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Petzer A.L.,Innsbruck Medical University | Fong D.,Innsbruck Medical University | Lion T.,CCRI Childrens Cancer Research Institute | Dyagil I.,RC Radiation Medicine | And 15 more authors.
Haematologica | Year: 2012

Background Previous data suggest that the response of chronic myeloid leukemia cells to imatinib is dosedependent. The potential benefit of initial dose intensification of imatinib in pre-treated patients with chronic phase chronic myeloid leukemia remains unknown. Design and Methods Two hundred and twenty-seven pre-treated patients with chronic myeloid leukemia in chronic phase were randomly assigned to continuous treatment with a standard dose of imatinib (400 mg/day; n=113) or to 6 months of high-dose induction with imatinib (800 mg/day) followed by a standard dose of imatinib as maintenance therapy (n=114). Results The rates of major and complete cytogenetic responses were significantly higher in the highdose arm than in the standard-dose arm at both 3 and 6 months (major cytogenetic responses: 36.8% versus 21.2%, P=0.01 and 50.0% versus 34.5%, P=0.018; complete cytogenetic responses: 22.8% versus 6.2%, P<0.001 and 40.4% versus 16.8%, P<0.001) on the basis of an intentionto-treat analysis. At 12 months, the difference between treatment arms remained statistically significant for complete cytogenetic responses (40.4% versus 24.8%, P=0.012) but not for major cytogenetic responses (49.1% versus 44.2%, P=0.462). The rate of major molecular responses was also significantly better at 3 and 6 months in the high-dose arm (month 3: 14.9% versus 3.5%, P=0.003; month 6: 32.5% versus 8.8%, P<0.001). Overall and progression-free survival rates were comparable between arms, but event-free survival was significantly worse in the high-dose arm (P=0.014). Conclusions Standard-dose imatinib remains the standard of care for pre-treated patients with chronic phase chronic myeloid leukemia (Clinicaltrials.gov identifier: NCT00327262). ©2012 Ferrata Storti Foundation.


Dellago H.,University of Natural Resources and Life Sciences, Vienna | Preschitz-Kammerhofer B.,University of Natural Resources and Life Sciences, Vienna | Terlecki-Zaniewicz L.,University of Natural Resources and Life Sciences, Vienna | Schreiner C.,University of Natural Resources and Life Sciences, Vienna | And 16 more authors.
Aging Cell | Year: 2013

Cellular senescence of normal human cells has by now far exceeded its initial role as a model system for aging research. Many reports show the accumulation of senescent cells in vivo, their effect on their microenvironment and its double-edged role as tumour suppressor and promoter. Importantly, removal of senescent cells delays the onset of age-associated diseases in mouse model systems. To characterize the role of miRNAs in cellular senescence of endothelial cells, we performed miRNA arrays from HUVECs of five different donors. Twelve miRNAs, comprising hsa-miR-23a, hsa-miR-23b, hsa-miR-24, hsa-miR-27a, hsa-miR-29a, hsa-miR-31, hsa-miR-100, hsa-miR-193a, hsa-miR-221, hsa-miR-222 and hsa-let-7i are consistently up-regulated in replicatively senescent cells. Surprisingly, also miR-21 was found up-regulated by replicative and stress-induced senescence, despite being described as oncogenic. Transfection of early passage endothelial cells with miR-21 resulted in lower angiogenesis, and less cell proliferation mirrored by up-regulation of p21CIP1 and down-regulation of CDK2. These two cell-cycle regulators are indirectly regulated by miR-21 via its validated direct targets NFIB (Nuclear factor 1 B-type), a transcriptional inhibitor of p21CIP1, and CDC25A, which regulates CDK2 activity by dephosphorylation. Knock-down of either NFIB or CDC25A shows a phenocopy of over-expressing miR-21 in regard to cell-cycle arrest. Finally, miR-21 over-epxression reduces the replicative lifespan, while stable knock-down by sponges extends the replicative lifespan of endothelial cells. Therefore, we propose that miR-21 is the first miRNA that upon its knock-down extends the replicative lifespan of normal human cells. © 2013 John Wiley & Sons Ltd and the Anatomical Society.


Sieczkowski E.,Medical University of Vienna | Lehner C.,Medical University of Vienna | Ambros P.F.,CCRI Childrens Cancer Research Institute | Hohenegger M.,Medical University of Vienna
International Journal of Cancer | Year: 2010

The development of multidrug resistance (MDR) is a major problem during cancer treatment. Drug efflux via ATP-binding cassette (ABC) transporters is the main mechanism responsible for resistance to chemotherapeutics. We have recently observed that statins enhance susceptibility to doxorubicin-induced apoptosis in human rhabdomyosarcoma cells, which is now also observed in human SH-SY5Y neuroblastoma cells. We have therefore investigated the ABC transporter activity to confirm a possible inhibition by statins in SH-SY5Y cells. Indeed, simvastatin directly inhibited dye transport at equimolar concentrations of the ABC transporter inhibitor, verapamil. Making use of the fluorescence behavior of doxorubicin the accumulation of anthracycline was monitored in real-time confocal microscopy. The intracellular doxorubicin accumulation was immediately enhanced by statins in SH-SY5Y cells and also in a MYCN-amplified neuroblastoma cell line STA-NB-10. The heavily glycosylated P-glycoprotein (ABCB1, P-gp) transporter appeared as a 180-and 140-kDa species. Atorvastatin and simvastatin reduced the 180-kDa form of P-gp, but not verapamil. Thereby the fully glycosylated species is shifted to the core glycosylated species (140 kDa), which was only seen at statin exposure times longer than 24 hr. The functional importance of glycosylation of the transporter was highlighted by exogenous application of N-glycosidase F, which was sufficient to enhance doxorubicin accumulation. Hence, these novel findings of statins' dual impact on P-gp have clinical implications. The enhanced intracellular accumulation of chemotherapeutics or other ABC transporter substrates in the presence of statins may represent a novel concept to overcome MDR in cancer therapy and improve drug safety. © 2009 UICC.


PubMed | Medical University of Vienna and CCRI Childrens Cancer Research Institute
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2016

Immunodetection is described in this chapter as a technique for producing specific antibodies for antigen detection of the major human fungal pathogens. In the case of Candida spp., heat-killed cells are used to immunize mice over a couple of weeks and then splenocytes are isolated and further fused with myelomas to easily propagate the antibodies produced in the mice. The resulting antibodies follow a purification process where antibody levels and concentrations are determined. Fungal cells are also lysed to obtain whole cell extracts as a prior step for identification of antigens using immunoprecipitation. Finally, this method permits the production of specific antibodies against fungi and the identification of the respective antigens in an in vivo model.

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