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  • 1
    Online Resource
    Online Resource
    Proceedings of the 3rd IPLeiria’s International Health Congress : Leiria, Portugal. 6-7 May 2016
    Springer Science and Business Media LLC ; 2016
    In:  BMC Health Services Research Vol. 16, No. S3 ( 2016-7)
    Details
    In: BMC Health Services Research, Springer Science and Business Media LLC, Vol. 16, No. S3 ( 2016-7)
    Type of Medium: Online Resource
    ISSN: 1472-6963
    URL: Article
    DOI: 10.1186/s12913-016-1423-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
    detail.hit.zdb_id: 2050434-2
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  • 2
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    Trichostatin A effectively induces apoptosis in chronic lymphocytic leukemia cells via inhibition of Wnt signaling and histone deacetylation
    Springer Science and Business Media LLC ; 2014
    In:  Journal of Cancer Research and Clinical Oncology Vol. 140, No. 8 ( 2014-8), p. 1283-1293
    Details
    In: Journal of Cancer Research and Clinical Oncology, Springer Science and Business Media LLC, Vol. 140, No. 8 ( 2014-8), p. 1283-1293
    Type of Medium: Online Resource
    ISSN: 0171-5216 , 1432-1335
    URL: Article
    DOI: 10.1007/s00432-014-1689-0
    RVK:
    XA 52301
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2014
    detail.hit.zdb_id: 1459285-X
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  • 3
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    Physiological inhibitors of Wnt signaling : Physiological Wnt inhibitors
    Wiley ; 2011
    In:  European Journal of Haematology Vol. 86, No. 6 ( 2011-06), p. 453-465
    Details
    In: European Journal of Haematology, Wiley, Vol. 86, No. 6 ( 2011-06), p. 453-465
    Type of Medium: Online Resource
    ISSN: 0902-4441
    URL: Issue
    URL: Article
    DOI: 10.1111/ejh.2011.86.issue-6
    DOI: 10.1111/j.1600-0609.2011.01592.x
    Language: English
    Publisher: Wiley
    Publication Date: 2011
    detail.hit.zdb_id: 2027114-1
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  • 4
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    Angiogenic factors in chronic lymphocytic leukaemia (CLL): Where do we stand?
    Elsevier BV ; 2015
    In:  Critical Reviews in Oncology/Hematology Vol. 93, No. 3 ( 2015-03), p. 225-236
    Details
    In: Critical Reviews in Oncology/Hematology, Elsevier BV, Vol. 93, No. 3 ( 2015-03), p. 225-236
    Type of Medium: Online Resource
    ISSN: 1040-8428
    URL: Article
    DOI: 10.1016/j.critrevonc.2014.10.007
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2015
    detail.hit.zdb_id: 2025731-4
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  • 5
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    The antineoplastic effect of nitric oxide-donating acetylsalicylic acid (NO-ASA) in chronic lymphocytic leukemia (CLL) cells is highly dependent on its positional isomerism
    SAGE Publications ; 2011
    In:  Therapeutic Advances in Hematology Vol. 2, No. 5 ( 2011-10), p. 279-289
    Details
    In: Therapeutic Advances in Hematology, SAGE Publications, Vol. 2, No. 5 ( 2011-10), p. 279-289
    Abstract: Background: Chronic lymphocytic leukemia (CLL) is not curable in patients that are not eligible for allogeneic stem cell transplantation. Therefore, new treatment options are highly desirable. Chemically modified nonsteroidal anti-inflammatory drugs (NSAIDs), such as nitric-oxide-donating acetylsalicylic acid (NO-ASA), have been described to possess antineoplastic capacity. Recently, we could demonstrate a potent apoptosis induction in primary CLL cells in vitro and tumor growth inhibition by para-NO-ASA in a xenograft mouse model. However, little is known about the impact of positional isomerism of NO-ASA on its antineoplastic capacity in CLL. Methods: Primary CLL cells were treated with the meta- or para-isomer of NO-ASA at varying concentrations and durations. Viability was assessed flow cytometrically by annexin V-FITC/PI staining and by CellTiter-Glo luminescence cell viability assay. Caspase and PARP cleavage as well as involvement of β-catenin/Lef-1 signaling was determined by immunoblotting. For caspase inhibition, BD™ ApoBlock was used. Nude mice were xenografted with JVM3 cells and treated with meta-NO-ASA, para-NO-ASA or vehicle control. Results: The meta-isomer was entirely ineffective in inducing CLL cell apoptosis in concentrations up to 100 µM, while para-NO-ASA acted in the low micromolar range. meta-NO-ASA, in contrast to para-NO-ASA, did not alter caspase activity. While para-NO-ASA action involved inhibition of β-catenin/Lef-1 signaling, meta-NO-ASA did not show any impact on this signaling pathway. Further, meta-NO-ASA did not significantly reduce tumor growth in a CLL xenograft mouse model, while para-NO-ASA was highly potent. Conclusion: We conclude that positional isomerism is crucial for the antineoplastic effect of NO-ASA in CLL. It can be suggested that the para-isomer, but not the meta-isomer, generates a chemical structure which is essential for the neoplastic effect of NO-ASA.
