1,414 research outputs found
The Atacama Cosmology Telescope: Extragalactic Sources at 148 GHz in the 2008 Survey
We report on extragalactic sources detected in a 455 square-degree map of the
southern sky made with data at a frequency of 148 GHz from the Atacama
Cosmology Telescope 2008 observing season. We provide a catalog of 157 sources
with flux densities spanning two orders of magnitude: from 15 to 1500 mJy.
Comparison to other catalogs shows that 98% of the ACT detections correspond to
sources detected at lower radio frequencies. Three of the sources appear to be
associated with the brightest cluster galaxies of low redshift X-ray selected
galaxy clusters. Estimates of the radio to mm-wave spectral indices and
differential counts of the sources further bolster the hypothesis that they are
nearly all radio sources, and that their emission is not dominated by
re-emission from warm dust. In a bright (>50 mJy) 148 GHz-selected sample with
complete cross-identifications from the Australia Telescope 20 GHz survey, we
observe an average steepening of the spectra between 5, 20, and 148 GHz with
median spectral indices of , , and . When the
measured spectral indices are taken into account, the 148 GHz differential
source counts are consistent with previous measurements at 30 GHz in the
context of a source count model dominated by radio sources. Extrapolating with
an appropriately rescaled model for the radio source counts, the Poisson
contribution to the spatial power spectrum from synchrotron-dominated sources
with flux density less than 20 mJy is C^{\rm Sync} = (2.8 \pm 0.3) \times
10^{-6} \micro\kelvin^2.Comment: Accepted to Ap
The Atacama Cosmology Telescope: Sunyaev Zel'dovich Selected Galaxy Clusters at 148 GHz in the 2008 Survey
We report on twenty-three clusters detected blindly as Sunyaev-Zel'dovich
(SZ) decrements in a 148 GHz, 455 square-degree map of the southern sky made
with data from the Atacama Cosmology Telescope 2008 observing season. All SZ
detections announced in this work have confirmed optical counterparts. Ten of
the clusters are new discoveries. One newly discovered cluster, ACT-CL
J0102-4915, with a redshift of 0.75 (photometric), has an SZ decrement
comparable to the most massive systems at lower redshifts. Simulations of the
cluster recovery method reproduce the sample purity measured by optical
follow-up. In particular, for clusters detected with a signal-to-noise ratio
greater than six, simulations are consistent with optical follow-up that
demonstrated this subsample is 100% pure. The simulations further imply that
the total sample is 80% complete for clusters with mass in excess of 6x10^14
solar masses referenced to the cluster volume characterized by five hundred
times the critical density. The Compton y -- X-ray luminosity mass comparison
for the eleven best detected clusters visually agrees with both self-similar
and non-adiabatic, simulation-derived scaling laws.Comment: 13 pages, 7 figures, Accepted for publication in Ap
Small forest losses degrade stream macroinvertebrate assemblages in the eastern Brazilian Amazon
Generally, habitat loss and fragmentation negatively affect biota, often in nonlinear ways. Such nonlinear responses suggest the existence of critical limits for habitat loss beyond which taxa experience substantial changes. Therefore, we identified change points for aquatic macroinvertebrate assemblages at both local-riparian and catchment extents in response to a forest-loss gradient in agriculture-altered landscapes of 51 small (1st to 3rd Strahler order) eastern Amazon streams. We used Threshold Indicator Taxa Analysis (TITAN) to identify change points for individual taxa and segmented regression analysis for assemblage richness. Considering the patterns of the cumulative frequency distributions of sum(Z−) maxima across bootstrap replications, peak changes in macroinvertebrate assemblages were at ∼9% (5–95 percentiles = 1–15%) of forest-loss at the catchment extent, and at ∼1.4% (5–95 percentiles = 0–35%) of forest-loss at the local-riparian extent. Although the assemblage change point at the site extent was less than that detected at the catchment extent, the markedly lower percentile range indicates that biotic assemblages are more clearly responsive to forest-loss at the catchment/network-riparian extents than the site extent. For catchment and site extents, segmented regression analysis determined a change point for assemblage richness at 57% and 79% of forest-loss, respectively. This indicates the low capacity of total richness to separate early and synchronous decreases of sensitive taxa from gradual increases of tolerant taxa. Our results also show that it is not enough to focus management and conservation actions on riparian zones, but that conservation strategies should be expanded to entire catchments as well. The sharp decline of sensitive taxa in response to removal of a small portion of forest cover, even at catchment extents, indicates that the Brazilian Forest Code is insufficient for protecting stream macroinvertebrates. Consequently, we recommend strategies to reverse the potential collapse of aquatic biodiversity, particularly through avoiding deforestation and forest degradation, encouraging socio-economic incentives for restoring degraded areas, creating protected areas, and maintaining the current protected areas. We argue that reducing habitat loss should be a top priority for conservation planners in tropical forests because the sensitivity of aquatic biodiversity to removal of riparian forest-cover in Amazon rainforests is higher than previously thought. Therefore, the Forest Code regulatory framework needs complementary regulation that may be achived by more restrictive State and biome policies. © 2019 Elsevier Lt
CD4 + T cells recognize conserved influenza A epitopes through shared patterns of V-Gene usage and complementary biochemical features
T cell recognition of peptides presented by human leukocyte antigens (HLAs) is mediated by the highly variable T cell receptor (TCR). Despite this built-in TCR variability, individuals can mount immune responses against viral epitopes by using identical or highly related TCRs expressed on CD8+ T cells. Characterization of these TCRs has extended our understanding of the molecular mechanisms that govern the recognition of peptide-HLA. However, few examples exist for CD4+ T cells. Here, we investigate CD4+ T cell responses to the internal proteins of the influenza A virus that correlate with protective immunity. We identify five internal epitopes that are commonly recognized by CD4+ T cells in five HLA-DR1+ subjects and show conservation across viral strains and zoonotic reservoirs. TCR repertoire analysis demonstrates several shared gene usage biases underpinned by complementary biochemical features evident in a structural comparison. These epitopes are attractive targets for vaccination and other T cell therapies
Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial
Background
Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy
Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial
BACKGROUND
Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.
METHODS
Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).
FINDINGS
2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.
INTERPRETATION
Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.
FUNDING
Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research
Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA.See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275.</p
Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
UNLABELLED: Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275
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