Heidrun Karlic - Academia.edu (original) (raw)

Papers by Heidrun Karlic

Biochemical Pharmacology, 2013

There is growing evidence that aminobisphosphonates like ibandronate show anticancer activity by ... more There is growing evidence that aminobisphosphonates like ibandronate show anticancer activity by an unknown mechanism. Biochemically, they prevent posttranslational isoprenylation of small GTPases, thus inhibiting their activity. In tumor cells, activated RAS-GTPase, the founding member of the gene family, down-regulates the expression of the pro-apoptotic gene FAS via epigenetic DNA-methylation by DNMT1. We compared ibandronate treatment in neoplastic human U-2 osteosarcoma and in mouse CCL-51 breast cancer cells as well as in the immortalized non-neoplastic MC3T3-E1 osteoblastic cells. Ibandronate attenuated cell proliferation in all cell lines tested. In the neoplastic cells we found upregulation of caspases suggesting apoptosis. Further we found stimulation of FAS-expression as a result of epigenetic DNA demethylation that was due to down-regulation of DNMT1, which was rescued by reisoprenylation by both geranylgeranyl-pyrophosphate and farnesylpyrophosphate. In contrast, ibandronate did not affect FAS and DNMT1 expression in MC3T3-E1 non-neoplastic cells. Data suggest that bisphosphonates via modulation of the activity of small-GTPases induce apoptosis in neoplastic cells by DNA-CpG-demethylation and stimulation of FAS-expression. In conclusion the shown epigenetic mechanism underlying the anti-neoplastic activity of farnesyl-transferase-inhibition, also explains the clinical success of other drugs, which target this pathway.

Functional Food Science

The main argument for the optimization of nutritional strategies in athletes, besides improved pe... more The main argument for the optimization of nutritional strategies in athletes, besides improved performance, is the preservation of health and the prevention of unwanted training effects. This highlights the importance of personalized nutrition strategies, as well as functional foods and phytonutrients based on individual requirements which can be precisely defined by detailed analyses, including genetics, epigenetics, gut microbiota, gender, and environmental factors. Recently, a miRNA-based “Fitness Score to Assess the Individual Response to Diet, Metabolism and Exercise” was developed by our group. Formulations of sports drinks and sports foods should be carefully considered, as they frequently contain a mixture of multiple ingredients. Macronutrient supplements, such as carbohydrates, proteins, protein components, fatty acids and probiotics are known to provide benefits for athletes with energy deficits, electrolyte imbalance, gastrointestinal issues, fatigue, and cardiovascular ...

Background: Up-regulation of energy metabolism is a key feature of proliferating cells from cance... more Background: Up-regulation of energy metabolism is a key feature of proliferating cells from cancers and leukemias. Thus, targeting of metabolic pathways represents a therapeutic challenge involving both dietary and drug-mediated strategies. The aim of this study was to evaluate the impact of the DNA-methyltransferase-inhibitor 5-desoxy-2-azacytidine (Decitabine, DAC) and the histone-deacetylase-inhibitor suberoyl anilide hydroxamic acid (SAHA, Vorinostat) on malignancy-associated metabolic pathways. Methods: HL60 promyelocytic cells and KG1 myeloblastic leukemia cells were treated with DAC or SAHA for 3 days. RNA was isolated and gene expression was analyzed using Affymetrix human gene 1.0 arrays in comparison with published databases from normal CD34 positive hematopoietic progenitors. Pathvisio software tool was used for comparative quantification of gene-expression patterns from metabolic pathways based on established data banks such as KEGG and Wikipathways. Results: A comparison of both leukemia cell lines to normal CD34 + cells indicated malignancy-associated stimulation of energy metabolism. Global evaluation on pathways demonstrated a significant drug-mediated downregulation of the intra-mitochondrial pathways, namely the tri-carbonic acid cycle and beta oxidation and to a lesser extent also cytoplasmic glycolysis. Conclusion: The observation that the KG1 cell line reacted more sensitive to demethylating drugs than the HL60 cell line, where drug treatment selected for survival of differentiated cells, may support application of DAC and SAHA to leukemias with an undifferentiated phenotype but also with the potential to induce differentiation. Efficient targeting of intra-mitochondrial pathways appears to be associated with multiple pro-apoptotic activities of these drugs.

