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Fagerholm R.,University of Helsinki | Sprott K.,On-Q-ity | Heikkinen T.,University of Helsinki | Bartkova J.,Danish Cancer Society | And 7 more authors.
Annals of Oncology | Year: 2013

Background: Defective DNA repair is central to the progression and treatment of breast cancer. Immunohistochemically detected DNA repair markers may be good candidates for novel prognostic and predictive factors that could guide the selection of individualized treatment strategies. Patients and methods: We have analyzed nuclear immunohistochemical staining of BRCA1, FANCD2, RAD51, XPF, and PAR in relation to clinicopathological and survival data among 1240 paraffin-embedded breast tumors, and additional gene expression microarray data from 76 tumors. The antioxidant enzyme NQO1 was analyzed as a potential modifier of prognostic DNA repair markers. Results: RAD51 [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.70-0.94, P = 0.0050] and FANCD2 expression (HR 1.50, 95% CI 1.28-1.76, P = 1.50 × 10-7) were associated with breast cancer survival. High FANCD2 expression correlated with markers of adverse prognosis but remained independently prognostic in multivariate analysis (HR 1.27, 95% CI 1.08-1.49, P = 0.0043). The FANCD2-associated survival effect was most pronounced in hormone receptor positive, HER2-negative tumors, and in tumors with above-median NQO1 expression. In the NQO1-high subset, patients belonging to the highest quartile of FANCD2 immunohistochemical scores had a threefold increased risk of metastasis or death (HR 3.10, 95% CI 1.96-4.92). Global gene expression analysis indicated that FANCD protein overabundance is associated with the upregulation of proliferation-related genes and a downregulated nucleotide excision repair pathway. Conclusion: FANCD2 immunohistochemistry is a sensitive, independent prognostic factor in breast cancer, particularly when standard markers indicate relatively favorable prognosis. Taken together, our results suggest that the prognostic effect is linked to proliferation, DNA damage, and oxidative stress; simultaneous detection of FANCD2 and NQO1 provides additional prognostic value. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology All rights reserved. Source


Roubec M.,University of Ostrava | Kuliha M.,University of Ostrava | Kuliha M.,Comprehensive Stroke Center | Prochazka V.,University of Ostrava | And 9 more authors.
Radiology | Year: 2013

Purpose: To compare safety and utility of intraarterial revascularization with use of stents to no revascularization in patients who either failed to respond to intravenous thrombolysis (IVT) or have contraindications to IVT. Materials and Methods: The case-control study was approved by local ethics committees; all patients signed informed consent. One hundred thirty-one patients (74 men; mean age, 65.9 years ± 12.3; range, 25-86 years) with acute ischemic stroke (AIS) due to middle cerebral artery (MCA) occlusion were enrolled; 75 underwent IVT. No further recanalization therapy was performed in 26 (35%) IVT-treated patients with MCA recanalization (group 1). Patients with IVT failure after 60 minutes were allocated to endovascular treatment (group 2A) or no further therapy (group 2B). Patients with contraindication to IVT were allocated to endovascular treatment within 8 hours since AIS onset (group 3A) or to no recanalization therapy (group 3B). Neurologic deficit at admission, MCA recanalization, symptomatic intracerebral hemorrhage (SICH), and 3-month clinical outcome were evaluated. Favorable clinical outcome was defined as modified Rankin scale score 0-2 at 3 months after stroke onset. Two-sided Mann-Whitney U test, independent samples t test, Fisher exact test, multivariate logistic regression analysis of baseline variables, and complete MCA recanalization for the prediction of favorable clinical outcome were used for statistical evaluation. Results: Median National Institutes of Health Stroke Scale score at admission was 13.5, 16.0, 15.5, 15.0, and 16.0 in groups 1, 2A, 2B, 3A, and 3B, respectively (P > .05); SICH occurred in one of 26 (3.8%), one of 23 (4.3%), one of 26 (3.8%), one of 31 (3.2%), and one of 25 (4.0%) patients, respectively (P > .05). MCA recanalization after endovascular treatment was achieved in 50 of 54 (92.6%) patients. Favorable outcome was significantly different between groups 2A and 2B (10 of 23 [43.5%] and four of 26 [15.4%], respectively; P = .03) and groups 3A and 3B (14 of 31 [45.2%] and two of 25 [8.0%], respectively; P = .004) and was dependent on MCA recanalization (odds ratio, 5.55; P = .006). Conclusion: In this controlled trial, intraarterial revascularization with stents was an effective and safe-effective treatment option in patients with acute MCA occlusion with contraindication to IVT or after IVT failure. © RSNA, 2012. Source


