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

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

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

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

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

Late-time phenomenology required to solve the H0H_0 tension in view of the cosmic ladders and the anisotropic and angular BAO data sets

The $\sim 5\sigma$ mismatch between the value of the Hubble parameter measured by SH0ES and the one inferred from the inverse distance ladder (IDL) constitutes the biggest tension afflicting the standard model of cosmology, which could be pointing to the need of physics beyond $\Lambda$CDM. In this paper we study the background history required to solve the $H_0$ tension if we consider standard prerecombination physics, paying special attention to the role played by the data on baryon acoustic oscillations (BAO) employed to build the IDL. We show that the anisotropic BAO data favor an ultra-late-time (phantom-like) enhancement of $H(z)$ at $z\lesssim 0.2$ to solve the tension, accompanied by a transition in the absolute magnitude of supernovae of Type Ia $M(z)$ in the same redshift range. The effective dark energy (DE) density must be smaller than in the standard model at higher redshifts. Instead, when angular BAO data (claimed to be less subject to model dependencies) is employed in the analysis, we find that the increase of $H(z)$ starts at much higher redshifts, typically in the range $z\sim 0.6-0.9$. In this case, $M(z)$ could experience also a transition (although much smoother) and the effective DE density becomes negative at $z\gtrsim 2$. Both scenarios require a violation of the weak energy condition (WEC), but leave an imprint on completely different redshift ranges and might also have a different impact on the perturbed observables. They allow for the effective crossing of the phantom divide. Finally, we employ two alternative methods to show that current data from cosmic chronometers do not exclude the violation of the WEC, but do not add any strong evidence in its favor neither. Our work puts the accent on the utmost importance of the choice of the BAO data set in the study of the possible solutions to the $H_0$ tension.Comment: 20 pages, 13 figures, 3 table