Examining the common aetiology of serous ovarian cancers and basal-like breast cancers using double primaries

Background: The somatic molecular profiles of basal-like breast cancers and high-grade serous ovarian cancers share many similarities, leading to the hypothesis that they have similar aetiologies, in which case they should occur together in the same patient more often than expected. Methods: We identified 545 women with double independent primary cancers of the breast and ovary reported to the California Cancer Registry from 1999 to 2013 and examined the coincidence of subtype combinations. Results: For most subtype combinations the observed frequencies were similar to their expected frequencies, but in 103 observed cases vs 43.8 expected (O/E=2.35; 95% CI 1.90–2.81) a triple-negative breast tumour (typically basal-like) was matched with a serous ovarian tumour (typically high-grade). Conclusions: The results provide compelling evidence that basal-like breast cancer and high-grade serous ovarian cancer share a much more similar aetiology than breast and ovarian cancers more broadly. Further research is needed to clarify the influence of germ-line BRCA1 mutations and other risk factors on these results

Effect of exacerbation history on clinical response to dupilumab in moderate-to-severe uncontrolled asthma

Background The phase 3 LIBERTY ASTHMA QUEST study (ClinicalTrials.gov: NCT02414854) in patients with uncontrolled, moderate-to-severe asthma has demonstrated the efficacy and safety of dupilumab 200 and 300 mg every 2 weeks versus placebo. This post hoc analysis assessed the effect of dupilumab on efficacy outcomes and asthma control across a range of historical exacerbation rates in patients with type 2-high asthma. Methods Annualised severe exacerbation rates over the 52-week treatment period, pre-bronchodilator forced expiratory volume in 1 s (FEV1) at weeks 12 and 52, and the five-item Asthma Control Questionnaire (ACQ-5) score at weeks 24 and 52 were assessed in patients with ≥1, ≥2 or ≥3 exacerbations in the previous year. Subgroups were stratified by baseline blood eosinophils ≥150 or ≥300 cells·μL-1 or baseline exhaled nitric oxide fraction ≥25 ppb and baseline inhaled corticosteroid (ICS) dose. Results Across all type 2-high subgroups, dupilumab versus placebo significantly reduced severe exacerbations by 54–90%, with greater improvements in patients with more exacerbations prior to study initiation. Similarly, improvements in FEV1 (least squares (LS) mean difference versus placebo: ≥1 exacerbations, 0.15–0.25 L; ≥2 exacerbations, 0.12–0.32 L; ≥3 exacerbations, 0.09–0.38 L; majority p<0.05) and ACQ-5 score (LS mean difference range: ≥1 exacerbations, -0.30 to -0.57; ≥2 exacerbations, -0.29 to -0.56; ≥3 exacerbations, -0.43 to -0.61; all p<0.05) were observed, irrespective of prior exacerbation history, across all subgroups. Conclusions Dupilumab significantly reduced severe exacerbations and improved FEV1 and asthma control in patients with elevated type 2 biomarkers irrespective of exacerbation history and baseline ICS dose

Addition of a polygenic risk score, mammographic density, and endogenous hormones to existing breast cancer risk prediction models: A nested case–control study

Background No prior study to our knowledge has examined the joint contribution of a polygenic risk score (PRS), mammographic density (MD), and postmenopausal endogenous hormone levels D all well-confirmed risk factors for invasive breast cancer D to existing breast cancer risk prediction models. Methods and findings We conducted a nested case-control study within the prospective Nurses\u27 Health Study and Nurses\u27 Health Study II including 4,006 cases and 7,874 controls ages 34-70 years up to 1 June 2010. We added a breast cancer PRS using 67 single nucleotide polymorphisms, MD, and circulating testosterone, estrone sulfate, and prolactin levels to existing risk models. We calculated area under the curve (AUC), controlling for age and stratified by menopausal status, for the 5-year absolute risk of invasive breast cancer. We estimated the population distribution of 5-year predicted risks for models with and without biomarkers. For the Gail model, the AUC improved (p-values \u3c 0.001) from 55.9 to 64.1 (8.2 units) in premenopausal women (Gail + PRS + MD), from 55.5 to 66.0 (10.5 units) in postmenopausal women not using hormone therapy (HT) (Gail + PRS + MD + all hormones), and from 58.0 to 64.9 (6.9 units) in postmenopausal women using HT (Gail + PRS + MD + prolactin). For the Rosner-Colditz model, the corresponding AUCs improved (p-values \u3c 0.001) by 5.7, 6.2, and 6.5 units. For estrogen-receptor-positive tumors, among postmenopausal women not using HT, the AUCs improved (p-values \u3c 0.001) by 14.3 units for the Gail model and 7.3 units for the Rosner-Colditz model. Additionally, the percentage of 50-year-old women predicted to be at more than twice 5-year average risk (\u3e= 2.27%) was 0.2% for the Gail model alone and 6.6% for the Gail + PRS + MD + all hormones model. Limitations of our study included the limited racial/ethnic diversity of our cohort, and that general population exposure distributions were unavailable for some risk factors. Conclusions In this study, the addition of PRS, MD, and endogenous hormones substantially improved existing breast cancer risk prediction models. Further studies will be needed to confirm these findings and to determine whether improved risk prediction models have practical value in identifying women at higher risk who would most benefit from chemoprevention, screening, and other risk-reducing strategies

