Glucocorticoid-enhanced expression of dioxin target genes through regulation of the rat aryl hydrocarbon receptor

The aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR) are ligand-activated transcription factors and members of the basic helix–loop–helix Period-aryl hydrocarbon nuclear translocator-single minded and nuclear hormone receptor superfamilies, respectively. Besides their individual role as activators of specific gene transcription, also interplay between both transcription factors can be an important mechanism of regulation. In this study, we report that GR can strongly activate AhRmediated transcription and consequent gene expression in rat H4IIe cells. Reporter gene assays showed an enhanced effect of dexamethasone on the dioxin response mediated by GR in rat H4IIe cells and mouse Hepa 1c1c7 cells, but not in human HepG2 cells and human T47D cells. These deviations between the rodent and human cell lines were confirmed by CYP1A1 enzyme activities. In addition, quantitative reverse transcription–PC

Development of Androgen- and Estrogen-Responsive bio-assays, members of a panel of human cell line-based highly selective steroid-responsive bioassays

We have established highly sensitive and specific androgen and estrogen reporter cell lines which we have named AR (androgen receptor) and ERα (estrogen receptor alpha) CALUX® (Chemically Activated LUciferase eXpression), respectively. Both bioassays are member of a panel of CALUX reporter cell lines derived from the human U2-OS osteosarcoma cell line, all using highly selective reporter constructs based with a basal promoter element linked to multimerized. response elements, allowing efficient and specific measurement of compounds interfering with androgen, estrogen, progesterone, and glucocorticoid receptors. The AR CALUX bioassay contains the human androgen receptor and a luciferase reporter construct containing three androgen-responsive elements coupled to a minimal TATA promoter. This cell line was characterized by its stable expression of AR protein, its highly selective response to low levels of different natural and synthetic androgens, and its insignificant response to other nuclear hormone receptor ligands such as estrogens, progestins, and glucocorticoids. The EC50 of dihydrotestosterone (DHT) was found to be 0.13 nM, consistent with the high affinity of this ligand to the human AR. Flutamide, cyproterone acetate, and the environmental contaminants vinclozolin, DDT, methoxychlor, its metabolite HPTE, and penta-BFR showed clear antagonistic activity in the AR CALUX bioassay, competitively inhibiting DHT-mediated transactivation. The established AR CALUX bioassay proved to excel in terms of easy cell line maintenance, high fold induction range (typical 30 times over solvent control), low minimal detection limit (3.6 pM), and high androgen selectivity. Potential applications such as testing the androgenic or estrogenic activity of pure chemicals and pharmaceuticals and complex mixtures (environmental, food, feed, and clinical) are discussed. © Society of Toxicology 2005; all rights reserved

Recurrence of ventricular arrhythmias in ischaemic secondary prevention implantable cardioverter defibrillator recipients: long-term follow-up of the Leiden out-of-hospital cardiac arrest study (LOHCAT)

Aims to assess the long-term rate of mortality and the recurrence of potentially life-threatening ventricular arrhythmias in secondary prevention implantable cardioverter defibrillator (ICD) patients and to construct a model for baseline risk stratification.Methods and resultsSince 1996, all patients with ischaemic heart disease, receiving ICD therapy for secondary prevention of sudden death, were included in the current study. Patients were evaluated at implantation and during long-term follow-up. A total of 456 patients were included in the analysis and followed for 54 ± 35 months. During follow-up, 100 (22) patients died and ICD therapy was noted in 216 (47) patients, of which 138 (30) for fast, potentially life-threatening ventricular arrhythmia. Multivariate analysis revealed a history of atrial fibrillation or flutter (AF), ventricular tachycardia as presenting arrhythmia, and wide QRS and poor left ventricular ejection fraction as independent predictors of life-threatening ventricular arrhythmias. The strongest predictor was AF with a hazard ratio of 2.1 (95 confidence interval 1.3-3.2). On the basis of the available clinical data, it was not possible to identify a group which exhibited no risk on recurrence of potentially life-threatening ventricular arrhythmias.ConclusionIschaemic secondary prevention ICD recipients exhibit a high recurrence rate of potentially life-threatening ventricular arrhythmias. Factors that increase risk can be identified but, even with these factors, it was not possible to distinguish a recurrence-free group

Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer

Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic. Since preclinical data suggest that Cremophor EL (CrEL), the formulation vehicle of paclitaxel, has a protective effect on haematological toxicity of cisplatin, CrEL was added to the combination cisplatin and topotecan. In this phase I study, escalating doses of oral topotecan administered on day 1, 2, 8, 9, 15, 16, 29, 30, 36, 37, 43, 44 were combined with weekly cisplatin 70 mg m−2d−1on day 1, 8, 15, 29, 36, 43 (scheme A) or with the presumably less myelotoxic sequence weekly cisplatin day 2, 9, 16, 30, 37, 44 (scheme B). In scheme C, CrEL 12 ml was administered prior to cisplatin in the sequence of Scheme A. 18 patients have received a total of 85 courses. In scheme A 4/10 patients, all treated with topotecan 0.45 mg m−2d−1, experienced DLT: 1 patient had vomiting grade 4, 1 patient had grade 4 neutropenia >5 days, 1 patient had >2 weeks delay due to thrombocytopenia and 1 patient due to neutropenia. Both patients in scheme B (topotecan 0.45 mg m−2d−1) had DLT due to a delay > 2 weeks because of prolonged haematological toxicity. No DLT was observed in the first 3 patients in scheme C (topotecan 0.45 mg m−2d−1). However, 2 out of 3 patients treated at dose level topotecan 0.60 mg m−2d−1in scheme C experienced DLT due to >2 weeks delay because of persistent thrombocytopenia or neutropenia. We conclude that there is a modest clinical effect of CrEL on haematological toxicity for this cisplatin-based combination regimen, which seems to reduce these side effects but does not really enable an increase of the oral topotecan dose. © 2001 Cancer Research Campaign  http://www.bjcancer.co

Prospects for high-z cluster detections with Planck, based on a follow-up of 28 candidates using MegaCam@CFHT

The Planck catalogue of SZ sources limits itself to a significance threshold of 4.5 to ensure a low contamination rate by false cluster candidates. This means that only the most massive clusters at redshift z>0.5, and in particular z>0.7, are expected to enter into the catalogue, with a large number of systems in that redshift regime being expected around and just below that threshold. In this paper, we follow-up a sample of SZ sources from the Planck SZ catalogues from 2013 and 2015. In the latter maps, we consider detections around and at lower significance than the threshold adopted by the Planck Collaboration. To keep the contamination rate low, our 28 candidates are chosen to have significant WISE detections, in combination with non-detections in SDSS/DSS, which effectively selects galaxy cluster candidates at redshifts $z\gtrsim0.5$. By taking r- and z-band imaging with MegaCam@CFHT, we bridge the 4000A rest-frame break over a significant redshift range, thus allowing accurate redshift estimates of red-sequence cluster galaxies up to z~0.8. After discussing the possibility that an overdensity of galaxies coincides -by chance- with a Planck SZ detection, we confirm that 16 of the candidates have likely optical counterparts to their SZ signals, 13 (6) of which have an estimated redshift z>0.5 (z>0.7). The richnesses of these systems are generally lower than expected given the halo masses estimated from the Planck maps. However, when we follow a simplistic model to correct for Eddington bias in the SZ halo mass proxy, the richnesses are consistent with a reference mass-richness relation established for clusters detected at higher significance. This illustrates the benefit of an optical follow-up, not only to obtain redshift estimates, but also to provide an independent mass proxy that is not based on the same data the clusters are detected with, and thus not subject to Eddington bias.Comment: 13 pages, 7 figures. Accepted for publication in A&

Prognostic factors for survival in patients with advanced oesophageal cancer treated with cisplatin-based combination chemotherapy

The objective of this study was to identify prognostic factors for survival in patients with advanced oesophageal cancer, who are treated with cisplatin-based combination chemotherapy. We analysed the baseline characteristics of 350 patients who were treated in six consecutive prospective trials with one of the following regimens: cisplatin/etoposide, cisplatin/etoposide/5-fluorouracil, cisplatin/paclitaxel (weekly) and cisplatin/paclitaxel (biweekly). Predictive factors in univariate analyses were further evaluated using multivariate analysis (Cox regression). The median survival of all patients was 9 months. The 1, 2 and 5-year survival rates were 33, 12 and 4%, respectively. The main prognostic factors were found to be WHO performance status (0 or 1 vs 2), lactate dehydrogenase (normal vs elevated), extent of disease (limited disease defined as locoregional irresectable disease or lymph node metastases confined to either the supraclavicular or celiac region vs extensively disseminated disease) in addition to the type of treatment (weekly or biweekly cisplatin/paclitaxel regimen vs 4-weekly cisplatin/etoposide with or without 5-fluorouracil). Although weight loss, liver metastases and alkaline phosphatase were significant prognostic factors in univariate analyses, these factors lost their significance in multivariate analyses. The median survival for patients without any risk factors was 12 months, compared to only 4 months in patients with WHO 2 plus elevated LDH and extensive disease. The performance status, extent of disease, LDH and the addition of paclitaxel to cisplatin are independent prognostic factors in patients with advanced oesophageal cancer, who are treated with cisplatin-based combination chemotherapy

