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Berlin Brandenburg

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  • 1
    Language: English
    In: Experimental Hematology, 2007, Vol.35(5), pp.712-723
    Description: Deregulated epigenetic mechanisms are likely involved in the pathogenesis of myelodysplastic syndromes (MDSs). Which genes are silenced by aberrant promotor methylation during MDS hematopoiesis has not been equivalently investigated. Using an in vitro differentiation model of human hematopoiesis, we generated defined differentiation stages (day 0, day 4, day 7, day 11) of erythro-, thrombo- and granulopoiesis from 13 MDS patients and seven healthy donors. Promotor methylation analysis of key regulatory genes involved in cell cycle control (p14, p15, p16, CHK2), DNA repair (hMLH1), apoptosis (p73, survivin, DAPK), and differentiation (RARb, WT1) was performed by methylation-specific polymerase chain reaction. Corresponding gene expression was analyzed by microarray (Affymetrix, HG-U133A). We provide evidence that p16, survivin, CHK2, and WT1 are affected by promotor hypermethylation in MDSs displaying a selective International Prognostic Scoring System risk association. A methylation-associated mRNA downregulation for specific hematopoietic lineages and differentiation stages is demonstrated for survivin, CHK2, and WT1. We identified a suppressed survivin mRNA expression in methylated samples during erythropoiesis, whereas WT1 and CHK2 methylation-related reduction of mRNA expression was found during granulopoiesis in all MDS risk types. Our data suggest that lineage-specific methylation-associated gene silencing of survivin, CHK2, and WT1 in MDS hematopoietic precursor cells may contribute to the MDS-specific phenotype.
    Keywords: Medicine
    ISSN: 0301-472X
    E-ISSN: 1873-2399
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  • 2
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 01 May 2010, Vol.16(9), pp.2634-45
    Description: This study was aimed at detecting and characterizing circulating tumor cells (CTC) before and after neoadjuvant therapy (NT) in the peripheral blood of patients with breast cancer. The clinical trial GeparQuattro incorporated NT approaches (epirubicin/cyclophosphamide prior to randomization to docetaxel alone, docetaxel in combination with capecitabine, or docetaxel followed by capecitabine) and additional trastuzumab treatment for patients with HER2-positive tumors. We used the Food and Drug Administration-approved CellSearch system for CTC detection and evaluation of HER2 expression and developed HER2 immunoscoring for CTC. We detected 〉 or =1 CTC/7.5 mL in 46 of 213 patients (21.6%) before NT and in 22 of 207 patients (10.6%) after NT (P = 0.002). Twenty (15.0%) initially CTC-positive cases were CTC-negative after NT, whereas 11 (8.3%) cases were CTC-positive after NT, although no CTC could be found before NT. CTC detection did not correlate with primary tumor characteristics. Furthermore, there was no association between tumor response to NT and CTC detection. HER2-overexpressing CTC were observed in 14 of 58 CTC-positive patients (24.1%), including 8 patients with HER2-negative primary tumors and 3 patients after trastuzumab treatment. CTC scored HER2-negative or weakly HER2-positive before or after NT were present in 11 of 21 patients with HER2-positive primary tumors. HER2 overexpression on CTC was restricted to ductal carcinomas and associated with high tumor stage (P = 0.002). CTC number was low in patients with primary breast cancer. The decrease in CTC incidence during treatment was not correlated with standard clinical characteristics and primary tumor response. Information on the HER2 status of CTC might be helpful for stratification and monitoring of HER2-directed therapies.