Molecular Cancer Research, 2016

The metabolic oncogene fatty acid synthase (FASN) is overexpressed in 80% of ovarian cancers (OC)... more The metabolic oncogene fatty acid synthase (FASN) is overexpressed in 80% of ovarian cancers (OC) and indicates poor prognosis. Exposure of OC to inhibitors of FASN elicits a complex stress response that interferes with receptor-PI3K-mTORC1 signaling (briefly designated ‘PI3K pathway’). Here we demonstrate that FASN inhibitors capitalize on multiple mechanisms to interfere with the PI3K pathway, and that silencing this cascade is crucial for the anticancer action of the drugs. Data were obtained using thin-layer chromatography, ELISA, Western blotting, quantitative micropatterning and growth assays, respectively. Exposure of OC cells (SKOV3, OVCAR-3) to FASN inhibitors (C75, G28UCM) causes lipid redistribution toward storage lipids, whereas membrane lipid rafts and signaling lipids are diminished, which significantly impairs EGF receptor/ErbB/HER function and expression. A severe depletion of phosphatidylinositol (3,4,5) trisphosphate (PIP3), which represents the crucial product of ...

Blood, 2005

Osteocalcin (OCN) is defined as a marker for osteoblasts but incompletely spliced variants as cha... more Osteocalcin (OCN) is defined as a marker for osteoblasts but incompletely spliced variants as characterised by intron retention may also occur in non-osseous tissues including tumour cells. Bone marrow of haematological diseases was shown to harbour a stem cell candidate common to MSC (mesenchymal stem cells) and HSC (haematopoietic stem cells), which expressed OCN. In this study, we analysed cells from bone marrow samples obtained from 4 patients with AMLs, one patient with CML at blast crisis, one CML patient in chronic phase and 7 patients with myeloproliferative disease (MPD), as well as stem cells from peripheral blood and bone marrow obtained from healthy donors. In attempt to find out whether the presence of such stem cells is associated with disease status, sequential bone marrow samples from a patient with acute myeloid leukaemia (AML/M2Eo) were analysed at 6 time points including diagnosis, remission (= months 4, 5 and 17 after diagnosis) and relapse (months 29 and 41 afte...

dihydroxyvitamin D3 regulates essential pathways of cellular metabolism and differentiation via i... more dihydroxyvitamin D3 regulates essential pathways of cellular metabolism and differentiation via its nuclear receptor (VDR). Molecular mechanisms which are known to play key roles in aging and cancer are mediated by complex processes involving epigenetic mechanisms contributing to efficiency of VD-activating CYP27A1 and CYP27B1 or inactivating CYP24 enzymes as well as VDR which binds to specific genomic sequences (VD response elements or VDREs). Activity of VDR can be modulated epigenetically by histone acetylation. It co-operates with other nuclear receptors which are influenced by histone acetyl transferases (HATs) as well as several types of histone deacetylases (HDACs). HDAC inhibitors (HDACi) and/or demethylating drugs may contribute to normalization of VD metabolism. Studies link VD signaling through the VDR directly to distinct molecular mechanisms of both HAT activity and the sirtuin class of HDACs (SIRT1) as well as the forkhead transcription factors thus contributing to elu...

Functional Foods in Health and Disease, 2020

Following research obtained from the previous SARS and MERS outbreaks, we’ve gained knowledge abo... more Following research obtained from the previous SARS and MERS outbreaks, we’ve gained knowledge about the mechanisms of bioactive plant ingredients against the attachment and replication of COVID-19 as well as overshooting immune responses. This could be used for designing COVID-19 trials utilizing bioactive compounds. The receptors for SARS, ACE-2, and CD26 show associations with mechanisms that regulate human senescence. Several functional foods interact with the epigenetic regulation of viral infection and mechanisms of senescence. This review concentrates on the link between bioactive plant ingredients and their activities against mechanisms of viral infections.Keywords: COVID-19, Epigenetic, Quercetin, Curcumin, Epigallocatechin gallate, Phloretin, Berberine

