Estrogens and genomic instability in human cancer cells-involvement of Src/Raf/Erk signaling in micronucleus formation by estrogenic chemicals

This article is available open access through the publisher’s website. Copyright @ 2008 The Authors.Reports of the ability of estrogenic agents such as 17β-estradiol (E2), estriol (E3) and bisphenol A (BPA) to induce micronuclei (MN) in MCF-7 breast cancer cells have prompted us to investigate whether these effects are linked to activation of the estrogen receptor (ER) α. Coadministration of tamoxifen and the pure ER antagonist ICI 182 780 to cells treated with E2 and E3 did not lead to significant reductions in micronucleus frequencies. Since these antiestrogens interfere with the transcriptional activity of the ER and block promotion of ER-dependent gene expression, it appears that this process is not involved in micronucleus formation. However, ER activation also triggers rapid signaling via the Src/Raf/extracellular signal-regulated kinase (Erk) pathway. When MCF-7 cells were exposed to E2 and BPA in combination with the specific kinase inhibitors pyrazolopyrimidine and 2′-amino-3′-methoxyflavone, reductions in micronucleus frequencies occurred. These findings suggest that the Src/Raf/Erk pathway plays a role in micronucleus formation by estrogenic agents. Enhanced activation of the Src/Raf/Erk cascade disturbs the localization of Aurora B kinase to kinetochores, leading to a defective spindle checkpoint with chromosome malsegregation. Using antikinetochore CREST antibody staining, a high proportion of micronucleus containing kinetochores was observed, indicating that such processes are relevant to the induction of MN by estrogens. Our results suggest that estrogens induce MN by causing improper chromosome segregation, possibly by interfering with kinase signaling that controls the spindle checkpoint, or by inducing centrosome amplification. Our findings may have some relevance in explaining the effects of estrogens in the later stages of breast carcinogenesis.European Commissio

GATA1 gets personal

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Microwave satellite remote sensing for a sustainable sea

The oceans cover roughly 2/3 of the Earth’s surface and are a fundamental ecosystem regulating climate, weather and representing a huge reservoir of biodiversity and natural resources. The preservation of the oceans is therefore not only relevant on an environmental perspective but also on an economical one. A sustainable approach is requested that cannot be simply achieved by improving technologies but calls for a shared new vision of common goods.Within such a complex and holistic problem, the role of satellite microwave remote sensing to observe marine ecosystem and to assist a sustainable development of human activities must be considered. In such a view the paper is meant. Accordingly, the key microwave sensor technologies are reviewed paying particular emphasis on those applications that can provide effective support to pursue some of the UN Sustainable Development Goals. Three meaningful sectors are showcased:oil and gas, where microwave sensors can provide continuous fine-resolution monitoring of critical infrastructures; renewable energy, where microwave satellite remote sensing allows supporting the management of offshore wind farms during both feasibility and operational stages; plastic pollution, where microwave technologies that exploit signals of opportunity offer large-scale monitoring capability to provide marine litter maps of the oceans

LSD1: more than demethylation of histone lysine residues

Lysine-specific histone demethylase 1 (LSD1) represents the first example of an identified nuclear protein with histone demethylase activity. In particular, it plays a special role in the epigenetic regulation of gene expression, as it removes methyl groups from mono- and dimethylated lysine 4 and/or lysine 9 on histone H3 (H3K4me1/2 and H3K9me1/2), behaving as a repressor or activator of gene expression, respectively. Moreover, it has been recently found to demethylate monomethylated and dimethylated lysine 20 in histone H4 and to contribute to the balance of several other methylated lysine residues in histone H3 (i.e., H3K27, H3K36, and H3K79). Furthermore, in recent years, a plethora of nonhistone proteins have been detected as targets of LSD1 activity, suggesting that this demethylase is a fundamental player in the regulation of multiple pathways triggered in several cellular processes, including cancer progression. In this review, we analyze the molecular mechanism by which LSD1 displays its dual effect on gene expression (related to the specific lysine target), placing final emphasis on the use of pharmacological inhibitors of its activity in future clinical studies to fight cancer

A novel CMB polarization likelihood package for large angular scales built from combined WMAP and Planck LFI legacy maps