    Keywords: Antineoplastic Combined Chemotherapy Protocols -- Therapeutic Use ; Breast Neoplasms -- Drug Therapy ; Neoplastic Cells, Circulating -- Metabolism ; Receptor, Erbb-2 -- Biosynthesis
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 3
    Language: English
    In: The Journal of cell biology, 11 October 2004, Vol.167(1), pp.123-33
    Description: Disruption of latent TGF-beta binding protein (LTBP)-4 expression in the mouse leads to abnormal lung development and colorectal cancer. Lung fibroblasts from these mice produced decreased amounts of active TGF-beta, whereas secretion of latent TGF-beta was significantly increased. Expression and secretion of TGF-beta2 and -beta3 increased considerably. These results suggested that TGF-beta activation but not secretion would be severely impaired in LTBP-4 -/- fibroblasts. Microarrays revealed increased expression of bone morphogenic protein (BMP)-4 and decreased expression of its inhibitor gremlin. This finding was accompanied by enhanced expression of BMP-4 target genes, inhibitors of differentiation 1 and 2, and increased deposition of fibronectin-rich extracellular matrix. Accordingly, increased expression of BMP-4 and decreased expression of gremlin were observed in mouse lung. Transfection of LTBP-4 rescued the -/- fibroblast phenotype, while LTBP-1 was inefficient. Treatment with active TGF-beta1 rescued BMP-4 and gremlin expression to wild-type levels. Our results indicate that the lack of LTBP-4-mediated targeting and activation of TGF-beta1 leads to enhanced BMP-4 signaling in mouse lung.
    Keywords: Signal Transduction ; Adaptor Proteins, Signal Transducing -- Physiology ; Bone Morphogenetic Proteins -- Metabolism ; Transforming Growth Factor Beta -- Metabolism
    ISSN: 0021-9525
    E-ISSN: 15408140
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  • 4
    In: European Journal of Haematology, February 2012, Vol.88(2), pp.144-153
    Description: Myelodysplastic syndromes (MDS) are characterized by dyserythropoiesis resulting in anemia. This pathological hallmark is incompletely understood. Notch signaling has been linked to impaired erythropoietic and megakaryopoietic development of CD34+ progenitor cells, but its role in MDS is unclear. We have analyzed the transcriptional activity of Notch pathway elements and its association with the key erythroid factor () and the apoptosis regulatory gene () in MDS. The methylation of erythroid promoter CpG dinucleotides flanking cis‐regulatory elements, including an N‐box suppressor binding site for and a ‐box binding site, was examined in normal and MDS erythropoiesis. We have generated a kinetic model of MDS erythropoiesis using CD34+ bone marrow cells from healthy donors ( = 7) and patients with MDS (low risk: RA/ = 6, RARS/ = 3; high risk: RAEB/ = 4, RAEB‐T/ = 2). RNA expression of , , , , , and was measured by real‐time RT‐PCR (qPCR). DNA methylation at seven CpG dinucleotides of the gene promoter was quantitatively analyzed by pyrosequencing of bisulfite‐treated genomic DNA at any specific time point. For the Notch pathway elements, no conclusive expression differences were found between MDS and normal erythropoiesis. But we found steadily up‐regulated RNA expression of and of during late normal erythropoietic differentiation. In contrast, during MDS, erythropoiesis a loss of typical up‐regulation of and was observed. Hypermethylation of CpG dinucleotides flanking the repressor binding site within the 5′ region of was detected particularly during late MDS erythropoiesis. Interestingly, decremental promotor methylation values were seen during normal erythropoiesis matching RNA up‐regulation. Our data show that the critical erythropoietic transcription factor as well as the antiapoptotic molecule fails to be normally up‐regulated during MDS erythropoiesis. The higher residual 5′‐ methylation values in MDS erythropoiesis but decremental loss thereof in normal erythropoiesis suggest a gene dose effect for during erythropoiesis being finely tuned by CpG methylation. Its dysregulation may contribute to the ineffective erythropoiesis observed in MDS.
    Keywords: Bclxl ; Dlk1 ; Dna Methylation ; Erythropoiesis ; Gata1 ; Hematopoietic Stem Cells ; Hes1 ; Mds ; Notch1
    ISSN: 0902-4441
    E-ISSN: 1600-0609
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  • 5
    Language: English
    In: Studies in health technology and informatics, 2012, Vol.180, pp.1135-7
    Description: The German Consortium for Translational Cancer Research (DKTK) and the Rhine-Main Translational Cancer Research Network (RM-TCRN) are designed to exploit large population cohorts of cancer patients for the purpose of bio-banking, clinical trials, and clinical cancer registration. Hence, the success of these platforms is heavily dependent on the close interlinking of clinical data from cancer patients, information from study registries, and data from bio-banking systems of different laboratories and scientific institutions. This article referring to the poster discusses the main challenges of the platforms from an information technology point of view, legal and data security issues, and outlines an integrative IT-concept concerning a decentralized, distributed search approach where data management and search is in compliance with existing legislative rules.
