There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have ...failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician’s choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.
Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10mg/kg by intravenous infusion every 2weeks or physician’s choice of chemotherapy (paclitaxel 80mg/m2 on days 1, 8, and 15 or irinotecan 150mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.
A total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0months; hazard ratio (HR)=1.1 95% confidence interval (CI) 0.9–1.4; P=0.81} or the secondary end points of PFS median, 1.4 versus 2.7months; HR=1.73 (95% CI 1.4–2.2); P>0.99 or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.
Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.
ClinicalTrials.gov: NCT02625623.
BACKGROUND AND PURPOSE The transcriptional co‐activator with PDZ‐binding motif (TAZ) is characterized as a transcriptional modulator of mesenchymal stem cell differentiation into osteoblasts and ...adipocytes. Moreover, increased TAZ activity in the nucleus enhances osteoblast differentiation and suppresses adipocyte development by interacting with runt‐related transcription factor 2 (RUNX2) and PPARγ, respectively. Therefore, it would be of interest to identify low MW compounds that modulate nuclear TAZ activity.
EXPERIMENTAL APPROACH High‐throughput screening was performed using a library of low MW compounds in order to identify TAZ modulators that enhance nuclear TAZ localization. The effects and molecular mechanisms of a TAZ modulator have been characterized in osteoblast and adipocyte differentiation.
KEY RESULTS We identified 2‐butyl‐5‐methyl‐6‐(pyridine‐3‐yl)‐3‐2′‐(1H‐tetrazole‐5‐yl)‐biphenyl‐4‐ylmethyl‐3H‐imidazo4,5‐bpyridine (TM‐25659) as a TAZ modulator. TM‐25659 enhanced nuclear TAZ localization in a dose‐dependent manner and attenuated PPARγ‐mediated adipocyte differentiation by facilitating PPARγ suppression activity of TAZ. In addition, TAZ‐induced RUNX2 activity activation was further increased in osteoblasts, causing increased osteoblast differentiation. Accordingly, TM‐25659 suppressed bone loss in vivo and decreased weight gain in an obesity model. After oral administration, TM‐25659 had a favourable pharmacokinetic profile.
CONCLUSION AND IMPLICATIONS TM‐25659 stimulated nuclear TAZ localization and thus caused TAZ to suppress PPARγ‐dependent adipogenesis and enhance RUNX2‐induced osteoblast differentiation in vitro and in vivo. Our data suggest that TM‐25659 could be beneficial in the control of obesity and bone loss.
Historically, human uses of land have transformed and fragmented ecosystems
, degraded biodiversity
, disrupted carbon and nitrogen cycles
and added prodigious quantities of greenhouse gases (GHGs) ...to the atmosphere
. However, in contrast to fossil-fuel carbon dioxide (CO
) emissions, trends and drivers of GHG emissions from land management and land-use change (together referred to as 'land-use emissions') have not been as comprehensively and systematically assessed. Here we present country-, process-, GHG- and product-specific inventories of global land-use emissions from 1961 to 2017, we decompose key demographic, economic and technical drivers of emissions and we assess the uncertainties and the sensitivity of results to different accounting assumptions. Despite steady increases in population (+144 per cent) and agricultural production per capita (+58 per cent), as well as smaller increases in emissions per land area used (+8 per cent), decreases in land required per unit of agricultural production (-70 per cent) kept global annual land-use emissions relatively constant at about 11 gigatonnes CO
-equivalent until 2001. After 2001, driven by rising emissions per land area, emissions increased by 2.4 gigatonnes CO
-equivalent per decade to 14.6 gigatonnes CO
-equivalent in 2017 (about 25 per cent of total anthropogenic GHG emissions). Although emissions intensity decreased in all regions, large differences across regions persist over time. The three highest-emitting regions (Latin America, Southeast Asia and sub-Saharan Africa) dominate global emissions growth from 1961 to 2017, driven by rapid and extensive growth of agricultural production and related land-use change. In addition, disproportionate emissions are related to certain products: beef and a few other red meats supply only 1 per cent of calories worldwide, but account for 25 per cent of all land-use emissions. Even where land-use change emissions are negligible or negative, total per capita CO
-equivalent land-use emissions remain near 0.5 tonnes per capita, suggesting the current frontier of mitigation efforts. Our results are consistent with existing knowledge-for example, on the role of population and economic growth and dietary choice-but provide additional insight into regional and sectoral trends.
Evolution of galaxy habitability Gobat, R.; Hong, S. E.
Astronomy and astrophysics (Berlin),
08/2016, Letnik:
592
Journal Article
Recenzirano
Odprti dostop
We combine a semi-analytic model of galaxy evolution with constraints on circumstellar habitable zones and the distribution of terrestrial planets in order to probe the suitability of galaxies of ...different mass and type to host habitable planets, and how it evolves with time. We find that the fraction of stars with terrestrial planets in their habitable zone (known as habitability) depends only weakly on galaxy mass, with a maximum around 4 × 1010M⊙. We estimate that 0.7% of all stars in Milky Way-type galaxies to host a terrestrial planet within their habitable zone, consistent with the value derived from Kepler observations. On the other hand, the habitability of passive galaxies is slightly but systematically higher, unless we assume an unrealistically high sensitivity of planets to supernovae. We find that the overall habitability of galaxies has not changed significantly in the last ~8 Gyr, with most of the habitable planets in local disk galaxies having formed ~1.5 Gyr before our own solar system. Finally, we expect that ~1.4 ×109 planets similar to present-day Earth have existed so far in our galaxy.