Dupilumab improves lung function in patients with uncontrolled, moderate-to-severe asthma

Background: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation. In the phase 3 LIBERTY ASTHMA QUEST trial (NCT02414854) in patients with uncontrolled, moderate-to-severe asthma, add-on dupilumab 200 mg or 300 mg every 2 weeks reduced exacerbations and improved forced expiratory volume in 1 s (FEV1) and quality of life over 52 weeks. This analysis evaluates dupilimab's effect on lung function in the overall population, and subgroups with baseline elevated type 2 inflammatory biomarkers. Methods: Patients were randomised to 52 weeks of subcutaneous dupilumab 200 mg every 2 weeks, 300 mg every 2 weeks, or matched-volume placebos. Lung function outcomes were analysed in the overall population, in patients with ≥150 eosinophils·µL−1, ≥300 eosinophils·µL−1, ≥25 ppb fractional exhaled nitric oxide (FeNO), and both ≥150 eosinophils·µL−1 and ≥25 ppb FeNO, at baseline. Results: Dupilumab treatment (200 mg and 300 mg every 2 weeks) resulted in significant improvements versus placebo after 52 weeks in pre-bronchodilator FEV1 (0.20 and 0.13 L, respectively, versus placebo) and post-bronchodilator FEV1 (0.19 and 0.13 L, respectively), forced vital capacity (FVC) (0.20 and 0.14 L, respectively), forced expiratory flow (0.19 and 0.13 L·s−1, respectively) and pre-bronchodilator FEV1/FVC ratio (1.75% and 1.61%, respectively) in the overall population (p<0.001). Difference versus placebo in post-bronchodilator FEV1 slope of change (weeks 4–52) was significant (0.04 L·year−1; p<0.05). Greater improvements were achieved in patients with elevated baseline blood eosinophil and/or FeNO levels for most outcomes. Conclusions: Dupilumab improves lung function outcomes, including large and small airway measurements and fixed airway obstruction, in patients with uncontrolled, moderate-to-severe asthma; particularly in patients with elevated biomarkers of type 2 inflammation

The Thermal Regulation of Gravitational Instabilities in Protoplanetary Disks III. Simulations with Radiative Cooling and Realistic Opacities

This paper presents a fully three-dimensional radiative hydrodymanics simulation with realistic opacities for a gravitationally unstable 0.07 Msun disk around a 0.5 Msun star. We address the following aspects of disk evolution: the strength of gravitational instabilities under realistic cooling, mass transport in the disk that arises from GIs, comparisons between the gravitational and Reynolds stresses measured in the disk and those expected in an alpha-disk, and comparisons between the SED derived for the disk and SEDs derived from observationally determined parameters. The mass transport in this disk is dominated by global modes, and the cooling times are too long to permit fragmentation for all radii. Moreover, our results suggest a plausible explanation for the FU Ori outburst phenomenon.Comment: 45 pages, 17 figures; submitted to Ap

What's in a message? Delivering sexual health promotion to young people in Australia via text messaging