    Type of Medium: Online Resource
    ISSN: 2040-6207 , 2040-6215
    URL: Article
    DOI: 10.1177/2040620711416272
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2011
    detail.hit.zdb_id: 2585183-4
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  • 6
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    Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) - a Putative Diagnostic Marker for Chronic Lymphocytic Leukemia (CLL).
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 1587-1587
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1587-1587
    Abstract: Abstract 1587 Poster Board I-613 In chronic lymphocytic leukemia (CLL) WNT signaling is constitutively active and several members of this signaling pathway are uniformely upregulated in these cells. Apart from classical WNT receptors like FZD and LRP6, receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been shown to function as a receptor for WNT proteins, too. Furthermore, it could recently be demonstrated that ROR1 is frequently expressed on the surface of CLL cells and might therefore serve as a therapeutic target in this disease. However, so far only little is known about the expression status of this protein in different patients. Moreover, a diagnostic antibody for flow cytometric investigations is lacking. Thus, the aim of our study was to i) establish a directly labelled anti-ROR1 antibody for flow cytometry, ii) to confirm previous results on ROR1 expression in CLL, iii) to investigate ROR1 expression in different cell compartments and iv) correlate our findings to known markers of risk and disease progression. Peripheral blood of CLL patients as well as healthy volunteers was subjected to flow cytometric analysis. Besides standard determination of leukocyte subpopulations ZAP70 and CD38 status was assessed according to current diagnostic recommendations. In addition, ROR1 surface expression was first detected by flow cytometry using a specific primary antibody directed against ROR1 and a fluorescent labelled secondary antibody. Using this experimental setting we found that ROR1 is expressed on 63.4% of all neoplastic CLL cells and also on 30.5% of T cells in the peripheral CLL blood. In contrast, no ROR1 expression could be detected on NK cells, B cells, CD8+- or CD4+-T cells of healthy individuals. To improve the analytical technique the ROR1 antibody was directly conjugated with Phycoerythrin (PE) and the experiments were repeated. With the conjugated antibody we detected ROR1 expression on 97.1% of neoplastic CLL cells and virtually on no T lymphocytes. ROR1 expression levels correlated neither with the expression of ZAP70 nor with CD38. Again, we could not detect ROR1 expression on peripheral blood cells of our healthy volunteers. Taken together, ROR1 expression appears to be highly restricted to CLL cells. If in addition to CD5 and CD19 ROR1 detection is included into diagnostic flow cytometric panels the specificity and sensitivity of immunophenotypic CLL diagnostics may be greatly enhanced. Disclosures Hallek: Roche: Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.1587.1587
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
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    Evidence for a Pathological Ratio of CD44s/CD44v6 in Chronic Lymphoctic Leukemia (CLL) Cells.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2628-2628
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2628-2628