Abstract
Magnetization plateaus in quantum magnets—where bosonic quasiparticles crystallize into emergent spin superlattices—are spectacular yet simple examples of collective quantum phenomena ...escaping classical description. While magnetization plateaus have been observed in a number of spin-1/2 antiferromagnets, the description of their magnetic excitations remains an open theoretical and experimental challenge. Here, we investigate the dynamical properties of the triangular-lattice spin-1/2 antiferromagnet Ba
3
CoSb
2
O
9
in its one-third magnetization plateau phase using a combination of nonlinear spin-wave theory and neutron scattering measurements. The agreement between our theoretical treatment and the experimental data demonstrates that magnons behave semiclassically in the plateau in spite of the purely quantum origin of the underlying magnetic structure. This allows for a quantitative determination of Ba
3
CoSb
2
O
9
exchange parameters. We discuss the implication of our results to the deviations from semiclassical behavior observed in zero-field spin dynamics of the same material and conclude they must have an intrinsic origin.
AbstractStarting from a very accurate model for density-in-cells statistics of dark matter based on large deviation theory, a bias model for the tracer density in spheres is formulated. It adopts a ...mean bias relation based on a quadratic bias model to relate the log-densities of dark matter to those of mass-weighted dark haloes in real and redshift space. The validity of the parametrized bias model is established using a parametrization-independent extraction of the bias function. This average bias model is then combined with the dark matter PDF, neglecting any scatter around it: it nevertheless yields an excellent model for densities-in-cells statistics of mass tracers that is parametrized in terms of the underlying dark matter variance and three bias parameters. The procedure is validated on measurements of both the one- and two-point statistics of subhalo densities in the state-of-the-art Horizon Run 4 simulation showing excellent agreement for measured dark matter variance and bias parameters. Finally, it is demonstrated that this formalism allows for a joint estimation of the non-linear dark matter variance and the bias parameters using solely the statistics of subhaloes. Having verified that galaxy counts in hydrodynamical simulations sampled on a scale of 10 Mpc h-1 closely resemble those of subhaloes, this work provides important steps towards making theoretical predictions for density-in-cells statistics applicable to upcoming galaxy surveys like Euclid or WFIRST.
Targeted methylation sequencing of plasma cell-free DNA (cfDNA) has a potential to expand liquid biopsies to patients with tumors without detectable oncogenic alterations, which can be potentially ...useful in early diagnosis.
We developed a comprehensive methylation sequencing assay targeting 9223 CpG sites consistently hypermethylated according to The Cancer Genome Atlas. Next, we carried out a clinical validation of our method using plasma cfDNA samples from 78 patients with advanced colorectal cancer, non-small-cell lung cancer (NSCLC), breast cancer or melanoma and compared results with patients’ outcomes.
Median methylation scores in plasma cfDNA samples from patients on therapy were lower than from patients off therapy (4.74 versus 85.29; P = 0.001). Of 68 plasma samples from patients off therapy, methylation scores detected the presence of cancer in 57 (83.8%), and methylation-based signatures accurately classified the underlying cancer type in 45 (78.9%) of these. Methylation scores were most accurate in detecting colorectal cancer (96.3%), followed by breast cancer (91.7%), melanoma (81.8%) and NSCLC (61.1%), and most accurate in classifying the underlying cancer type in colorectal cancer (88.5%), followed by NSCLC (81.8%), breast cancer (72.7%) and melanoma (55.6%). Low methylation scores versus high were associated with longer survival (10.4 versus 4.4 months, P < 0.001) and longer time-to-treatment failure (2.8 versus 1.6 months, P = 0.016).
Comprehensive targeted methylation sequencing of 9223 CpG sites in plasma cfDNA from patients with common advanced cancers detects the presence of cancer and underlying cancer type with high accuracy. Methylation scores in plasma cfDNA correspond with treatment outcomes.
ABSTRACT We present NuSTAR hard X-ray observations of Sh 2-104, a compact H ii region containing several young massive stellar clusters (YMSCs). We have detected distinct hard X-ray sources ...coincident with localized VERITAS TeV emission recently resolved from the giant gamma-ray complex MGRO J2019+37 in the Cygnus region. Fainter, diffuse X-rays coincident with the eastern YMSC in Sh2-104 likely result from the colliding winds of a component star. Just outside the radio shell of Sh 2-104 lies 3XMM J201744.7+365045 and a nearby nebula, NuSTAR J201744.3+364812, whose properties are most consistent with extragalactic objects. The combined XMM-Newton and NuSTAR spectrum of 3XMM J201744.7+365045 is well-fit to an absorbed power-law model with cm−2 and a photon index . Based on possible long-term flux variation and the lack of detected pulsations (≤43% modulation), this object is likely a background active galactic nucleus rather than a Galactic pulsar. The spectrum of the NuSTAR nebula shows evidence of an emission line at E = 5.6 keV, suggesting an optically obscured galaxy cluster at z = 0.19 0.02 (d = 800 Mpc) and LX = 1.2 × 1044 erg s−1. Follow-up Chandra observations of Sh 2-104 will help identify the nature of the X-ray sources and their relation to MGRO J2019+37. We also show that the putative VERITAS excess south of Sh 2-104, is most likely associated with the newly discovered Fermi pulsar PSR J2017+3625 and not the H ii region.
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