Blood, 2011

3463 Epigenetic and apoptosis-regulating mechanisms have been implicated as critical factors cont... more 3463 Epigenetic and apoptosis-regulating mechanisms have been implicated as critical factors contributing to the progression from myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (AML). However, the exact molecular mechanisms and genes involved in disease evolution have not been identified yet. We screened for epigenetically regulated pro-apoptotic effector molecules in neoplastic cells in patients with MDS (n=50) and AML (n=30). Among a series of potential regulators, we identified FAS (CD95) as an epigenetically regulated critical death regulator in neoplastic cells. As assessed by qPCR, bone marrow cells obtained from patients with low risk MDS were found to display high levels of FAS, whereas FAS mRNA levels were lower or undetectable in patients with advanced MDS (with excess of blasts) or secondary AML. Moreover, we were able to show by multicolor flow cytometry that CD34+/CD38+ progenitor cells and CD34+/CD38- stem cells in MDS and AML display measurable FA...

Blood, 2006

Hypermethylation of CpG islands within gene promoter regions is associated with transcriptional i... more Hypermethylation of CpG islands within gene promoter regions is associated with transcriptional inactivation of genes involved in cellular proliferation and differentiation and represents, in addition to genetic aberrations, an important mechanism of transcriptional silencing in the pathogenesis of age-associated diseases such as myelodysplastic syndromes (MDS). We have previously reported downregulation of enzymes associated with carnitine-metabolism (including the carnitine transporter OCTN2, which is responsible for carnitine uptake into cells) in healthy elderly persons, as well as a specific downregulation of microsomal carnitine palmitoyltransferase (mCPT; also known as glucose regulated protein GRP58 or endoplasmatic reticulum protein ERp61) a marker for proliferative potential of cells in MDS patients (J.Mol.Med, 81:435ff 2003). Aim of this study was to elucidate the mechanism of this downregulation by analysing the methylation status of the mCPT promoter in 14 MDS patients ...

Blood, 2009

4423 Background Dysregulation of energy metabolism is a key feature of malignancy and known to be... more 4423 Background Dysregulation of energy metabolism is a key feature of malignancy and known to be regulated by epigenetic mechanisms. This study explores gene expression in the KG1 cell line and a primary culture of leukemic blasts from a patient, both incubated with SAHA (suberoyl anilide hydroxamic acid, also known as Vorinostat) in comparison to other epigenetic drugs such as Decitabine (DAC) but also nutritional compounds such as genistein and vitamin D3 with a known activity on metabolism where epigenetic mechanisms play a role. Methods Following a 3 days incubation with pharmacologic concentrations of the above mentioned compounds, gene expression patterns of the KG1 cell-line were analysed on an Affymetrix Gene Expression Array and specifically evaluated by quantitative real time PCR from KG1 cells and primary leukemic cells of a patient with an AML-M2 which were cultured at the same conditions as the KG1 cells. In order to confirm epigenetic mechanisms induced by targeted dr...

Flora, 1983

Summary Leaf water characteristics of two evergreen shrubs, Prunus laurocerasus L. and Ilex aquif... more Summary Leaf water characteristics of two evergreen shrubs, Prunus laurocerasus L. and Ilex aquifolium L., were followed for one year by means of the pressure-volume curve technique. Osmotic potentials of newly emerged leaves were about 1 MPa higher (less negative) than those of mature, over-wintered leaves. This difference disappeared during the first months of leaf development, when the vacuolar solution in newly emerged leaves gradually became more concentrated. Daycourses of total water potential show the most negative values for fully mature leaves. Pressurevolume curves were used to convert these field data into corresponding values for the turgor potential, which were byfar higher for old than for young leaves. Recently emerged leaves in spring may therefore come under severe stress during periods of only moderately lowered total water potentials.

