Identification of novel ER-alpha target genes in breast cancer cells: Gene- and cell-selective co-regulator recruitment at target promoters determines the response to 17beta-estradiol and tamoxifen

International audienceTamoxifen and 17β-estradiol are capable of up-regulating the expression of some genes and down-regulate the expression of others simultaneously in the same cell. In addition, tamoxifen shows distinct transcriptional activities in different target tissues.To elucidate whether these events are determined by differences in the recruitment of co-regulators by activated estrogen receptor-α (ER-α) at target promoters, we applied chromatin-immunoprecipitation (ChIP) with promoter microarray hybridisation in breast cancer T47D cells and identified 904 ER-α targets genome-wide. On a selection of newly identified targets, we show that 17β-estradiol and tamoxifen stimulated up- or down-regulation of transcription correlates with the selective recruitment of co-activators or co-repressors, respectively. This is shown for both breast (T47D) and endometrial carcinoma cells (ECC1). Moreover, differential co-regulator recruitment also explains that tamoxifen regulates a number of genes in opposite direction in breast and endometrial cancer cells. Over-expression of co-activator SRC-1 or co-repressor SMRT is sufficient to alter the transcriptional action of tamoxifen on a number of targets. Our findings support the notion that recruitment of co-regulator at target gene promoters and their expression levels determine the effect of ER-α on gene expression to a large extent

Bivariate stochastic modeling of functional response with natural mortality

A correction due to Abbott (1925) is the standard method of dealing with control mortality in insect bioassay to estimate the mortality of an insect conditional on control mortality not having occurred. In this article a bivariate stochastic process for overall mortality is developed in which natural mortality and predation are jointly modeled to take account of the competing-risks associated with prey loss. The total mortality estimate from this model is essentially identical with that from more classical modeling. However, when predation loss is estimated in the absence of control mortality the results are somewhat different, with the estimate from the bivariate model being lower than that from using Abbott’s formula in conjunction with the classical model. It is argued that overdispersion in observed mortality data corresponds to correlated outcomes (death or survival) for the prey initially present, while Abbott’s correction relies implicitly on independence

Defective Differentiation of Myeloid and Plasmacytoid Dendritic Cells in Advanced Cancer Patients is not Normalized by Tyrosine Kinase Inhibition of the Vascular Endothelial Growth Factor Receptor

Tumor-derived vascular endothelial growth factor (VEGF) has previously been identified as a causative factor in the disturbed differentiation of myeloid dendritic cells (DC) in advanced cancer patients. Here, we investigated the potential of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase (TK) inhibition to overcome this defective DC differentiation. To this end, peripheral blood DC (PBDC) precursor and subset frequencies were measured in 13 patients with advanced cancer before and after treatment with AZD2171, a TK inhibitor (TKI) of VEGFR, coadministered with gefitinib, and an epidermal growth factor receptor (EGFR) TKI. Of note, not only myeloid DC but also plasmacytoid DC frequencies were significantly reduced in the blood of the cancer patients prior to treatment, as compared to healthy controls. Moreover, besides an accumulated population of immature myeloid cells (ImC), a population of myeloid suppressor cells (MSC) was significantly increased. Upon systemic VEGFR TK inhibition, DC frequencies did not increase, whereas the rate of circulating MSC showed a slight, but not significant, decrease. In conclusion, TK inhibition of VEGFR with AZD2171 does not restore the defective PBDC differentiation observed in advanced cancer patients

Immune checkpoint inhibitor-associated myocarditis:Case reports and a review of the literature

Immune checkpoint inhibitors (ICIs) are increasingly recognised to effectuate long-lasting therapeutic responses in solid tumours. However, ICI therapy can also result in various immune-related adverse events, such as ICI-associated myocarditis, a rare but serious complication. The clinical spectrum is wide and includes asymptomatic patients and patients with fulminant heart failure, making it challenging to diagnose this condition. Furthermore, the optimal diagnostic algorithm and treatment of ICI-associated myocarditis is unknown. In this review, we describe two cases on both ends of the spectrum and discuss the challenges in recognising, diagnosing and treating ICI-associated myocarditis

Control of primary productivity and the significance of photosynthetic bacteria in a meromictic kettle lake.

During 1986 planktonic primary production and controlling factors were investigated in a small (A0 = 11.8 · 103 m2, Zmax = 11.5 m) meromictic kettle lake (Mittlerer Buchensee). Annual phytoplankton productivity was estimated to ca 120 gC · m–2 · a–1 (1,42 tC · lake–1 · a–1). The marked thermal stratification of the lake led to irregular vertical distributions of chlorophylla concentrations (Chla) and, to a minor extent, of photosynthesis (Az). Between the depths of 0 to 6 m low Chla concentrations (< 7 mg · m–3) and comparatively high background light attenuation (kw = 0,525 m–1, 77% of total attenuation due to gelbstoff and abioseston) was found. As a consequence, light absorption by algae was low (mean value 17,4%) and self-shading was absent. Because of the small seasonal variation of Chla concentrations, no significant correlation between Chla and areal photosynthesis (A) was observed. Only in early summer (June–July) biomass appears to influence the vertical distribution of photosynthesis on a bigger scale. Around 8 m depth, low-light adapted algae and phototrophic bacteria formed dense layers. Due to low ambient irradiances, the contribution of these organisms to total primary productivity was small. Primary production and incident irradiance were significantly correlated with each other (r2 = 0.68). Although the maximum assimilation number (Popt) showed a clear dependence upon water temperature (Q10 = 2.31), the latter was of minor importance to areal photosynthesis

