59 research outputs found

    The mitochondrial calcium uniporter regulates breast cancer progression via HIF-1α

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    Triple-negative breast cancer (TNBC) represents the most aggressive breast tumor subtype. However, the molecular determinants responsible for the metastatic TNBC phenotype are only partially understood. We here show that expression of the mitochondrial calcium uniporter (MCU), the selective channel responsible for mitochondrial Ca(2+) uptake, correlates with tumor size and lymph node infiltration, suggesting that mitochondrial Ca(2+) uptake might be instrumental for tumor growth and metastatic formation. Accordingly, MCU downregulation hampered cell motility and invasiveness and reduced tumor growth, lymph node infiltration, and lung metastasis in TNBC xenografts. In MCU-silenced cells, production of mitochondrial reactive oxygen species (mROS) is blunted and expression of the hypoxia-inducible factor-1α (HIF-1α) is reduced, suggesting a signaling role for mROS and HIF-1α, downstream of mitochondrial Ca(2+) Finally, in breast cancer mRNA samples, a positive correlation of MCU expression with HIF-1α signaling route is present. Our results indicate that MCU plays a central role in TNBC growth and metastasis formation and suggest that mitochondrial Ca(2+) uptake is a potential novel therapeutic target for clinical intervention

    Transcriptional co-activators YAP1-TAZ of Hippo signalling in doxorubicin-induced cardiomyopathy

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    Aims Hippo signalling is an evolutionarily conserved pathway that controls organ size by regulating apoptosis, cell proliferation, and stem cell self-renewal. Recently, the pathway has been shown to exert powerful growth regulatory activity in cardiomyocytes. However, the functional role of this stress-related and cell death-related pathway in the human heart and cardiomyocytes is not known. In this study, we investigated the role of the transcriptional co-activators of Hippo signalling, YAP and TAZ, in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in response to cardiotoxic agents and investigated the effects of modulating the pathway on cardiomyocyte function and survival. Methods and results RNA-sequencing analysis of human heart samples with doxorubicin-induced end-stage heart failure and healthy controls showed that YAP and ERBB2 (HER2) as upstream regulators of differentially expressed genes correlated with doxorubicin treatment. Thus, we tested the effects of doxorubicin on hiPSC-CMs in vitro. Using an automated high-content screen of 96 clinically relevant antineoplastic and cardiotherapeutic drugs, we showed that doxorubicin induced the highest activation of YAP/TAZ nuclear translocation in both hiPSC-CMs and control MCF7 breast cancer cells. The overexpression of YAP rescued doxorubicin-induced cell loss in hiPSC-CMs by inhibiting apoptosis and inducing proliferation. In contrast, silencing of YAP and TAZ by siRNAs resulted in elevated mitochondrial membrane potential loss in response to doxorubicin. hiPSC-CM calcium transients did not change in response to YAP/TAZ silencing. Conclusions Our results suggest that Hippo signalling is involved in clinical anthracycline-induced cardiomyopathy. Modelling with hiPSC-CMs in vitro showed similar responses to doxorubicin as adult cardiomyocytes and revealed a potential cardioprotective effect of YAP in doxorubicin-induced cardiotoxicity

    Antifascism, the 1956 Revolution and the politics of communist autobiographies in Hungary 1944-2000

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    This is a postprint of an article whose final and definitive form has been published in Europe-Asia Studies © 2006 University of Glasgow; Europe-Asia Studies is available online at http://www.informaworld.com.Using oral history, this contribution explores the reshaping of individuals' public and private autobiographies in response to different political environments. In particular, it analyses the testimony of those who were communists in Hungary between 1945 and 1956, examining how their experiences of fascism, party membership, the 1956 Revolution and the collapse of communism led them in each case to refashion their life stories. Moreover, it considers how their biographies played varying functions at different points in their lives: to express identification with communism, to articulate resistance and to communicate ambition before 1956; to protect themselves from the state after 1956; and to rehabilitate themselves morally in a society which stigmatised them after 1989.I didn't use this word 'liberation' (felszabadulĂĄs), because in 1956 my life really changed. Everybody's lives went through a great change, but mine especially. 
 I wasn't disgusted with myself that I had called the arrival of the Red Army in 1945 a liberation, but [after 1956] I didn't use it anymore