Methods in Pharmacology and Toxicology, 2016

Wiener klinische Wochenschrift, Jan 13, 2018

In 2008 the Ludwig Boltzmann Cluster Oncology (LBC ONC) was established on the basis of two previ... more In 2008 the Ludwig Boltzmann Cluster Oncology (LBC ONC) was established on the basis of two previous Ludwig Boltzmann Institutes working in the field of hematology and cancer research. The general aim of the LBC ONC is to improve treatment of hematopoietic neoplasms by eradicating cancer-initiating and disease-propagating cells, also known as leukemic stem cells (LSC) in the context of leukemia. In a first phase, the LBC ONC characterized the phenotype and molecular aberration profiles of LSC in various malignancies. The LSC phenotypes were established in acute and chronic myeloid leukemia, in acute lymphoblastic leukemia and in chronic lymphocytic leukemia. In addition, the concept of preleukemic (premalignant) neoplastic stem cells (pre-L-NSC) was coined by the LBC ONC and was tested in myelodysplastic syndromes and myeloproliferative neoplasms. Phenotypic characterization of LSC provided a solid basis for their purification and for the characterization of specific target expressi...

Studies in athletes have shown that carnitine supplementation may foster exercise performance. As... more Studies in athletes have shown that carnitine supplementation may foster exercise performance. As reported in the majority of studies, an increase in maximal oxygen consumption and a lowering of the respiratory quotient indicate that dietary carnitine has the potential to stimulate lipid metabolism. Treatment with L-carnitine also has been shown to induce a significant postexercise decrease in plasma lactate, which is formed and used continuously under fully aerobic conditions. Data from preliminary studies have indicated that L-carnitine supplementation can attenuate the deleterious effects of hypoxic training and speed up recovery from exercise stress. Recent data have indicated that L-carnitine plays a decisive role in the prevention of cellular damage and favorably affects recovery from exercise stress. Uptake of L-carnitine by blood cells may induce at least three mechanisms: 1) stimulation of hematopoiesis, 2) a dose-dependent inhibition of collagen-induced platelet aggregatio...

Reference Module in Biomedical Sciences

Katharina Tomek, Renate Wagner, Franz Varga, Christian F. Singer, Heidrun Karlic4, Thomas W. Grun... more Katharina Tomek, Renate Wagner, Franz Varga, Christian F. Singer, Heidrun Karlic4, Thomas W. Grunt1,4 Signaling Networks Program, Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University Vienna; Ludwig Boltzmann Institute of Osteology and 4th Medical Department, Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, Vienna; Department of Obstetrics/Gynecology, Comprehensive Cancer Center, Medical University Vienna; Ludwig Boltzmann Cluster Oncology, Medical University Vienna, Austria

Blood

Background: In contrast to other human endogenous retrovirus families which are highly defective,... more Background: In contrast to other human endogenous retrovirus families which are highly defective, HERV-K proviruses possess all viral gene types of exogenous retroviruses. In malignancy (tumor cell lines, breast cancer, melanoma as well as leukemias and lymphomas) but also in many normal tissues, including placenta HERV-K mRNA expression has been detected. In hematopoietic stem cells, an interaction of HERV-K with elements from vectors which are used for gene therapy may lead to unforeseen consequences. The purpose of this study was to localize HERV-K mRNA expression in hematopoietic stem cells of different sources and to evaluate a potential association of HERV-expression with hematologic diseases and to define a possible risk of HERV-expression for transplantation. Methods: Quantitative real time PCR (RTQPCR) was used for detecting HERV-K expression in MNC from blood and/or bone marrow samples of patients with leukemias ( 10 MDS, 16 MPD, 14 AML and 1 CML blast crisis) and MNC from...

Blood

Besides blockade of tyrosine kinases such as c-kit, Imatinib mesylate (IM) regulates glucose flux... more Besides blockade of tyrosine kinases such as c-kit, Imatinib mesylate (IM) regulates glucose flux through downregulation of GLUT-1 transporters in human leukemia cells. This mechanism has the potential to induce regression of type 2 diabetes and hyperlipidemia as observed in patients with chronic myeloid leukemia or hypereosinophilic syndrome. In addition, there is a stimulatory effect of IM on differentiation of human mesenchymal stem cells. Its synergism with retinoic acid or low dose Ara-C is applied in treatment of acute myeloid leukemia (AML). Thus, the AML-derived c-kit positive cell line HL60 was chosen for studying the effect of IM on expression of genes associated with differentiation and metabolism. We analysed the possible feedback on transcription factors (AML1 and AML3) and consequences regarding differentiation and metabolism - associated genes. Quantitative reverse transcriptase PCR analyses revealed that IM treatment of HL60 cells downregulates mRNA synthesis of AML1...