Is NGC 3108 transforming itself from an early to late type galaxy -- an astronomical hermaphrodite?

A common feature of hierarchical galaxy formation models is the process of "inverse" morphological transformation: a bulge dominated galaxy accretes a gas disk, dramatically reducing the system's bulge-to-disk mass ratio. During their formation, present day galaxies may execute many such cycles across the Hubble diagram. A good candidate for such a "hermaphrodite" galaxy is NGC 3108: a dust-lane early-type galaxy which has a large amount of HI gas distributed in a large scale disk. We present narrow band H_alpha and R-band imaging, and compare the results with the HI distribution. The emission is in two components: a nuclear bar and an extended disk component which coincides with the HI distribution. This suggests that a stellar disk is currently being formed out of the HI gas. The spatial distributions of the H_alpha and HI emission and the HII regions are consistent with a barred spiral structure, extending some 20 kpc in radius. We measure an extinction- corrected SFR of 0.42 Msun/yr. The luminosity function of the HII regions is similar to other spiral galaxies, with a power law index of -2.1, suggesting that the star formation mechanism is similar to other spiral galaxies. We measured the current disk mass and find that it is too massive to have been formed by the current SFR over the last few Gyr. It is likely that the SFR in NGC 3108 was higher in the past. With the current SFR, the disk in NGC 3108 will grow to be ~6.2x10^9 Msun in stellar mass within the next 5.5 Gyr. While this is substantial, the disk will be insignificant compared with the large bulge mass: the final stellar mass disk-to-bulge ratio will be ~0.02. NGC 3108 will fail to transform into anything resembling a spiral without a boost in the SFR and additional supply of gas.Comment: 9 pages, 3 figures, accepted for publication in MNRA

Identification of major dioxin-like compounds and androgen receptor antagonist in acid-treated tissue extracts of high trophic-level animals

We evaluated the applicability of combining in vitro bioassays with instrument analyses to identify potential endocrine disrupting pollutants in sulfuric acid-treated extracts of liver and/or blubber of high trophic-level animals. Dioxin-like and androgen receptor (AR) antagonistic activities were observed in Baikal seals, common cormorants, raccoon dogs, and finless porpoises by using a panel of rat and human cell-based chemical-activated luciferase gene expression (CALUX) reporter gene bioassays. On the other hand, no activity was detected in estrogen receptor α (ERα)-, glucocorticoid receptor (GR)-, progesterone receptor (PR)-, and peroxisome proliferator-activated receptor γ2 (PPARγ2)-CALUX assays with the sample amount applied. All individual samples (n = 66) showed dioxin-like activity, with values ranging from 21 to 5500 pg CALUX-2,3,7,8-tetrachlorodibenzo-p-dioxin equivalent (TEQ)/g-lipid. Because dioxins are expected to be strong contributors to CALUX-TEQs, the median theoretical contribution of dioxins calculated from the result of chemical analysis to the experimental CALUX-TEQs was estimated to explain up to 130% for all the tested samples (n = 54). Baikal seal extracts (n = 31), but not other extracts, induced AR antagonistic activities that were 8-150 μg CALUX-flutamide equivalent (FluEQ)/g-lipid. p,p′-DDE was identified as an important causative compound for the activity, and its median theoretical contribution to the experimental CALUX-FluEQs was 59% for the tested Baikal seal tissues (n = 25). Our results demonstrate that combining in vitro CALUX assays with instrument analysis is useful for identifying persistent organic pollutant-like compounds in the tissue of wild animals on the basis of in vitro endocrine disruption toxicity. © 2011 American Chemical Society