Liontos M.,National and Kapodistrian University of Athens | Velimezi G.,National and Kapodistrian University of Athens | Pateras I.S.,National and Kapodistrian University of Athens | Angelopoulou R.,National and Kapodistrian University of Athens | And 4 more authors.
Journal of Cellular and Molecular Medicine | Year: 2010

DNA lesions trigger the DNA damage response (DDR) machinery, which protects genomic integrity and sustains cellular survival. Increasing data underline the significance of the integrity of the DDR pathway in chemotherapy response. According to a recent work, persistent exposure of A549 lung carcinoma cells to doxorubicin induces an initial DDR-dependent checkpoint response, followed by a later DDR-independent, but p27Kip1-dependent one. Prompted by the above report and to better understand the involvement of the DDR signaling after chemotherapeutic stress, we examined the potential role of the canonical DDR pathway in A549 cells treated with doxorubicin. Exposure of A549 cells, prior to doxorubicin treatment, to ATM, ATR and DNA-PKcs inhibitors either alone or in various combinations, revealed that the earlier documented two-step response was DDR-dependent in both steps. Notably, inhibition of both ATM and ATR or selective inhibition of ATM or DNA-PKcs resulted in cell-cycle re-entry despite the increased levels of p27Kip1 at all time points analyzed. We further investigated the regulation of p27Kip1 protein levels in the particular setting. Our results showed that the protein status of p27Kip1 is mainly determined by p38-MAPK, whereas the role of SKP2 is less significant in the doxoroubicin-treated A549 cells. Cumulatively, we provide evidence that the DNA damage signaling is responsible for the prolonged cell cycle arrest observed after persistent chemotherapy-induced genotoxic stress. In conclusion, precise identification of the molecular mechanisms that are activated during the chemotherapeutic cycles could potentially increase the sensitization to the therapy applied. © 2010 The Authors. Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. Source


Burglova K.,Institute of Molecular and Translational Medicine | Hlavac J.,Institute of Molecular and Translational Medicine | Bartlett J.R.,University of The Sunshine Coast
Journal of Nanoparticle Research | Year: 2015

In this paper, we describe a new approach for producing metal oxide nano- and microparticles via sol–gel processing in confined media (sodium bis(2-ethylhexyl)sulfosuccinate reverse micelles), in which the chemical and physical properties of the polar aqueous core of the reverse micelles are modulated by the inclusion of a second polar co-solvent. The co-solvents were selected for their capacity to solubilise compounds with low water solubility and included dimethylsulfoxide, dimethylformamide, ethylene glycol, n-propanol, dimethylacetamide and N-methylpyrrolidone. A broad range of processing conditions across the sodium bis(2-ethylhexyl)sulfosuccinate/cyclohexane/water phase diagram were identified that are suitable for preparing particles with dimensions <50 to >500 nm. In contrast, only a relatively narrow range of processing conditions were suitable for preparing such particles in the absence of the co-solvents, highlighting the role of the co-solvent in modulating the properties of the polar core of the reverse micelles. A mechanism is proposed that links the interactions between the various reactive sites on the polar head group of the surfactant and the co-solvent to the nucleation and growth of the particles. © 2015, Springer Science+Business Media Dordrecht. Source


Briza T.,Institute of Chemical Technology Prague | Kralova J.,Academy of Sciences of the Czech Republic | Dolensky B.,Institute of Chemical Technology Prague | Rimpelova S.,Institute of Chemical Technology Prague | And 8 more authors.
ChemBioChem | Year: 2015

A novel pentamethinium salt was synthesized with an unforeseen expanded conjugated quinoxaline unit directly incorporated into a pentamethinium chain. The compound exhibited high fluorescence intensity, selective mitochondrial localization, high cytotoxicity, and selectivity toward malignant cell lines, and resulted in remarkable in vivo suppression of tumor growth in mice. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

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