Gynäkologisch-geburtshilfliche Rundschau

Biochemical Pharmacology, 2013

There is growing evidence that aminobisphosphonates like ibandronate show anticancer activity by ... more There is growing evidence that aminobisphosphonates like ibandronate show anticancer activity by an unknown mechanism. Biochemically, they prevent posttranslational isoprenylation of small GTPases, thus inhibiting their activity. In tumor cells, activated RAS-GTPase, the founding member of the gene family, down-regulates the expression of the pro-apoptotic gene FAS via epigenetic DNA-methylation by DNMT1. We compared ibandronate treatment in neoplastic human U-2 osteosarcoma and in mouse CCL-51 breast cancer cells as well as in the immortalized non-neoplastic MC3T3-E1 osteoblastic cells. Ibandronate attenuated cell proliferation in all cell lines tested. In the neoplastic cells we found upregulation of caspases suggesting apoptosis. Further we found stimulation of FAS-expression as a result of epigenetic DNA demethylation that was due to down-regulation of DNMT1, which was rescued by reisoprenylation by both geranylgeranyl-pyrophosphate and farnesylpyrophosphate. In contrast, ibandronate did not affect FAS and DNMT1 expression in MC3T3-E1 non-neoplastic cells. Data suggest that bisphosphonates via modulation of the activity of small-GTPases induce apoptosis in neoplastic cells by DNA-CpG-demethylation and stimulation of FAS-expression. In conclusion the shown epigenetic mechanism underlying the anti-neoplastic activity of farnesyl-transferase-inhibition, also explains the clinical success of other drugs, which target this pathway.

Functional Food Science

The main argument for the optimization of nutritional strategies in athletes, besides improved pe... more The main argument for the optimization of nutritional strategies in athletes, besides improved performance, is the preservation of health and the prevention of unwanted training effects. This highlights the importance of personalized nutrition strategies, as well as functional foods and phytonutrients based on individual requirements which can be precisely defined by detailed analyses, including genetics, epigenetics, gut microbiota, gender, and environmental factors. Recently, a miRNA-based “Fitness Score to Assess the Individual Response to Diet, Metabolism and Exercise” was developed by our group. Formulations of sports drinks and sports foods should be carefully considered, as they frequently contain a mixture of multiple ingredients. Macronutrient supplements, such as carbohydrates, proteins, protein components, fatty acids and probiotics are known to provide benefits for athletes with energy deficits, electrolyte imbalance, gastrointestinal issues, fatigue, and cardiovascular ...

Background: Up-regulation of energy metabolism is a key feature of proliferating cells from cance... more Background: Up-regulation of energy metabolism is a key feature of proliferating cells from cancers and leukemias. Thus, targeting of metabolic pathways represents a therapeutic challenge involving both dietary and drug-mediated strategies. The aim of this study was to evaluate the impact of the DNA-methyltransferase-inhibitor 5-desoxy-2-azacytidine (Decitabine, DAC) and the histone-deacetylase-inhibitor suberoyl anilide hydroxamic acid (SAHA, Vorinostat) on malignancy-associated metabolic pathways. Methods: HL60 promyelocytic cells and KG1 myeloblastic leukemia cells were treated with DAC or SAHA for 3 days. RNA was isolated and gene expression was analyzed using Affymetrix human gene 1.0 arrays in comparison with published databases from normal CD34 positive hematopoietic progenitors. Pathvisio software tool was used for comparative quantification of gene-expression patterns from metabolic pathways based on established data banks such as KEGG and Wikipathways. Results: A comparison of both leukemia cell lines to normal CD34 + cells indicated malignancy-associated stimulation of energy metabolism. Global evaluation on pathways demonstrated a significant drug-mediated downregulation of the intra-mitochondrial pathways, namely the tri-carbonic acid cycle and beta oxidation and to a lesser extent also cytoplasmic glycolysis. Conclusion: The observation that the KG1 cell line reacted more sensitive to demethylating drugs than the HL60 cell line, where drug treatment selected for survival of differentiated cells, may support application of DAC and SAHA to leukemias with an undifferentiated phenotype but also with the potential to induce differentiation. Efficient targeting of intra-mitochondrial pathways appears to be associated with multiple pro-apoptotic activities of these drugs.

