Loss of histone macroH2A1 in hepatocellular carcinoma cells promotes paracrine-mediated chemoresistance and CD4+CD25+FoxP3+ regulatory T cells activation

Rationale: Loss of histone macroH2A1 induces appearance of cancer stem cells (CSCs)-like cells in hepatocellular carcinoma (HCC). How CSCs interact with the tumor microenvironment and the adaptive immune system is unclear. Methods: We screened aggressive human HCC for macroH2A1 and CD44 CSC marker expression. We also knocked down (KD) macroH2A1 in HCC cells, and performed integrated transcriptomic and secretomic analyses. Results: Human HCC showed low macroH2A1 and high CD44 expression compared to control tissues. MacroH2A1 KD CSC-like cells transferred paracrinally their chemoresistant properties to parental HCC cells. MacroH2A1 KD conditioned media transcriptionally reprogrammed parental HCC cells activated regulatory CD4+/CD25+/FoxP3+ T cells (Tregs). Conclusions: Loss of macroH2A1 in HCC cells drives cancer stem-cell propagation and evasion from immune surveillance

Keratin 19 marks poor differentiation and a more aggressive behaviour in canine and human hepatocellular tumours

Keratin 19 marks poor differentiation and a more aggressive behaviour in canine and human hepatocellular tumours Renee GHM van Sprundel1, Ted SGAM van den Ingh2, Valeer J Desmet3, Azeam Katoonizadeh3, Louis C Penning1, Jan Rothuizen1, Tania Roskams3 and Bart Spee13* * Corresponding author: Bart Spee [email protected] Author Affiliations 1 Department of Clinical Sciences of Companion Animals, Faculty of Veterinary medicine, Utrecht University, Utrecht, The Netherlands 2 TCCI Consultancy BV, Utrecht, The Netherlands 3 Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium For all author emails, please log on. Comparative Hepatology 2010, 9:4 doi:10.1186/1476-5926-9-4 The electronic version of this article is the complete one and can be found online at: http://www.comparative-hepatology.com/content/9/1/4 Received: 23 November 2009 Accepted: 18 February 2010 Published: 18 February 2010 © 2010 van Sprundel et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Propranolol, a β-adrenoceptor antagonist, worsens liver injury in a model of non-alcoholic steatohepatitis

AbstractPrazosin an α1-adrenoceptor (AR) antagonist has been shown to reduce liver injury in a mouse model of non-alcoholic steatohepatitis (NASH) and is suggested as a potential treatment of NASH especially given its concomitant anti-fibrotic properties. The effect however, of β-AR blockade in non-cirrhotic NASH is unknown and is as such investigated here. In the presence of the β-blocker propranolol (PRL), mice fed normal chow or a half methionine and choline deficient diet, supplemented with ethionine (HMCDE), to induce NASH, showed significantly enhanced liver injury, as evidenced by higher hepatic necrosis scores and elevated serum aminotransferases (ALT). Mechanistically, we showed that murine hepatocytes express α and β adrenoceptors; that PRL directly induces hepatocyte injury and death as evidenced by increased release of lactate dehydrogenase, FASL and TNF-α from hepatocytes in the presence of PRL; and that PRL activated the apoptotic pathway in primary hepatocyte cultures, as indicated by upregulation of Fas receptor and caspase-8 proteins. The β-AR antagonist PRL therefore appears to enhance liver injury through induction of hepatocyte death via the death pathway. Further studies are now required to extrapolate these findings to humans but meanwhile, β-AR antagonists should be avoided or used with caution in patients with non-cirrhotic NASH as they may worsen liver injury

InForm software: A semi-Automated research tool to identify presumptive human hepatic progenitor cells, and other histological features of pathological significance

Hepatic progenitor cells (HPCs) play an important regenerative role in acute and chronic liver pathologies. Liver disease research often necessitates the grading of disease severity, and pathologists' reports are the current gold-standard for assessment. However, it is often impractical to recruit pathologists in large cohort studies. In this study we utilise PerkinElmer's "InForm" software package to semi-Automate the scoring of patient liver biopsies, and compare outputs to a pathologist's assessment. We examined a cohort of eleven acute hepatitis samples and three non-Alcoholic fatty liver disease (NAFLD) samples, stained with HPC markers (GCTM-5 and Pan Cytokeratin), an inflammatory marker (CD45), Sirius Red to detect collagen and haematoxylin/eosin for general histology. InForm was configured to identify presumptive HPCs, CD45 +ve inflammatory cells, areas of necrosis, fat and collagen deposition (p < 0.0001). Hepatitis samples were then evaluated both by a pathologist using the Ishak-Knodell scoring system, and by InForm through customised algorithms. Necroinflammation as evaluated by a pathologist, correlated with InForm outputs (r 2 = 0.8192, p < 0.05). This study demonstrates that the InForm software package provides a useful tool for liver disease research, allowing rapid, and objective quantification of the presumptive HPCs and identifies histological features that assist with assessing liver disease severity, and potentially can facilitate diagnosis

Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis

Amphiregulin (AR) involvement in liver fibrogenesis and hepatic stellate cells (HSC) regulation is under study. Non-alcoholic fatty liver disease (NAFLD) and its more severe form non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular cancer (HCC). Our aim was to investigate ex vivo the effect of AR on human primary HSC (hHSC) and verify in vivo the relevance of AR in NAFLD fibrogenesis. hHSC isolated from healthy liver segments were analyzed for expression of AR and its activator, TNF- converting enzyme (TACE). AR induction of hHSC proliferation and matrix production was estimated in the presence of antagonists. AR involvement in fibrogenesis was also assessed in a mouse model of NASH and in humans with NASH. hHSC time dependently expressed AR and TACE. AR increased hHSC proliferation through several mitogenic signaling pathways such as EGFR, PI3K and p38. AR also induced marked upregulation of hHSC fibrogenic markers and reduced hHSC death. AR expression was enhanced in the HSC of a murine model of NASH and of severe human NASH. In conclusion, AR induces hHSC fibrogenic activity via multiple mitogenic signaling pathways, and is upregulated in murine and human NASH, suggesting that AR antagonists may be clinically useful anti-fibrotics in NAFLD

Экспериментальные исследования процессов миграции водорода в титане электрическими методами

В работе исследован процесс диффузионного переноса водорода в титановой пластине вихретоковым методом по глубине образца. Интегральный перенос изучен методом измерения термоэдс. Разработана установка для исследования процесса миграции водорода в сплаве титана при его насыщении электролитически в присутствии тиокарбомида. Исследована роль тиокарбамида. Проведено измерение вихревых токов по координате и во времени на различных частотах, что позволяет исследовать процессы миграции на разных глубинах образца. Исследован процесс миграции водорода в титановом сплаве методом измерения термоэдс.The process of diffusion transport of hydrogen in a titanium plate by the eddy current method has been investigated in the depth of samples. The integral transport has been studied by measuring thermoelectric powers. An installation was developed for studying the process of hydrogen shift in titanium alloys when electrolytically saturated with thiocarbomide. The role of thiourea is investigated. The measurement of eddy currents in coordinate and time is carried out at different frequencies, which makes it is possible to study the shift processes at different depths of the sample. The process of hydrogen shift in titanium alloys is studied by measuring thermoelectric powers

Impact of pollen on throughfall biochemistry in European temperate and boreal forests

Pollen is known to affect forest throughfall biochemistry, but underlying mechanisms are not fully understood. We used generalized additive mixed modelling to study the relationship between long-term series of measured throughfall fluxes in spring (April–June) at forest plots and corresponding airborne pollen concentrations (Seasonal Pollen Integral, SPIn) from nearby aerobiological monitoring stations. The forest plots were part of the intensive long term monitoring (Level II) network of the UNECE International Co-operative Programme on Assessment and Monitoring of Air Pollution Effects on Forests (ICP Forests) with dominant tree genera Fagus, Quercus, Pinus and Picea, and were distributed all across Europe. We also conducted a 7-day laboratory dissolution experiment with bud scales and flower stalks of European beech (Fagus sylvatica L.), pollen of beech, common oak (Quercus robur L.), silver birch (Betula pendula L.), Scots pine (Pinus sylvestris L.), Corsican pine (Pinus nigra Arnold ssp. laricio (Poiret) Maire), Norway spruce (Picea abies (L.) Karst.) and sterilized pollen of silver birch in a nitrate (NO3--N) solution (11.3 mg N L-1). Throughfall fluxes of potassium (K+), ammonium (NH4+-N), dissolved organic carbon (DOC) and dissolved organic nitrogen (DON) showed a positive relationship with SPIn whereas NO3--N fluxes showed a negative relationship with SPIn. In years with massive seed production of beech and oak SPIn and throughfall fluxes of K+ and DOC were higher, but fluxes of NO3--N were lower. The experiment broadly confirmed the findings based on field data. Within two hours, pollen released large quantities of K+, phosphate, DOC and DON, and lesser amounts of sulphate, sodium and calcium. After 24-48 hours, NO3--N started to disappear, predominantly in the treatments with broadleaved pollen, while concentrations of nitrite and NH4+-N increased. At the end of the experiment, the inorganic nitrogen (DIN) was reduced, presumably because it was lost as gaseous nitric oxide (NO). There was no difference for sterilized pollen, indicating that the involvement of microbial activity was limited in above N transformations. Our results show that pollen dispersal might be an overlooked factor in forest nutrient cycling and might induce complex canopy N transformations, although the net-impact on N throughfall fluxes is rather lo

Investigation of Performance and Cavitation Treatment in a Kaplan Hydro Turbine

Cavitation is a phenomenon that occurs in various turbomachinery applications causing drawbacks on the. Some of these downsides are damaging the components of the system, generating noise and vibration, and loss of the turbine efficiency over time. Thus, it is imperative to address issue of cavitation to increase the life span of the equipment in addition to improve the system performance. This thesis introduces a method used to mitigate the cavitation phenomenon in a 3-inch Kaplan hydro turbine via injecting air at the leading edge of the rotor blades. The study is based on modeling the turbine using Computational Fluid Dynamics (CFD) software as well as carrying out experimental tests. The simulations were conducted at different air injection pressures over a spectrum of rotational speeds using Large Eddy Simulation (LES) for turbulence and volume of fluid for multiphase interactions: water, vapor water and air. The cavitation behavior was observed first without aeration, then followed by air injection simulations to investigate the effect of aeration. Each case was simulated for 12 cycles at rotational speeds of 1000, 2000, 3000, 4000, and 5000 rpm. The Vapor Volume Fraction (VVF) and the output mechanical power were monitored throughout the simulations. The data acquired from the simulations were compared to the experimental results for verifications. It was observed that the cavitation was mitigated in both the computer simulations and the experiment testing reaching up to 49.7% as an average reduction, while the output power was reduced by 6.6%