Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells

Antiestrogens used for breast cancer (BC) treatment differ among each other for the ability to affect estrogen receptor (ER) activity and thereby inhibit hormone-responsive cell functions and viability. We used high-density cDNA microarrays for a comprehensive definition of the gene pathways affected by 17b-estradiol (E2), ICI 182,780 (ICI), 4OHtamoxifen (Tamoxifen), and raloxifene (RAL) in ER-positive ZR-75.1 cells, a suitable model to investigate estrogen and antiestrogen actions in hormone-responsive BC. The expression of 601 geneswas significantly affected by E2 in these cells; in silico analysis reveals that 86 among theminclude one ormore potential ER binding sitewithin or near the promoter and that the binding site signatures for E2F-1, NF-Y, and NRF-1 transcription factors are significantly enriched in the promoters of genes induced by estrogen treatment, while those for CAC-binding protein and LF-A1 in those repressed by the hormone, pointing to novel transcriptional effectors of secondary responses to estrogen in BC cells. Interestingly, expression of 176 E2- regulated mRNAs was unaffected by any of the antiestrogens tested, despite the fact that under the same conditions the transcriptional and cell cycle stimulatory activities of ER were inhibited.On the other hand, of 373 antiestrogen-responsive genes identifiedhere,52wereunresponsive to estrogen and 25%respondedspecifically toonlyoneof thecompounds tested, revealing non-overlapping and clearly distinguishable effects of the different antiestrogens in BC cells. As some of these differences reflect specificities of themechanismof action of the antiestrogens tested, we propose to exploit this gene set for characterization of novel hormonal antagonists and selective estrogen receptor modulators (SERMs) and as a tool for testing newassociations of antiestrogens,more effective against BC

14 MeV calibration of JET neutron detectors-phase 1:calibration and characterization of the neutron source

\u3cp\u3eIn view of the planned DT operations at JET, a calibration of the JET neutron monitors at 14 MeV neutron energy is needed using a 14 MeV neutron generator deployed inside the vacuum vessel by the JET remote handling system. The target accuracy of this calibration is 10% as also required by ITER, where a precise neutron yield measurement is important, e.g. for tritium accountancy. To achieve this accuracy, the 14 MeV neutron generator selected as the calibration source has been fully characterised and calibrated prior to the in-vessel calibration of the JET monitors. This paper describes the measurements performed using different types of neutron detectors, spectrometers, calibrated long counters and activation foils which allowed us to obtain the neutron emission rate and the anisotropy of the neutron generator, i.e.The neutron flux and energy spectrum dependence on emission angle, and to derive the absolute emission rate in 4π sr. The use of high resolution diamond spectrometers made it possible to resolve the complex features of the neutron energy spectra resulting from the mixed D/T beam ions reacting with the D/T nuclei present in the neutron generator target. As the neutron generator is not a stable neutron source, several monitoring detectors were attached to it by means of an ad hoc mechanical structure to continuously monitor the neutron emission rate during the in-vessel calibration. These monitoring detectors, two diamond diodes and activation foils, have been calibrated in terms of neutrons/counts within ± 5% total uncertainty. A neutron source routine has been developed, able to produce the neutron spectra resulting from all possible reactions occurring with the D/T ions in the beam impinging on the Ti D/T target. The neutron energy spectra calculated by combining the source routine with a MCNP model of the neutron generator have been validated by the measurements. These numerical tools will be key in analysing the results from the in-vessel calibration and to derive the response of the JET neutron detectors to DT plasma neutrons starting from the response to the generator neutrons, and taking into account all the calibration circumstances.\u3c/p\u3

Overview of the JET preparation for deuterium-tritium operation with the ITER like-wall

\u3cp\u3eFor the past several years, the JET scientific programme (Pamela et al 2007 Fusion Eng. Des. 82 590) has been engaged in a multi-campaign effort, including experiments in D, H and T, leading up to 2020 and the first experiments with 50%/50% D-T mixtures since 1997 and the first ever D-T plasmas with the ITER mix of plasma-facing component materials. For this purpose, a concerted physics and technology programme was launched with a view to prepare the D-T campaign (DTE2). This paper addresses the key elements developed by the JET programme directly contributing to the D-T preparation. This intense preparation includes the review of the physics basis for the D-T operational scenarios, including the fusion power predictions through first principle and integrated modelling, and the impact of isotopes in the operation and physics of D-T plasmas (thermal and particle transport, high confinement mode (H-mode) access, Be and W erosion, fuel recovery, etc). This effort also requires improving several aspects of plasma operation for DTE2, such as real time control schemes, heat load control, disruption avoidance and a mitigation system (including the installation of a new shattered pellet injector), novel ion cyclotron resonance heating schemes (such as the three-ions scheme), new diagnostics (neutron camera and spectrometer, active Alfven eigenmode antennas, neutral gauges, radiation hard imaging systems...) and the calibration of the JET neutron diagnostics at 14 MeV for accurate fusion power measurement. The active preparation of JET for the 2020 D-T campaign provides an incomparable source of information and a basis for the future D-T operation of ITER, and it is also foreseen that a large number of key physics issues will be addressed in support of burning plasmas.\u3c/p\u3

Lower Health Literacy is Associated with Poorer Health Status and Outcomes in Chronic Obstructive Pulmonary Disease

BACKGROUND: Limited health literacy is associated with poor outcomes in many chronic diseases, but little is known about health literacy in chronic obstructive pulmonary disease (COPD). OBJECTIVE: To examine the associations between health literacy and both outcomes and health status in COPD. PARTICIPANTS, DESIGN AND MAIN MEASURES: Structured interviews were administered to 277 subjects with self-report of physician-diagnosed COPD, recruited through US random-digit telephone dialing. Health literacy was measured with a validated three-item battery. Multivariable linear regression, controlling for sociodemographics including income and education, determined the cross-sectional associations between health literacy and COPD-related health status: COPD Severity Score, COPD Helplessness Index, and Airways Questionnaire-20R [measuring respiratory-specific health-related quality of life (HRQoL)]. Multivariable logistic regression estimated associations between health literacy and COPD-related hospitalizations and emergency department (ED) visits. KEY RESULTS: Taking socioeconomic status into account, poorer health literacy (lowest tertile compared to highest tertile) was associated with: worse COPD severity (+2.3 points; 95 % CI 0.3–4.4); greater COPD helplessness (+3.7 points; 95 % CI 1.6–5.8); and worse respiratory-specific HRQoL (+3.5 points; 95 % CI 1.8–4.9). Poorer health literacy, also controlling for the same covariates, was associated with higher likelihood of COPD-related hospitalizations (OR = 6.6; 95 % CI 1.3–33) and COPD-related ED visits (OR = 4.7; 95 % CI 1.5–15). Analyses for trend across health literacy tertiles were statistically significant (p < 0.05) for all above outcomes. CONCLUSIONS: Independent of socioeconomic status, poor health literacy is associated with greater COPD severity, greater COPD helplessness, worse respiratory-specific HRQoL, and higher odds of COPD-related emergency health-care utilization. These results underscore that COPD patients with poor health literacy may be at particular risk for poor health-related outcomes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11606-012-2177-3) contains supplementary material, which is available to authorized users