Molecular Cancer Research, 2016

The metabolic oncogene fatty acid synthase (FASN) is overexpressed in 80% of ovarian cancers (OC)... more The metabolic oncogene fatty acid synthase (FASN) is overexpressed in 80% of ovarian cancers (OC) and indicates poor prognosis. Exposure of OC to inhibitors of FASN elicits a complex stress response that interferes with receptor-PI3K-mTORC1 signaling (briefly designated ‘PI3K pathway’). Here we demonstrate that FASN inhibitors capitalize on multiple mechanisms to interfere with the PI3K pathway, and that silencing this cascade is crucial for the anticancer action of the drugs. Data were obtained using thin-layer chromatography, ELISA, Western blotting, quantitative micropatterning and growth assays, respectively. Exposure of OC cells (SKOV3, OVCAR-3) to FASN inhibitors (C75, G28UCM) causes lipid redistribution toward storage lipids, whereas membrane lipid rafts and signaling lipids are diminished, which significantly impairs EGF receptor/ErbB/HER function and expression. A severe depletion of phosphatidylinositol (3,4,5) trisphosphate (PIP3), which represents the crucial product of ...

Blood, 2005

Osteocalcin (OCN) is defined as a marker for osteoblasts but incompletely spliced variants as cha... more Osteocalcin (OCN) is defined as a marker for osteoblasts but incompletely spliced variants as characterised by intron retention may also occur in non-osseous tissues including tumour cells. Bone marrow of haematological diseases was shown to harbour a stem cell candidate common to MSC (mesenchymal stem cells) and HSC (haematopoietic stem cells), which expressed OCN. In this study, we analysed cells from bone marrow samples obtained from 4 patients with AMLs, one patient with CML at blast crisis, one CML patient in chronic phase and 7 patients with myeloproliferative disease (MPD), as well as stem cells from peripheral blood and bone marrow obtained from healthy donors. In attempt to find out whether the presence of such stem cells is associated with disease status, sequential bone marrow samples from a patient with acute myeloid leukaemia (AML/M2Eo) were analysed at 6 time points including diagnosis, remission (= months 4, 5 and 17 after diagnosis) and relapse (months 29 and 41 afte...

dihydroxyvitamin D3 regulates essential pathways of cellular metabolism and differentiation via i... more dihydroxyvitamin D3 regulates essential pathways of cellular metabolism and differentiation via its nuclear receptor (VDR). Molecular mechanisms which are known to play key roles in aging and cancer are mediated by complex processes involving epigenetic mechanisms contributing to efficiency of VD-activating CYP27A1 and CYP27B1 or inactivating CYP24 enzymes as well as VDR which binds to specific genomic sequences (VD response elements or VDREs). Activity of VDR can be modulated epigenetically by histone acetylation. It co-operates with other nuclear receptors which are influenced by histone acetyl transferases (HATs) as well as several types of histone deacetylases (HDACs). HDAC inhibitors (HDACi) and/or demethylating drugs may contribute to normalization of VD metabolism. Studies link VD signaling through the VDR directly to distinct molecular mechanisms of both HAT activity and the sirtuin class of HDACs (SIRT1) as well as the forkhead transcription factors thus contributing to elu...

Functional Foods in Health and Disease, 2020

Following research obtained from the previous SARS and MERS outbreaks, we’ve gained knowledge abo... more Following research obtained from the previous SARS and MERS outbreaks, we’ve gained knowledge about the mechanisms of bioactive plant ingredients against the attachment and replication of COVID-19 as well as overshooting immune responses. This could be used for designing COVID-19 trials utilizing bioactive compounds. The receptors for SARS, ACE-2, and CD26 show associations with mechanisms that regulate human senescence. Several functional foods interact with the epigenetic regulation of viral infection and mechanisms of senescence. This review concentrates on the link between bioactive plant ingredients and their activities against mechanisms of viral infections.Keywords: COVID-19, Epigenetic, Quercetin, Curcumin, Epigallocatechin gallate, Phloretin, Berberine