We present a CMB large-scale polarization dataset obtained by combining WMAP Ka, Q and V with Planck 70 GHz maps. We employ the legacy frequency maps released by the WMAP and Planck collaborations and perform our own Galactic foreground mitigation technique, which relies on Planck 353 GHz for polarized dust and on Planck 30 GHz and WMAP K for polarized synchrotron. We derive a single, optimally-noise-weighted, low-residual-foreground map and the accompanying noise covariance matrix. These are shown, through $\chi^2$ analysis, to be robust over an ample collection of Galactic masks. We use this dataset, along with the Planck legacy Commander temperature solution, to build a pixel-based low-resolution CMB likelihood package, whose robustness we test extensively with the aid of simulations, finding excellent consistency. Using this likelihood package alone, we constrain the optical depth to reionazation $\tau=0.069^{+0.011}_{-0.012}$ at $68\%$ C.L., on 54\% of the sky. Adding the Planck high-$\ell$ temperature and polarization legacy likelihood, the Planck lensing likelihood and BAO observations we find $\tau=0.0714_{-0.0096}^{+0.0087}$ in a full $\Lambda$CDM exploration. The latter bounds are slightly less constraining than those obtained employing \Planck\ HFI CMB data for large angle polarization, that only include EE correlations. Our bounds are based on a largely independent dataset that does include also TE correlations. They are generally well compatible with Planck HFI preferring slightly higher values of $\tau$. We make the low-resolution Planck and WMAP joint dataset publicly available along with the accompanying likelihood code.Comment: The WMAP+LFI likelihood module is available on \http://www.fe.infn.it/u/pagano/low_ell_datasets/wmap_lfi_legacy

An Inexpensive 6D Motion Tracking System for Posturography

Computerized posturography is most often performed with a force plate measuring center-of-pressure (COP). COP is related to postural control actions but does not monitor the outcome of those actions, i.e., center-of-mass (COM) stability. For a more complete analysis of postural control COM should also be measured; however, existing motion tracking technology is prohibitively expensive and overcomplicated for routine use. The objective of this work was to create and validate an inexpensive and convenient stereo vision system which measured a trunk-fixed target's 3D position and orientation relating to COM. The stereo vision system would be complementary to typical force plate methods providing precise 6D position measurements under laboratory conditions. The developed system's measurement accuracy was worst in the inferior-superior axis (depth) and pitch coordinates with accuracy measures 1.1 mm and 0.8°, respectively. The system's precision was worst in the depth and roll coordinates with values 0.1 mm and 0.15°, respectively. Computer modeling successfully predicted this precision with 11.3% mean error. Correlation between in vivo target position (TP) and COP was above 0.73 with COP generally demonstrating larger excursions oscillating around TP. Power spectral analysis of TP revealed 99% of the signal was bound below 1.1 Hz matching expectations for COM. The new complementary measurement method enables identification of postural control strategies and as a result more complete analysis. Stereo vision is a useful complement to typical force plate equipment. The system presented here is inexpensive and convenient demonstrating potential for routine use in clinic and research. In order to use this system in clinic, future work is required in interpretation of this system's data and normal reference values must be established across gender and age in a healthy population followed by values from patients with different pathologies

La stima del campo di gravità da dati GOCE: i risultati finali dell’approccio space-wise

In questo lavoro vengono presentati i risultati finali del processamento dati della missione GOCE tramite l’approccio space-wise, da oltre vent’anni studiato ed implementato presso il Politecnico di Milano. In particolare sono stati elaborati i dati di tutta la missione, da novembre 2009 ad ottobre 2013, corrispondente ad oltre cento milioni di epoche. Questo periodo include sia la fase iniziale, durata quasi 3 anni, con il satellite all’altezza nominale di 255 km, sia la fase finale di abbassamento dell’orbita nella quale il satellite è stato lentamente portato fino a 224 km passando attraverso periodi intermedi di misura a quota costante. La fase di preprocessamento dati per la ricerca e la correzione di outlier è stata svolta in modo semi-automatico con una supervisione continua da parte dell’operatore e per questo motivo è stata molto onerosa; tuttavia l’eliminazione degli outlier, presenti in maggior numero nell’ultima fase di abbassamento dell’orbita, è cruciale per il raggiungimento di un risultato soddisfacente, indipendentemente dal metodo di analisi successivamente utilizzato. L’approccio space-wise è sostanzialmente un approccio iterativo di collocazione, che richiede la modellizzazione sia della correlazione temporale dell’errore di misura del gradiometro a bordo del satellite, sia della correlazione spaziale del segnale di gravità che si vuole recuperare. In particolare, l’idea base di questo approccio è quella di ridurre l’enorme mole di dati lungo orbita su una griglia globale all’altezza del satellite applicando la collocazione su aree locali, ciascuna caratterizzata da una covarianza del segnale adattata localmente. In questo modo il livello del filtraggio del dato risulta controllato localmente, diversamente da quanto avviene negli approcci diretto e time-wise dove viene applicata una regolarizzazione globale alla stima ai minimi quadrati dei coefficienti delle armoniche sferiche. Il risultato di questo processamento consiste quindi in griglie globali di derivate seconde del potenziale gravitazionale a una risoluzione spaziale di 0.2°x0.2°. Da queste griglie si deriva un modello globale in armoniche sferiche attraverso integrazione numerica. Sia per le griglie che per i coefficienti armonici viene fornita una stima dell’errore calcolata tramite un’opportuna simulazione Monte Carlo. Il contenuto informativo dei prodotti space-wise è stato valutato confrontandoli con altre griglie e altri modelli globali disponibili. Questo confronto mette in rilievo l’ovvia debolezza della collocazione locale nella stima dei gradi medio-bassi del campo gravitazionale, ma anche la sua miglior capacità di recuperare i più alti degree, ovvero i dettagli del campo. In questo senso l’approccio space-wise può fornire un risultato complementare a quello degli altri due approcci ufficiali all’analisi dati GOCE