Real-life glycaemic profiles in non-diabetic individuals with low fasting glucose and normal HbA1c: the A1C-Derived Average Glucose (ADAG) study

Abstract AIMS/HYPOTHESIS: Real-life glycaemic profiles of healthy individuals are poorly studied. Our aim was to analyse to what extent individuals without diabetes exceed OGTT thresholds for impaired glucose tolerance (IGT) and diabetes. METHODS: In the A1C-Derived Average Glucose (ADAG) study, 80 participants without diabetes completed an intensive glucose monitoring period of 12 weeks. From these data, we calculated the average 24 h glucose exposure as time spent above different plasma glucose thresholds. We also derived indices of postprandial glucose levels, glucose variability and HbA(1c). RESULTS: We found that 93% of participants reached glucose concentrations above the IGT threshold of 7.8 mmol/l and spent a median of 26 min/day above this level during continuous glucose monitoring. Eight individuals (10%) spent more than 2 h in the IGT range. They had higher HbA(1c), fasting plasma glucose (FPG), age and BMI than those who did not. Seven participants (9%) reached glucose concentrations above 11.1 mmol/l during monitoring. CONCLUSIONS/INTERPRETATION: Even though the non-diabetic individuals monitored in the ADAG study were selected on the basis of a very low level of baseline FPG, 10% of these spent a considerable amount of time at glucose levels considered to be 'prediabetic' or indicating IGT. This highlights the fact that exposure to moderately elevated glucose levels remains under-appreciated when individuals are classified on the basis of isolated glucose measurements

Mariprofundus ferrooxydans PV-1 the First Genome of a Marine Fe(II) Oxidizing Zetaproteobacterium

© The Author(s), 2011. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS One 6 (2011): e25386, doi:10.1371/journal.pone.0025386.Mariprofundus ferrooxydans PV-1 has provided the first genome of the recently discovered Zetaproteobacteria subdivision. Genome analysis reveals a complete TCA cycle, the ability to fix CO2, carbon-storage proteins and a sugar phosphotransferase system (PTS). The latter could facilitate the transport of carbohydrates across the cell membrane and possibly aid in stalk formation, a matrix composed of exopolymers and/or exopolysaccharides, which is used to store oxidized iron minerals outside the cell. Two-component signal transduction system genes, including histidine kinases, GGDEF domain genes, and response regulators containing CheY-like receivers, are abundant and widely distributed across the genome. Most of these are located in close proximity to genes required for cell division, phosphate uptake and transport, exopolymer and heavy metal secretion, flagellar biosynthesis and pilus assembly suggesting that these functions are highly regulated. Similar to many other motile, microaerophilic bacteria, genes encoding aerotaxis as well as antioxidant functionality (e.g., superoxide dismutases and peroxidases) are predicted to sense and respond to oxygen gradients, as would be required to maintain cellular redox balance in the specialized habitat where M. ferrooxydans resides. Comparative genomics with other Fe(II) oxidizing bacteria residing in freshwater and marine environments revealed similar content, synteny, and amino acid similarity of coding sequences potentially involved in Fe(II) oxidation, signal transduction and response regulation, oxygen sensation and detoxification, and heavy metal resistance. This study has provided novel insights into the molecular nature of Zetaproteobacteria.Funding has been provided by the NSF Microbial Observatories Program (KJE, DE), NSF’s Science and Technology Program, by the Gordon and Betty Moore Foundation (KJE), the College of Letters, Arts, and Sciences at the University of Southern California (KJE), and by the NASA Astrobiology Institute (KJE, DE). Advanced Light Source analyses at the Lawrence Berkeley National Lab are supported by the Office of Science, Basic Energy Sciences, Division of Materials Science of the United States Department of Energy (DE-AC02-05CH11231)

Emissions of methane in Europe inferred by total column measurements

Using five long-running ground-based atmospheric observatories in Europe, we demonstrate the utility of long-term, stationary, ground-based measurements of atmospheric total columns for verifying annual methane emission inventories. Our results indicate that the methane emissions for the region in Europe between Orléans, Bremen, Białystok, and Garmisch-Partenkirchen are overestimated by the state-of-the-art inventories of the Emissions Database for Global Atmospheric Research (EDGAR) v4.2 FT2010 and the high-resolution emissions database developed by the Netherlands Organisation for Applied Scientific Research (TNO) as part of the Monitoring Atmospheric Composition and Climate project (TNO-MACC_III), possibly due to the disaggregation of emissions onto a spatial grid. Uncertainties in the carbon monoxide inventories used to compute the methane emissions contribute to the discrepancy between our inferred emissions and those from the inventories