Blood, 2011

3463 Epigenetic and apoptosis-regulating mechanisms have been implicated as critical factors cont... more 3463 Epigenetic and apoptosis-regulating mechanisms have been implicated as critical factors contributing to the progression from myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (AML). However, the exact molecular mechanisms and genes involved in disease evolution have not been identified yet. We screened for epigenetically regulated pro-apoptotic effector molecules in neoplastic cells in patients with MDS (n=50) and AML (n=30). Among a series of potential regulators, we identified FAS (CD95) as an epigenetically regulated critical death regulator in neoplastic cells. As assessed by qPCR, bone marrow cells obtained from patients with low risk MDS were found to display high levels of FAS, whereas FAS mRNA levels were lower or undetectable in patients with advanced MDS (with excess of blasts) or secondary AML. Moreover, we were able to show by multicolor flow cytometry that CD34+/CD38+ progenitor cells and CD34+/CD38- stem cells in MDS and AML display measurable FA...

Blood, 2006

Hypermethylation of CpG islands within gene promoter regions is associated with transcriptional i... more Hypermethylation of CpG islands within gene promoter regions is associated with transcriptional inactivation of genes involved in cellular proliferation and differentiation and represents, in addition to genetic aberrations, an important mechanism of transcriptional silencing in the pathogenesis of age-associated diseases such as myelodysplastic syndromes (MDS). We have previously reported downregulation of enzymes associated with carnitine-metabolism (including the carnitine transporter OCTN2, which is responsible for carnitine uptake into cells) in healthy elderly persons, as well as a specific downregulation of microsomal carnitine palmitoyltransferase (mCPT; also known as glucose regulated protein GRP58 or endoplasmatic reticulum protein ERp61) a marker for proliferative potential of cells in MDS patients (J.Mol.Med, 81:435ff 2003). Aim of this study was to elucidate the mechanism of this downregulation by analysing the methylation status of the mCPT promoter in 14 MDS patients ...

Blood, 2009

4423 Background Dysregulation of energy metabolism is a key feature of malignancy and known to be... more 4423 Background Dysregulation of energy metabolism is a key feature of malignancy and known to be regulated by epigenetic mechanisms. This study explores gene expression in the KG1 cell line and a primary culture of leukemic blasts from a patient, both incubated with SAHA (suberoyl anilide hydroxamic acid, also known as Vorinostat) in comparison to other epigenetic drugs such as Decitabine (DAC) but also nutritional compounds such as genistein and vitamin D3 with a known activity on metabolism where epigenetic mechanisms play a role. Methods Following a 3 days incubation with pharmacologic concentrations of the above mentioned compounds, gene expression patterns of the KG1 cell-line were analysed on an Affymetrix Gene Expression Array and specifically evaluated by quantitative real time PCR from KG1 cells and primary leukemic cells of a patient with an AML-M2 which were cultured at the same conditions as the KG1 cells. In order to confirm epigenetic mechanisms induced by targeted dr...

Flora, 1983

Summary Leaf water characteristics of two evergreen shrubs, Prunus laurocerasus L. and Ilex aquif... more Summary Leaf water characteristics of two evergreen shrubs, Prunus laurocerasus L. and Ilex aquifolium L., were followed for one year by means of the pressure-volume curve technique. Osmotic potentials of newly emerged leaves were about 1 MPa higher (less negative) than those of mature, over-wintered leaves. This difference disappeared during the first months of leaf development, when the vacuolar solution in newly emerged leaves gradually became more concentrated. Daycourses of total water potential show the most negative values for fully mature leaves. Pressurevolume curves were used to convert these field data into corresponding values for the turgor potential, which were byfar higher for old than for young leaves. Recently emerged leaves in spring may therefore come under severe stress during periods of only moderately lowered total water potentials.

Methods in Pharmacology and Toxicology, 2016

Wiener klinische Wochenschrift, Jan 13, 2018

In 2008 the Ludwig Boltzmann Cluster Oncology (LBC ONC) was established on the basis of two previ... more In 2008 the Ludwig Boltzmann Cluster Oncology (LBC ONC) was established on the basis of two previous Ludwig Boltzmann Institutes working in the field of hematology and cancer research. The general aim of the LBC ONC is to improve treatment of hematopoietic neoplasms by eradicating cancer-initiating and disease-propagating cells, also known as leukemic stem cells (LSC) in the context of leukemia. In a first phase, the LBC ONC characterized the phenotype and molecular aberration profiles of LSC in various malignancies. The LSC phenotypes were established in acute and chronic myeloid leukemia, in acute lymphoblastic leukemia and in chronic lymphocytic leukemia. In addition, the concept of preleukemic (premalignant) neoplastic stem cells (pre-L-NSC) was coined by the LBC ONC and was tested in myelodysplastic syndromes and myeloproliferative neoplasms. Phenotypic characterization of LSC provided a solid basis for their purification and for the characterization of specific target expressi...

