesis, progenitor cells derived from GBM CSC are yet uncharacterized. We analyzed human CD133(+) CSC lines that were directly derived from CD133(+) primary astrocytic GBM. In these CSC lines, CD133(+)/telomerase(high) CSC give rise to non-tumorigenic, CD133(-)/telomerase(low) progenitor cells. The proliferation of the progenitor cell population results in significant telomere shortening as compared to the CD133(+) compartment comprising CSC. The average difference in telomere length as determined by a modified multi-color flow fluorescent in situ hybridization was 320 bp corresponding to 4-8 cell divisions. Taken together, we demonstrate that CD133(+) primary astrocytic GBM comprise proliferating, CD133(-)/telomerase(low) progenitor cell population characterized by low telomerase activity and shortened telomeres as compared to CSC.
    Cellular and Molecular Neurobiology 11/2010; 31(3):337-43. DOI:10.1007/s10571-010-9627-4 · 2.20 Impact Factor
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    ABSTRACT: Most members of the phylum Firmicutes harbour a two-component system (TCS), LiaSR, which is involved in the response to cell envelope stress elicited most notably by inhibitors of the lipid II cycle. In all LiaSR systems studied in detail, LiaSR-mediated signal transduction has been shown to be negatively controlled by a membrane protein, LiaF, encoded upstream of liaSR. In this study we have analysed the LiaSR orthologue of Listeria monocytogenes (LiaSR(Lm)). Whole-genome transcriptional profiling indicated that activation of LiaSR(Lm) results in a remodelling of the cell envelope via the massive upregulation of membrane-associated and extracytoplasmic proteins in the presence of inducing stimuli. As shown for other LiaSR TCSs, LiaSR(Lm) is activated by cell wall-active antibiotics. We demonstrate that the level of phosphorylated LiaR(Lm), which is required for the induction of the LiaSR(Lm) regulon, is controlled by the interplay between the histidine kinase and phosphatase activities of the bifunctional sensor protein LiaS(Lm). Our data suggest that the phosphatase activity of LiaS(Lm) is stimulated by LiaF(Lm) in the absence of cell envelope stress.
    Microbiology 10/2010; 157(Pt 2):373-86. DOI:10.1099/mic.0.044776-0 · 2.84 Impact Factor
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    ABSTRACT: Glioblastoma multiforme (GBM) is paradigmatic for the investigation of cancer stem cells (CSC) in solid tumors. Growing evidence suggests that different types of CSC lead to the formation of GBM. This has prompted the present comparison of gene expression profiles between 17 GBM CSC lines and their different putative founder cells. Using a newly derived 24-gene signature, we can now distinguish two subgroups of GBM: Type I CSC lines display "proneural" signature genes and resemble fetal neural stem cell (fNSC) lines, whereas type II CSC lines show "mesenchymal" transcriptional profiles similar to adult NSC (aNSC) lines. Phenotypically, type I CSC lines are CD133 positive and grow as neurospheres. Type II CSC lines, in contrast, display (semi-)adherent growth and lack CD133 expression. Molecular differences between type I and type II CSC lines include the expression of extracellular matrix molecules and the transcriptional activity of the WNT and the transforming growth factor-beta/bone morphogenetic protein signaling pathways. Importantly, these characteristics were not affected by induced adherence on laminin. Comparing CSC lines with their putative cells of origin, we observed greatly increased proliferation and impaired differentiation capacity in both types of CSC lines but no cancer-associated activation of otherwise silent signaling pathways. Thus, our data suggest that the heterogeneous tumor entity GBM may derive from cells that have preserved or acquired properties of either fNSC or aNSC but lost the corresponding differentiation potential. Moreover, we propose a gene signature that enables the subclassification of GBM according to their putative cells of origin.