    Keywords: Health Records, Personal ; Biomedical Research -- Organization & Administration ; Electronic Health Records -- Organization & Administration ; Medical Informatics -- Organization & Administration ; Medical Oncology -- Organization & Administration ; Medical Record Linkage -- Methods ; Translational Medical Research -- Organization & Administration
    ISSN: 0926-9630
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 6
    Language: English
    In: Experimental Hematology, 2010, Vol.38(9), pp.718-732.e6
    Description: Development of myelodysplastic syndrome (MDS) is suggested to follow a multistep pathogenesis and is characterized by accumulation of molecular defects of the hematopoietic stem/progenitor cells, resulting in aberrant differentiation and proliferation. To detect alterations within the transcriptional program in MDS-derived CD34 cells during lineage-specific differentiation, we performed serial gene expression analysis of in vitro differentiated erythro-, granulo-, and megakaryopoietic cells using oligonucleotide microarrays (HG-U133A, Affymetrix, Santa Clara, CA, USA). For selected genes, expression data were confirmed using real-time polymerase chain reaction. We identified genes with altered expression during lineage-specific differentiation in either low- or high-risk MDS cells compared to the expression patterns of continuously up- or downregulated genes from the normal transcriptional program of hematopoiesis. In cluster analyses, we could show that MDS samples have a distinct expression pattern of a set of selected genes compared to normal cells, which allows prediction of the affiliation of a sample to one group. Furthermore, this study gives an overview of genes that are differentially expressed in MDS cells compared to normal hematopoiesis. Our data provide the first comprehensive transcriptional analysis of differentiating human CD34 cells derived from MDS patients compared to normal individuals. It gives new insights into the alteration of differentiation and proliferation of MDS stem cells.
    Keywords: Medicine
    ISSN: 0301-472X
    E-ISSN: 1873-2399
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  • 7
    Language: English
    In: Blood, 15 November 2002, Vol.100(10), pp.3553-60
    Description: Gene patterns of expression in purified CD34(+) bone marrow cells from 7 patients with low-risk myelodysplastic syndrome (MDS) and 4 patients with high-risk MDS were compared with expression data from CD34(+) bone marrow cells from 4 healthy control subjects. CD34(+) cells were isolated by magnetic cell separation, and high-density oligonucleotide microarray analysis was performed. For confirmation, the expression of selected genes was analyzed by real-time polymerase chain reaction. Class membership prediction analysis selected 11 genes. Using the expression profile of these genes, we were able to discriminate patients with low-risk from patients with high-risk MDS and both patient groups from the control group by hierarchical clustering (Spearman confidence). The power of these 11 genes was verified by applying the algorithm to an unknown test set containing expression data from 8 additional patients with MDS (3 at low risk, 5 at high risk). Patients at low risk could be distinguished from those at high risk by clustering analysis. In low-risk MDS, we found that the retinoic-acid-induced gene (RAI3), the radiation-inducible, immediate-early response gene (IEX1), and the stress-induced phosphoprotein 1 (STIP1) were down-regulated. These data suggest that CD34(+) cells from patients with low-risk MDS lack defensive proteins, resulting in their susceptibility to cell damage. In summary, we propose that gene expression profiling may have clinical relevance for risk evaluation in MDS at the time of initial diagnosis. Furthermore, this study provides evidence that in MDS, hematopoietic stem cells accumulate defects that prevent normal hematopoiesis.