Studies in athletes have shown that carnitine supplementation may foster exercise performance. As... more Studies in athletes have shown that carnitine supplementation may foster exercise performance. As reported in the majority of studies, an increase in maximal oxygen consumption and a lowering of the respiratory quotient indicate that dietary carnitine has the potential to stimulate lipid metabolism. Treatment with L-carnitine also has been shown to induce a significant postexercise decrease in plasma lactate, which is formed and used continuously under fully aerobic conditions. Data from preliminary studies have indicated that L-carnitine supplementation can attenuate the deleterious effects of hypoxic training and speed up recovery from exercise stress. Recent data have indicated that L-carnitine plays a decisive role in the prevention of cellular damage and favorably affects recovery from exercise stress. Uptake of L-carnitine by blood cells may induce at least three mechanisms: 1) stimulation of hematopoiesis, 2) a dose-dependent inhibition of collagen-induced platelet aggregatio...

Reference Module in Biomedical Sciences

Katharina Tomek, Renate Wagner, Franz Varga, Christian F. Singer, Heidrun Karlic4, Thomas W. Grun... more Katharina Tomek, Renate Wagner, Franz Varga, Christian F. Singer, Heidrun Karlic4, Thomas W. Grunt1,4 Signaling Networks Program, Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University Vienna; Ludwig Boltzmann Institute of Osteology and 4th Medical Department, Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, Vienna; Department of Obstetrics/Gynecology, Comprehensive Cancer Center, Medical University Vienna; Ludwig Boltzmann Cluster Oncology, Medical University Vienna, Austria

Blood

Background: In contrast to other human endogenous retrovirus families which are highly defective,... more Background: In contrast to other human endogenous retrovirus families which are highly defective, HERV-K proviruses possess all viral gene types of exogenous retroviruses. In malignancy (tumor cell lines, breast cancer, melanoma as well as leukemias and lymphomas) but also in many normal tissues, including placenta HERV-K mRNA expression has been detected. In hematopoietic stem cells, an interaction of HERV-K with elements from vectors which are used for gene therapy may lead to unforeseen consequences. The purpose of this study was to localize HERV-K mRNA expression in hematopoietic stem cells of different sources and to evaluate a potential association of HERV-expression with hematologic diseases and to define a possible risk of HERV-expression for transplantation. Methods: Quantitative real time PCR (RTQPCR) was used for detecting HERV-K expression in MNC from blood and/or bone marrow samples of patients with leukemias ( 10 MDS, 16 MPD, 14 AML and 1 CML blast crisis) and MNC from...

Blood

Besides blockade of tyrosine kinases such as c-kit, Imatinib mesylate (IM) regulates glucose flux... more Besides blockade of tyrosine kinases such as c-kit, Imatinib mesylate (IM) regulates glucose flux through downregulation of GLUT-1 transporters in human leukemia cells. This mechanism has the potential to induce regression of type 2 diabetes and hyperlipidemia as observed in patients with chronic myeloid leukemia or hypereosinophilic syndrome. In addition, there is a stimulatory effect of IM on differentiation of human mesenchymal stem cells. Its synergism with retinoic acid or low dose Ara-C is applied in treatment of acute myeloid leukemia (AML). Thus, the AML-derived c-kit positive cell line HL60 was chosen for studying the effect of IM on expression of genes associated with differentiation and metabolism. We analysed the possible feedback on transcription factors (AML1 and AML3) and consequences regarding differentiation and metabolism - associated genes. Quantitative reverse transcriptase PCR analyses revealed that IM treatment of HL60 cells downregulates mRNA synthesis of AML1...

Gynäkologisch-geburtshilfliche Rundschau