<p>Abstract</p> <p>Background</p> <p>Advances in communication technologies have dramatically changed how individuals access information and communicate. Recent studies have found that mobile phone text messages (SMS) can be used successfully for short-term behaviour change. However there is no published information examining the acceptability, utility and efficacy of different characteristics of health promotion SMS. This paper presents the results of evaluation focus groups among participants who received twelve sexual health related SMS as part of a study examining the impact of text messaging for sexual health promotion to on young people in Victoria, Australia.</p> <p>Methods</p> <p>Eight gender-segregated focus groups were held with 21 males and 22 females in August 2008. Transcripts of audio recordings were analysed using thematic analysis. Data were coded under one or more themes.</p> <p>Results</p> <p>Text messages were viewed as an acceptable and 'personal' means of health promotion, with participants particularly valuing the informal language. There was a preference for messages that were positive, relevant and short and for messages to cover a variety of topics. Participants were more likely to remember and share messages that were funny, rhymed and/or tied into particular annual events. The message broadcasting, generally fortnightly on Friday afternoons, was viewed as appropriate. Participants said the messages provided new information, a reminder of existing information and reduced apprehension about testing for sexually transmitted infections.</p> <p>Conclusions</p> <p>Mobile phones, in particular SMS, offer health promoters an exciting opportunity to engage personally with a huge number of individuals for low cost. The key elements emerging from this evaluation, such as message style, language and broadcast schedule are directly relevant to future studies using SMS for health promotion, as well as for future health promotion interventions in other mediums that require short formats, such as social networking sites.</p

Testing the Interaction Between a Substellar Companion and a Debris Disk in the Hr 2562 System

The HR 2562 system is a rare case where a brown dwarf companion resides in a cleared inner hole of a debris disk, offering invaluable opportunities to study the dynamical interaction between a substellar companion and a dusty disk. We present the first ALMA observation of the system as well as the continued Gemini Planet Imager monitoring of the companion\u27s orbit with six new epochs from 2016 to 2018. We update the orbital fit, and in combination with absolute astrometry from GAIA, place a 3σ upper limit of 18.5 M J on the companion\u27s mass. To interpret the ALMA observations, we used radiative transfer modeling to determine the disk properties. We find that the disk is well resolved and nearly edge-on. While the misalignment angle between the disk and the orbit is weakly constrained, due to the short orbital arc available, the data strongly support a (near) coplanar geometry for the system. Furthermore, we find that the models that describe the ALMA data best have inner radii that are close to the companion\u27s semimajor axis. Including a posteriori knowledge of the system\u27s SED further narrows the constraints on the disk\u27s inner radius and places it at a location that is in reasonable agreement with (possibly interior to) predictions from existing dynamical models of disk truncation by an interior substellar companion. HR 2562 has the potential over the next few years to become a new test bed for dynamical interaction between a debris disk and a substellar companion

An Exo-Kuiper Belt with an Extended Halo around HD 191089 in Scattered Light

We have obtained Hubble Space Telescope STIS and NICMOS and Gemini/GPI scattered-light images of the HD 191089 debris disk. We identify two spatial components: a ring resembling the Kuiper Belt in radial extent (FWHM ∼ 25 au, centered at ∼46 au) and a halo extending to ∼640 au. We find that the halo is significantly bluer than the ring, consistent with the scenario that the ring serves as the birth ring for the smaller dust in the halo. We measure the scattering phase functions in the 30°-150° scattering-angle range and find that the halo dust is more forward- and backward-scattering than the ring dust. We measure a surface density power-law index of -0.68 ± 0.04 for the halo, which indicates the slowdown of the radial outward motion of the dust. Using radiative transfer modeling, we attempt to simultaneously reproduce the (visible) total and (near-infrared) polarized intensity images of the birth ring. Our modeling leads to mutually inconsistent results, indicating that more complex models, such as the inclusion of more realistic aggregate particles, are needed

Direct Imaging of the HD 35841 Debris Disk: a Polarized Dust Ring from Gemini Planet Imager and an Outer Halo From \u3ci\u3eHST/\u3c/i\u3eSTIS

We present new high resolution imaging of a light-scattering dust ring and halo around the young star HD 35841. Using spectroscopic and polarimetric data from the Gemini Planet Imager in H-band (1.6 μm), we detect the highly inclined (i = 85°) ring of debris down to a projected separation of ∼12 au (∼0.″12) for the first time. Optical imaging from HST/STIS shows a smooth dust halo extending outward from the ring to \u3e140 au (\u3e1.″4). We measure the ring\u27s scattering phase function and polarization fraction over scattering angles of 22°-125°, showing a preference for forward scattering and a polarization fraction that peaks at ∼30% near the ansae. Modeling of the scattered-light disk indicates that the ring spans radii of ∼60-220 au, has a vertical thickness similar to that of other resolved dust rings, and contains grains as small as 1.5 μm in diameter. These models also suggest the grains have a low porosity, are more likely to consist of carbon than astrosilicates, and contain significant water ice. The halo has a surface brightness profile consistent with that expected from grains pushed by radiation pressure from the main ring onto highly eccentric but still bound orbits. We also briefly investigate arrangements of a possible inner disk component implied by our spectral energy distribution models, and speculate about the limitations of Mie theory for doing detailed analyses of debris disk dust populations