    The global distribution of fatal pesticide self-poisoning: Systematic review

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    <p>Abstract</p> <p>Background</p> <p>Evidence is accumulating that pesticide self-poisoning is one of the most commonly used methods of suicide worldwide, but the magnitude of the problem and the global distribution of these deaths is unknown.</p> <p>Methods</p> <p>We have systematically reviewed the worldwide literature to estimate the number of pesticide suicides in each of the World Health Organisation's six regions and the global burden of fatal self-poisoning with pesticides. We used the following data sources: Medline, EMBASE and psycINFO (1990–2007), papers cited in publications retrieved, the worldwide web (using Google) and our personal collections of papers and books. Our aim was to identify papers enabling us to estimate the proportion of a country's suicides due to pesticide self-poisoning.</p> <p>Results</p> <p>We conservatively estimate that there are 258,234 (plausible range 233,997 to 325,907) deaths from pesticide self-poisoning worldwide each year, accounting for 30% (range 27% to 37%) of suicides globally. Official data from India probably underestimate the incidence of suicides; applying evidence-based corrections to India's official data, our estimate for world suicides using pesticides increases to 371,594 (range 347,357 to 439,267). The proportion of all suicides using pesticides varies from 4% in the European Region to over 50% in the Western Pacific Region but this proportion is not concordant with the volume of pesticides sold in each region; it is the pattern of pesticide use and the toxicity of the products, not the quantity used, that influences the likelihood they will be used in acts of fatal self-harm.</p> <p>Conclusion</p> <p>Pesticide self-poisoning accounts for about one-third of the world's suicides. Epidemiological and toxicological data suggest that many of these deaths might be prevented if (a) the use of pesticides most toxic to humans was restricted, (b) pesticides could be safely stored in rural communities, and (c) the accessibility and quality of care for poisoning could be improved.</p

    Energy dispersive spectroscopy and electron backscatter diffraction analysis of isothermally aged SAF 2507 type superduplex stainless steel

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    Due to thermal effects, several precipitation and segregation processes are known in duplex stainless steels. These microstructural changes influence both of the original phases, but in different ways. Isothermal ageing in a large range of temperature was performed on SAF 2507 type steel. The temperature range was 300–1000 8C, the ageing time was between 100 s and 24 h. This paper discusses the results of ageing at \n900 C°. Microstructural changes were investigated by electron microscopy, energy-dispersive spectroscopy and electron backscattered diffraction analysis. This technique allowed the determination of the microstructure of the secondary austenite and sigma phase and their mutual orientation properties. Beside this, thermoelectric power measurements were also performed, which gave information about the kinetics of the precipitation process. Results showed that sigma-phase precipitation started right after 200 s in the case of annealed steel, and \nfaster than 100 s in the cold-rolled state. After 5000 s, the delta-ferrite disappeared. Chemical composition of sigma phase was independent on the ageing time. A small decrease in nickel content was observed with a slight increase of Cr content. Small amount of chi phase had also been observed on the ferrite–ferrite boundaries, but later they changed into sigma phase. Similarly to sigma phase, chi phase showed significant phosphorus enrichment. During ageing, small chrome nitride precipitates developed, which amount increased in time, and some \nvanadium could be measured in them. The orientation relationship between austenite and sigma phase deviated from Nenno-orientationship with about 24°, and seems to form a [110]||[310] relationship, which was characteristic right from the beginning of the process, and remains more or less constant

    Generation and analysis of pluripotent stem cell-derived cardiomyocytes and endothelial cells for high content screening purposes

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    Human-induced pluripotent stem cells (hiPSCs) and their differentiated derivatives became a new, promising source for in vitro screening techniques. Cell lines derived from healthy individuals can be applied for drug safety testing, while patient-derived cells provide a platform to model diseases in vitro and can be used as a tool for personalized medicine including specific drug efficacy testing and identification of new pharmacological targets as well as for tailoring pharmacological therapies. Efficient differentiation protocols yielding cardiomyocytes or endothelial cells derived from iPSCs have been developed recently. Phenotypic characterization and gene expression profiling of these derivatives can reveal clues for developmental and pathological questions. Moreover, functional analysis and cell-based assays using automated fluorescence imaging platform and high content analysis characterize cell type-specific profiles of hiPSC-derived cardiomyocytes (hiPSC-CM) and endothelial cells (hiPSC-EC) at the cellular and subcellular levels. This can be utilized in a platform which can provide multiple endpoint profiles of candidate compounds
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