    Keywords: Gene Expression Profiling ; Antigens, Cd34 -- Genetics ; Myelodysplastic Syndromes -- Genetics
    ISSN: 0006-4971
    E-ISSN: 15280020
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  • 8
    Language: English
    In: Blood, 15 July 2003, Vol.102(2), pp.659-61
    Description: The tyrosine kinase inhibitor STI571 (imatinib) binds competitively to the adenosine triphosphate (ATP) binding site of the ABL kinase, thereby inhibiting auto- and substrate phosphorylation of the oncogenic protein BCR-ABL and preventing the activation of downstream signaling pathways. Comparative studies on leukemic cell samples obtained from chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) patients before and after treatment with STI571 reported point mutations in resistant samples after a short time of therapy. The aim of this study was to determine whether patients with Ph+ ALL in whom resistance developed as a consequence of the Glu255Lys mutation already harbored this subclone prior to STI571 treatment. First, the migration pattern of cDNAs from 30 bone marrow samples from patients with Ph+ ALL was analyzed by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). Thereafter, detailed mutational analysis using genomic DNA was performed on initial STI571-naive bone marrow samples of 4 individuals with Ph+ ALL, for whom the mutation Glu255Lys in association with STI571 treatment had been shown. A 166-bp PCR fragment spanning from nucleotide (nt) 862 to nt 1027 was cloned, and 108 clones per sample were analyzed by direct sequencing. This more sensitive technique revealed the presence of the Glu255Lys mutation in 2 initial samples, one clone each. We identified for the first time the mutation Glu255Lys in STI571-naive leukemic samples of Ph+ ALL patients. The findings suggest that the mutation exists in a very small subpopulation of leukemic cells at the beginning of STI571 therapy.
    Keywords: Mutation, Missense ; Point Mutation ; Antineoplastic Agents -- Therapeutic Use ; Drug Resistance, Neoplasm -- Genetics ; Enzyme Inhibitors -- Therapeutic Use ; Fusion Proteins, Bcr-Abl -- Genetics ; Neoplasm Proteins -- Genetics ; Neoplastic Stem Cells -- Enzymology ; Piperazines -- Therapeutic Use ; Precursor Cell Lymphoblastic Leukemia-Lymphoma -- Genetics ; Pyrimidines -- Therapeutic Use
    ISSN: 0006-4971
    E-ISSN: 15280020
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  • 9
    Language: English
    In: Blood, 15 January 2004, Vol.103(2), pp.523-9
    Description: Imatinib is a novel tyrosine kinase inhibitor used for the treatment of Philadelphia chromosome-positive leukemias and other malignancies. Side effects are mostly moderate; however, a dose-dependent hematologic toxicity affecting all hematopoietic lineages is observed clinically. The aim of this study was to investigate the effect of imatinib on normal hematopoietic stem and progenitor cells in vitro. A dose-dependent decrease in proliferation potential was found when CD34+ cells were expanded in serum-free medium supplemented with 6 growth factors and imatinib. Functionally, a decrease in colony-forming capacity was observed under increasing doses of imatinib. However, no such effect on more primitive cobblestone area-forming cells was detectable. Both withdrawal of stem cell factor from our expansion cultures or functional inhibition of c-kit led to a similar degree of inhibition of expansion, whereas the effect of imatinib was substantially greater at all dose levels tested. These data suggest a significant inhibitory effect of imatinib on normal CD34+ progenitor (but not stem) cells that is largely independent of c-kit signaling.
    Keywords: Endothelium, Vascular -- Physiology ; Fetal Blood -- Cytology ; Hematopoietic Stem Cells -- Cytology ; Piperazines -- Pharmacology ; Pyrimidines -- Pharmacology
    ISSN: 0006-4971
    E-ISSN: 15280020
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  • 10
    Language: English
    In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 01 January 2010, Vol.28(1), pp.105-13
    Description: PURPOSE Preclinical data suggest a contribution of the immune system to chemotherapy response. In this study, we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate in cancer tissue predicts the response to neoadjuvant chemotherapy. METHODS We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies (GeparDuo, n = 218, training cohort; and GeparTrio, n = 840, validation cohort). Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed, paraffin-embedded tumor samples. Results In a multivariate regression analysis including all known predictive clinicopathologic factors, the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response (pCR) in both cohorts (training cohort: P = .012; validation cohort: P = .001). Lymphocyte-predominant breast cancer responded, with pCR rates of 42% (training cohort) and 40% (validation cohort). In contrast, those tumors without any infiltrating lymphocytes had pCR rates of 3% (training cohort) and 7% (validation cohort). The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate, and logistic regression showed a significant association of the T-cell-related markers CD3D and CXCL9 with pCR. CONCLUSION The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy.
    Keywords: Breast Neoplasms -- Drug Therapy ; Lymphocytes, Tumor-Infiltrating -- Pathology
    ISSN: 0732183X
    E-ISSN: 1527-7755
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