Stress response to cadmium and manganese in Paracentrotus lividus developing embryos is mediated by nitric oxide

Increasing concentrations of contaminants, often resulting from anthropogenic activities, have been reported to occur in the marine environment and affect marine organisms. Among these, the metal ions cadmium and manganese have been shown to induce developmental delay and abnormalities, mainly reflecting skeleton elongation perturbation, in the sea urchin Paracentrotus lividus, an established model for toxicological studies. Here, we provide evidence that the physiological messenger nitric oxide (NO), formed by l-arginine oxidation by NO synthase (NOS), mediates the stress response induced by cadmium and manganese in sea urchins. When NO levels were lowered by inhibiting NOS, the proportion of abnormal plutei increased. Quantitative expression of a panel of 19 genes involved in stress response, skeletogenesis, detoxification and multidrug efflux processes was followed at different developmental stages and under different conditions: metals alone, metals in the presence of NOS inhibitor, NO donor and NOS inhibitor alone. These data allowed the identification of different classes of genes whose metal-induced transcriptional expression was directly or indirectly mediated by NO. These results open new perspectives on the role of NO as a sensor of different stress agents in sea urchin developing embryos. © 2014 Elsevier B.V

Tadalafil improves lean mass and endothelial function in nonobese men with mild ED/LUTS: in vivo and in vitro characterization

PURPOSE: Phosphodiesterase type-5 inhibitor administration in diabetic men with erectile dysfunction (ED) is associated with reduced waist circumference. We evaluated potential effects of daily tadalafil administration on body composition and investigated its possible mechanism(s) of action in C2C12 skeletal muscle cells in vitro. METHODS: Forty-three men on stable caloric intake (mean age 48.5 ± 7; BMI 25.5 ± 0.9 kg/m2) complaining mild ED and/or low urinary tract symptoms (LUTS) were randomly assigned to receive tadalafil (TAD) 5 mg/daily (once-a-day=OAD-TAD; n = 23) or 20 mg on-demand (on-demand=OD-TAD; n = 20) for 2 months. Primary outcomes were variations of body composition measured by Dual-energy X-ray absorptiometry; secondary outcomes were ED/LUTS questionnaire scores along with hormone (testosterone, estradiol, insulin) and endothelial function (Endopat2000) variations. RESULTS: OAD-TAD increased abdominal lean mass (p < 0.01) that returned to baseline after 2 months withdrawal. LUTS scores improved (p<0.01) in OD-TAD while ED scores improved (p < 0.01) in both groups. We found significant improvements in endothelial function (p < 0.05) that directly correlated with serum insulin (p < 0.01; r = 0.3641) and inversely correlated with estradiol levels (p < 0.01; r = 0.3655) even when corrected for potential confounders. Exposure of C2C12 cells upon increasing tadalafil concentrations (10-7 to 10-6 M) increased total androgen receptor mRNA and protein expression as well as myogenin protein expression after 24 and 72 h (2.8 ± 0.4-fold and 1.4 ± 0.02-fold vs. control, respectively, p < 0.05). CONCLUSIONS: Daily tadalafil improved lean mass content in non-obese men probably via enhanced insulin secretion, estradiol reduction, and improvement of endothelial function in vivo. The in vitro increased myogenin and androgen receptor protein expression in skeletal muscle cells suggests a translational action of phosphodiesterase type-5 on this receptor

Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model

Purpose Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD). Methods Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression. Results Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10−8–10−7 M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ERα, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation. Conclusions Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation. Keywords Tadalafil · Osteoblasts · Aromatase · Androgen receptor · Estrogen recepto