    Cancer Research 02/2010; 70(5):2030-40. DOI:10.1158/0008-5472.CAN-09-1707 · 9.28 Impact Factor
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    ABSTRACT: Although trastuzumab (Herceptin) has substantially improved the overall survival of patients with mammary carcinomas, even initially well-responding tumors often become resistant. Because natural killer (NK) cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) is thought to contribute to the therapeutic effects of trastuzumab, we have established a cell culture system to select for ADCC-resistant SK-OV-3 ovarian cancer and MCF7 mammary carcinoma cells. Ovarian cancer cells down-regulated HER2 expression, resulting in a more resistant phenotype. MCF7 breast cancer cells, however, failed to develop resistance in vitro. Instead, treatment with trastuzumab and polyclonal NK cells resulted in the preferential survival of individual sphere-forming cells that displayed a CD44(high)CD24(low) "cancer stem cell-like" phenotype and expressed significantly less HER2 compared with non-stem cells. Likewise, the CD44(high)CD24(low) population was also found to be more immunoresistant in SK-BR3, MDA-MB231, and BT474 breast cancer cell lines. When immunoselected MCF7 cells were then re-expanded, they mostly lost the observed phenotype to regenerate a tumor cell culture that displayed the initial HER2 surface expression and ADCC-susceptibility, but was enriched in CD44(high)CD24(low) cancer stem cells. This translated into increased clonogenicity in vitro and tumorigenicity in vivo. Thus, we provide evidence that the induction of ADCC by trastuzumab and NK cells may spare the actual tumor-initiating cells, which could explain clinical relapse and progress. Moreover, our observation that the "relapsed" in vitro cultures show practically identical HER2 surface expression and susceptibility toward ADCC suggests that the administration of trastuzumab beyond relapse might be considered, especially when combined with an immune-stimulatory treatment that targets the escape variants.
    Cancer Research 10/2009; 69(20):8058-66. DOI:10.1158/0008-5472.CAN-09-0834 · 9.28 Impact Factor
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    ABSTRACT: Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for. In this phase-I/II trial, pegylated liposomal doxorubicin (Caelyx, PEG-Dox) and prolonged administration of Temozolomide in addition to radiotherapy was investigated in 63 patients with newly diagnosed glioblastoma. In phase-I, PEG-Dox was administered in a 3-by-3 dose-escalation regimen. In phase-II, 20 mg/m2 PEG-Dox was given once prior to radiotherapy and on days 1 and 15 of each 28-day cycle starting 4 weeks after radiotherapy. Temozolomide was given in a dose of 75 mg/m2 daily during radiotherapy (60 Gy) and 150-200 mg/m2 on days 1-5 of each 28-day cycle for 12 cycles or until disease progression. The toxicity of the combination of PEG-Dox, prolonged administration of Temozolomide, and radiotherapy was tolerable. The progression free survival after 12 months (PFS-12) was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I. None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison. Together, the investigated combination is tolerable and feasible. Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data.
    BMC Cancer 10/2009; 9:308. DOI:10.1186/1471-2407-9-308 · 3.32 Impact Factor
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    ABSTRACT: The ArsRS two-component system is the master regulator of acid adaptation in the human gastric pathogen Helicobacter pylori. Low pH is supposed to trigger the autophosphorylation of the histidine kinase ArsS and the subsequent transfer of the phosphoryl group to its cognate response regulator ArsR which then acts as an activator or repressor of pH-responsive genes. Orthologs of the ArsRS two-component system are also present in H. pylori's close relatives H. hepaticus, Campylobacter jejuni and Wolinella succinogenes which are non-gastric colonizers. In order to investigate the mechanism of acid perception by ArsS, derivatives of H. pylori 26695 expressing ArsS proteins with substitutions of the histidine residues present in its periplasmic input domain were constructed. Analysis of pH-responsive transcription of selected ArsRS target genes in these mutants revealed that H94 is relevant for pH sensing, however, our data indicate that protonatable amino acids other than histidine contribute substantially to acid perception by ArsS. By the construction and analysis of H. pylori mutants carrying arsS allels from the related epsilon-proteobacteria we demonstrate that WS1818 of W. succinogenes efficiently responds to acidic pH. We show that H94 in the input domain of ArsS is crucial for acid perception in H. pylori 26695. In addition our data suggest that ArsS is able to adopt different conformations depending on the degree of protonation of acidic amino acids in the input domain. This might result in different activation states of the histidine kinase allowing a gradual transcriptional response to low pH conditions. Although retaining considerable similarity to ArsS the orthologous proteins of H. hepaticus and C. jejuni may have evolved to sensors of a different environmental stimulus in accordance with the non gastric habitat of these bacteria.