    Abstract: Abstract 2628 Poster Board II-604 Chronic Lymphocytic Leukemia (CLL) is the most common adult-onset leukemia in the western world. It is characterized by an accumulation of functionally incompetent monoclonal CD5+ B-lymphocytes and an increased resistance to apoptosis. CD44 is a cell surface transmembrane glycoprotein which has more than ten isoforms generated by alternative splicing. It is expressed on different cells as e.g. cells of lymphohematopoietic origin, epithelial cells and keratinocytes. CD44 is involved in lymphocyte activation, recirculation and homing. It acts as an adhesion molecule and plays an important role in angiogenesis, cell proliferation, differentiation and migration. One of these variants, CD44 variant 6 (CD44v6), is shown to be responsible for an increased apoptotic resistance in Jurkat cells. Our aim was to show that i) CD44 is overexpressed in CLL cells, ii) that this overexpression is regulated by the WNT pathway, which is known to be constitutively active in CLL cells, and iii) that this overexpression is a possible cause for the increased resistance to apoptosis in CLL cells. Peripheral blood of CLL patients was incubated with specific antibodies directed against CD5, CD19, CD44 standard (CD44s) and CD44v6 and measured by flow cytometry. We measured the mean fluorescence intensity of CD44s and CD44v6 on CD5/CD19 double positive CLL cells. The patient pool included patients with poor prognosis ( ZAP70+, CD38+) as well as patients having a good prognosis (ZAP70-, CD38-). CD19 positive B-cells from healthy volunteers, aged from 18 to 60, were analyzed for their expression of CD44s and CD44v6 as well. Expression levels of CD44s in 37 CLL samples and of CD44v6 in 29 CLL samples were measured and compared those of 22 healthy volunteers. We found a high expression of CD44s in CLL-cells (mean: 368.02) but an even higher expression in healthy B-cells (mean: 538.8; p 〈 0.05). In contrast, the CD44 variant 6 was expressed five- to six-fold higher in CLL cells compared to healthy B cells (mean CLL cells: 20.0; mean healthy B cells: 3.6; p 〈 0.001). Taken together, we found that there is a significantly altered ratio of CD44s/CD44v6 expression in CLL cells when compared to normal B cells. As CD44v6 is known to be oncogenic this phenomenon may contribute to the malignant phenotype of these cells. Currently, we are investigating the effect of WNT3a, a WNT signaling initiator, on the expression of CD44v6 in CLL cells and the effect of an anti human CD44v6 antibody on the apoptosis rate in CLL-cells. Disclosures: Hallek: BayerScheringAG: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2628.2628
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
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    The Para-Isomer of Nitric Oxide Donating Acetylsalicylic Acid (p-NO-ASA) Induces Apoptosis in Chronic Lymphocytic Leukemia (CLL) in Vitro and In Vivo without Gross Systemic Toxicities.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 3783-3783
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3783-3783
    Abstract: Abstract 3783 Poster Board III-719 Chronic lymphocytic leukemia (CLL) is characterized by an accumulation of mature, non functional B cells. WNT/β-catenin(CTNNB1)/TCF/Lef-1 signalling appears to be constitutively and aberrantly activated in these cells. Furthermore, several compounds related to the non-steroidal anti-inflammatory drugs (NSAIDs) are reported to inhibit β-catenin stability and/or function in WNT active cancers in vitro. However, so far clinical studies with such substances generated disappointing results which is likely to the fact that therapeutic plasma concentrations could not be reached without producing significant toxicities; hence, the required high concentrations limit their clinical use. Recently, nitric