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Background and objectiveSystemic sclerosis (SSc) is a severe autoimmune disease, in which the pathogenesis is dependent on both genetic and epigenetic factors. Altered gene expression in SSc monocytes, particularly of interferon (IFN)-responsive genes, suggests their involvement in SSc development. We investigated the correlation between epigenetic histone marks and gene expression in SSc monocytes.MethodsChromatin immunoprecipitation followed by sequencing (ChIPseq) for histone marks H3K4me3 and H3K27ac was performed on monocytes of nine healthy controls and 14 patients with SSc. RNA sequencing was performed in parallel to identify aberrantly expressed genes and their correlation with the levels of H3K4me3 and H3K27ac located nearby their transcription start sites. ChIP-qPCR assays were used to verify the role of bromodomain proteins, H3K27ac and STATs on IFN-responsive gene expression.Results1046 and 534 genomic loci showed aberrant H3K4me3 and H3K27ac marks, respectively, in SSc monocytes. The expression of 381 genes was directly and significantly proportional to the levels of such chromatin marks present near their transcription start site. Genes correlated to altered histone marks were enriched for immune, IFN and antiviral pathways and presented with recurrent binding sites for IRF and STAT transcription factors at their promoters. IFNα induced the binding of STAT1 and STAT2 at the promoter of two of these genes, while blocking acetylation readers using the bromodomain BET family inhibitor JQ1 suppressed their expression.ConclusionSSc monocytes have altered chromatin marks correlating with their IFN signature. Enzymes modulating these reversible marks may provide interesting therapeutic targets to restore monocyte homeostasis to treat or even prevent SSc.

The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the type of tumor. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and can thereby promote tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in patients with breast cancer. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role for this transcription factor in promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways.

Aim of the present study was to investigate survival rates of unselected patients with glioblastoma after multimodal treatment and estimation of prognostic factors. Data of 189 patients (118 men; 71 women; median age: 59 years) with histologically confirmed glioblastoma treated from 1999 to 2009 were analyzed retrospectively. Complete tumor resection was performed in 99 patients (52%), subtotal excision in 65 patients (34%), and stereotactic biopsy in 25 patients (13%). In 135 patients (71%), residual tumors were detectable in post-surgical imaging. All patients underwent three-dimensional conformal radiotherapy of the tumor region in shrinking-field technique to a total dose of 60 Gy. Beginning in 2002, 124 patients (66%) received concomitant temozolomide (TMZ) treatment, 76 patients among them were additionally treated with adjuvant TMZ. After disease progression, 74 patients underwent salvage therapy (salvage chemotherapy, n=61; local therapy, n=30). Actuarial 1- and 2- year progression-free survival (PFS) rates were 32% and 7%, overall survival (OS) rates were 54% and 22%, respectively. Without TMZ, 1- and 2- year OS rates were 47% and 11%, with concomitant TMZ 57% and 28%, and with concomitant and adjuvant TMZ 72% and 44%. In multivariate Cox proportional hazards regression models, age (p

The focused radiation produced by radiosurgery offers the theoretical advantage of a reduced radiation dose to surrounding structures during the treatment of residual craniopharyngiomas when compared with fractionated radiotherapy. A retrospective analysis of 23 patients treated since 1992 was undertaken. Intracystic bleomycin treatment in 10 patients with cystic tumors proved to be effective in preparing the tumors for radiosurgery. The mean prescription dose in this series was 10.8 ¿ 8.7 Gy delivered to a mean prescription 47% isodose. There was a volume reduction of the residual tumor in 74%. In this series, initial tumor volume and target volume were significant prognostic factors. Smaller tumors and targets were more likely to shrink. Five patients with large multicystic residual or recurrent tumors after multiple surgical attempts showed further progression. The maximum radiation dose, prescription dose and choice of prescription isodose were not significant prognostic factors within this series. Radiosurgery resulted in no mortality and no significant morbidity could be attributed to it. Clinically, the best results with radiosurgery were obtained with monocystic tumors amenable to stereotactic drainage and intracystic bleomycin treatment.

9th International Symposium on Flow Visualization 2000, Heriot-Watt University, Edinburgh, available, unclassified, unlimited

The 10th International Symposiumon Flow Visualization from 09/26/2002 to 09/02/2002, available, unclassified, unlimited

CFD 2003 from 5/28/2003 to 5/30/2003, Vancouver, Canada, available, unclassified, unlimited

7th Aerodynamics Symposium, 46th CASI Conference, Montreal, Quebec, Canada, available, unlimited

12th Annual Conference of the CFD Society of Canada (from 05/09/2004 to 05/11/2004), available, unclassified, unlimited

available, unclassified, unlimited

The effect of arsenic administered in drinking water in the form of sodium arsenite in concentrations of 5,50 and 250 mg As-3+/1 on dehydrogenase activity (DHA) of liver parenchyma homogenate of exposed mice was studied. After an exposure lasting 2, 4, 8, 16, 32, and 64 days, 8--10 exposed mice and 5--10 animals of the control series were studied at each interval. DHA was determined by means of tetrazolium chloride reduction to formazan whose quantity was assessed spectrophotometrically after extraction with butanol. At a concentration of 5 mg A3+/1 a moderate increase in DHA was observed which was replaced by a moderate decrease at the following intervals. At a concentration of 250 mg A3+/1 a deep decrease in DHA (p smaller than 0.05) was recorded which did not return to values compararable with those of the control series in spite of its fluctuating increase in the course of exposure. At a concentration of 50 mg A3+/1 in drinking water ensuring the supply of doses which induce an increase in the tolerance to arsenic a decrease in DHA was found only at the first exposure interval. DHA is thus substantially less altered in comparison with the metabolic consumption of oxygen (MCO) under the same conditions. This finding signifies that MCO is a more sensitive indicator of arsenic exposure than DHA in the used arrangement of the experiment.

Chromatographic conditions were elaborated to evaluate a model mixture of four sulfonamides (sulfamethoxazole, sulfamoxole, sulfisoxazole and sulfamethoxydiazine) in plasma using a reversed phase HPLC C18 column and a mobile phase composed of methanol and phosphate buffer (60:40; v/v) at pH 5.0. The detection was made using an electrochemical detection with the potential set at 1.1 V. In the case of sulfonamides deproteination of plasma with methanol was more advantageous than extraction with organic solvents. The recovery of analysed sulfonamides was in the range of 95-97%, the detection limits were 10 ng/ml of plasma.