    PLoS ONE 09/2009; 4(9):e6930. DOI:10.1371/journal.pone.0006930 · 3.53 Impact Factor
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    ABSTRACT: Sarcomatoid renal cell carcinoma represents high-grade transformation of different subtypes of renal cell carcinoma and is associated with a dismal prognosis and high resistance to chemotherapy. We report on the course of disease of a 63 years old patient undergoing a nearly complete remission of multiple intracranial and spinal metastatic lesions of a sarcomatoid renal cell carcinoma by a combined chemotherapy with temozolomide and pegylated liposomal doxorubicin.
    Cases Journal 11/2008; 1(1):210. DOI:10.1186/1757-1626-1-210
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    ABSTRACT: High-grade oligodendroglial tumors, that is, anaplastic oligodendroglial tumors and glioblastomas with oligodendroglial component, differ significantly in terms of prognosis and response to chemotherapy. Differentiation might be difficult because the histological differences are vague and reliable markers are not established. We correlated the presence of putative cancer stem cells (CSC) in high-grade oligodendroglial tumors (WHO grades III and IV) with clinical outcome. Tumors with favorable prognosis neither contained CSC nor did they show CD133 expression. Tumor cells resembled lineage-restricted progenitor cells with limited proliferative capacity and differentiation profile. In contrast, CD133 expression and stem cell-like tumor cells characterized tumors with poor prognosis. They showed neurosphere-like growth, differentiated into cells of all neural lineages, and were tumorigenic in nude mice. In our series, CSC and expression of CD133 predicted the clinical course of disease better than the histological grading. To confirm these results, we retrospectively analyzed 36 high-grade oligodendroglial tumors. Again, CD133 expression indicated shorter survival and predicted clinical outcome more reliable than the histological assessment. Our data show that detection of CSC and expression of CD133 is predictive of prognosis in high-grade oligodendroglial tumors. The presence or absence of CD133(+) CSC might explain the crucial biological difference between WHO grade III and IV oligodendroglial tumors.
    Brain Pathology 08/2008; 18(3):370-7. DOI:10.1111/j.1750-3639.2008.00130.x · 4.35 Impact Factor
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    ABSTRACT: We demonstrate that in Listeria monocytogenes, temperature-responsive transcriptional control of flagellar genes does not rely on the phosphorylation of the conserved phosphorylation site (D55) in the receiver domain of response regulator DegU. Furthermore, proper control of DegU-regulated genes involved in ethanol tolerance and virulence is independent of receiver phosphorylation.
    Journal of bacteriology 08/2008; 190(13):4777-81. DOI:10.1128/JB.00258-08 · 2.69 Impact Factor

Publication Stats

3k Citations
227.79 Total Impact Points

Institutions

  • 2011–2012
    • University Hospital RWTH Aachen
      • Department of Neurology
      Aachen, North Rhine-Westphalia, Germany
  • 2010–2012
    • RWTH Aachen University
      • Department of Neurology
      Aachen, North Rhine-Westphalia, Germany
    • University Hospital Regensburg
      Ratisbon, Bavaria, Germany
  • 1995–2010
    • University of Wuerzburg
      • Department of Microbiology
      Würzburg, Bavaria, Germany
  • 2009
    • Universität Regensburg
      • Lehrstuhl für Neurologie
      Regensburg, Bavaria, Germany
  • 2003
    • Max von Pettenkofer-Institut
      München, Bavaria, Germany
  • 2000
    • Heidelberg University
      • Center for Molecular Biology (ZMBH)
      Heidelburg, Baden-Württemberg, Germany