oxide-donating acetylsalicylic acid (NO-ASA) has been shown to achieve high plasma levels in doses not leading to any relevant side effects in humans. In addition, NO-ASA could disrupt complexation of β-catenin and TCF-4 in vitro. Because the general structure of NO-ASA enables more variants, the aim of our study was to evaluate the effect of the para- (p-NO-ASA) and meta-isomer (m-NO-ASA) in CLL in vitro and in vivo. Primary CLL cells as well as healthy peripheral blood monocytes (PBMCs) and healthy B cells were treated with varying concentrations of p- and m-NO-ASA. Cytotoxicity was assessed by microscopic cell viability testing and measurement of the reduction of the ATP content. Induction of apoptosis was investigated by Annexin V-FITC/propidiumiodide staining and immunoblotting of the caspases-9, -3 as well as PARP. Further, the β-catenin protein amount and the expression of WNT effector proteins like cyclin D1 (CCND1), C-MYC and LEF-1 was evaluated by immunoblot analysis. In vivo activity of NO-ASA was evaluated by treating irradiated CD1 nu/nu female mice, containing a JVM-3 cell line xenograft, with 100 mg/kg/day of p- and m-NO-ASA or vehicle control p.o. for 3 weeks continuously. We found a significant concentration dependent reduction of the ATP content in CLL cells after treatment with p-NO-ASA, whereas the meta-isomer showed no effect on CLL cells. While healthy B cells and healthy PBMCs were not significantly affected by any of the isomers the mean lethal concentration (LC50) was 4.64 μM in CLL cells. Annexin V-FITC/PI staining revealed that reduced cell survival occurs in a time and concentration dependent manner and is mediated by apoptosis. Treatment with 10 μM of p-NO-ASA for 24 hours reduced survival to 46.3 ± 10.1%. This effect was achieved as early as 6 hours after treatment. Immunoblot analysis showed that only p-NO-ASA but not m-NO-ASA activates caspases-9, -3 and cleaves PARP at the same concentrations, which lead to induction of cell death. β-catenin protein levels and WNT pathway target genes are down regulated between 1 to 10 μM also only by the para-isomer. In vivo results revealed that exclusively p-NO-ASA show a strong antitumor efficacy with an IRmax value of 83.1%. After 9 days of treatment p-NO-ASA lead to a significantly reduced tumor volume compared to vehicle control (126.4 ± 22.3 mm3 for p-NO-ASA vs. 290.0 ± 65.9 mm3 for the vehicle control, p=0.0303). Tumor volume of vehicle treated controls increased up to 775.4 ± 219.6 mm3 whereas the tumor volume of p-NO-ASA treated group remained stable at 128.7 ± 27.6 mm3 (p=0.0091) over a treatment period of 21 days. The meta-isomer exhibited no significant antineoplastic effect. Our findings show that the para- but not the meta-isomer of NO-ASA selectively induces caspase mediated apoptosis in CLL cells. The mechanism of action might include inhibition of β-catenin/Lef-1 signaling since we observed downregulation of specific target gene expression. Due to our promising in vivo results, discovering a strong inhibition of tumor growth without producing gross side effects, p-NO-ASA might be a valuable compound for the treatment of CLL. More investigations of the mechanism of action and the specific difference between the positional isomers are needed. Disclosures: Hallek: Roche: Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.3783.3783
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    Online Resource
    Online Resource
    The Para-Isomer of Nitric Oxide-Donating Acetylic Salicylic Acid (p-NO-ASA) Effectively Induces Cell Death in B-Cell Chronic Lymphocytic Leukemia (CLL) Cells at Low Micromolar Concentrations.
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 1606-1606
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 1606-1606
    Abstract: Introduction: B-cell chronic lymphocytic leukemia CLL is characterized by an accumulation of mature, non functional B cells. We and others have shown that WNT/β-catenin (CTNNB1) signaling appears to be constitutively activated in these cells. Furthermore, it is already long known that several compounds related to the non-steroidal antiinflamnmatory drugs (NSAID) can inhibit CTNNB1 stability and/or function. However, so far clinical studies with such substances generated disappointing results which is likely to the fact that therapeutic plasma concentrations could not be reached without producing significant toxicities. Recently, nitric oxide donating derivatives of acetylic salicylic acid (NO-ASA) have been shown to be well tolerated in humans. In addition NO-ASA could disrupt complexation of CTNNB1 and TCF-4 in vitro, whereas the latter belongs to the transcription factors which posses a central function in mediating WNT signaling. The aim of our study was to evaluate whether the para- and meta-isomers of NO-ASA selectively induce apoptosis in CLL cells. Methods: Primary CLL cells as well as healthy peripheral blood monocytes (PBMC) were treated with varying concentrations of p- and m-NO-ASA for different time periods. Cytotoxicity was assessed by microscopic cell viability testing and an ATP assay. Induction of apoptosis was investigated by immunoblotting of PARP, caspases 3 and 9. Further, CTNNB1 protein amount was measured by immunoblotting and expression of WNT effector proteins like cyclin D1 (CCND1), C-MYC and LEF-1 was evaluated with immunoblot analysis as well. Results: The meta-isoform of NO-ASA did not have any effect on CLL cells whereas the para-isomer showed a selective cytotoxic effect. Mean lethal concentration (LC50) values were 4.83 μM and 4.64 μM in CLL cells, respectively. LC50 values for healthy controls were more than 25-fold higher. Immunoblot analysis revealed that p-NO-ASA cleaves PARP; caspase 3 and caspase 9, decreases CTNNB1 protein levels and downregulates WNT pathway target genes in a concentration dependent manner. Conclusion: Our findings show that the para- but not the meta-isomer of NO-ASA induces caspase-mediated apoptosis by inhibition of WNT signaling in CLL cells. NO-ASA, consisting of a traditional molecule of ASA where the NO moiety is covalently bound via a spacer, has been shown to exhibit a lower gastric toxicity than traditional NSAIDs. Therefore p-NO-ASA might be a valuable compound for the treatment of CLL. More investigations of the exact mechanism of action and the specific difference between the positional isomers are indicated.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.1606.1606
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Expression of the Transcription Factor Lymphoid Enhancer Binding Factor-1 (LEF-1) Is Correlated to Aberrantly Increased Fibromodulin Transcripts in Chronic Lymphocytic Leukemia (CLL).
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 4589-4589
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4589-4589
    Abstract: Abstract 4589 Chronic lymphocytic leukemia (CLL) is characterized by accumulation of monoclonal CD5+ B lymphocytes. Fibromodulin is a secreted extracellular matrix protein usually found in articular cartilage, bones, connective tissue and collagen rich tissues but has been shown to be excessively expressed in CLL. Moreover, we and others could show that WNT signaling is highly activated in CLL. The aim of our study was to investigate a possible connection between fibromodulin overexpression and the WNT pathway. Moreover, we wanted to explore possible relations between these parameters and the prognosis of CLL. Fibromodulin mRNA transcripts were correlated with the mRNA expression of the WNT pathway transcription factors lymphoid enhancer binding factor-1 (LEF-1) and T cell factor-4 (TCF-4) in primary CLL cells. Furthermore, we assessed correlations between the mRNA expression levels with ZAP-70 and CD38 protein expression. These parameters have been shown to be associated with a poor prognosis. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was used and calculated PCR-efficiency corrected relative expression values of Fibromodulin, LEF-1 and TCF-4 mRNA in primary CLL-cells determined. ZAP-70 and CD38 expression was determined by flow cytometry analysis. Based on 20 primary CLL samples we found a significant positive correlation between Fibromodulin and LEF-1 mRNA levels (Spearman's rho = 0.65, p = 0.009). Also, LEF-1 and TCF-4 were found to be strongly correlated (Spearman's rho = 0.61, p = 0.027). In contrast, fibromodulin and TCF-4 mRNA levels were only weakly correlated (Spearman's rho = 0.33, p = 0.271). CD38 and ZAP-70 did not correlate significantly to any of the other values. Both parameters did also not exhibit significant correlations with fibromodulin, LEF-1, and TCF-4 mRNA. The positive correlation of TCF-4 and LEF-1 was expected as LEF-1 has been shown to be a target gene of TCF transcription factors. The strong positive correlation of fibromodulin and LEF-1 indicates that fibromodulin might be a target gene of LEF-1 or part of the same (TCF-4 independent) transcription regulation pathway. Studies investigating theses functional relationships are underway. Disclosures: Hallek: BayerScheringAG: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.4589.4589
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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