11,743 research outputs found
Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia.
High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4). Receptor tyrosine kinase (RTK)/Ras/MAPK signaling pathway mutations were found in two-thirds of patients, including novel mutations in ROS1, which mediates phosphorylation of the PTPN11-encoded protein SHP2. Mutations in FLT3 significantly co-occurred with DOT1L (p=0.04), suggesting functional cooperation in leukemogenesis. We detected an extraordinary level of tumor heterogeneity, with microclonal (mutant allele fraction <0.10) KRAS, NRAS, FLT3, and/or PTPN11 hotspot mutations evident in 31/57 (54.4%) patients. Multiple KRAS and NRAS codon 12 and 13 microclonal mutations significantly co-occurred within tumor samples (p=4.8x10-4), suggesting ongoing formation of and selection for Ras-activating mutations. Future work is required to investigate whether tumor microheterogeneity impacts clinical outcome and to elucidate the functional consequences of epigenetic dysregulation in HD-ALL, potentially leading to novel therapeutic approaches
Language structure in the n-object naming game
We examine a naming game with two agents trying to establish a common
vocabulary for n objects. Such efforts lead to the emergence of language that
allows for an efficient communication and exhibits some degree of homonymy and
synonymy. Although homonymy reduces the communication efficiency, it seems to
be a dynamical trap that persists for a long, and perhaps indefinite, time. On
the other hand, synonymy does not reduce the efficiency of communication, but
appears to be only a transient feature of the language. Thus, in our model the
role of synonymy decreases and in the long-time limit it becomes negligible. A
similar rareness of synonymy is observed in present natural languages. The role
of noise, that distorts the communicated words, is also examined. Although, in
general, the noise reduces the communication efficiency, it also regroups the
words so that they are more evenly distributed within the available "verbal"
space.Comment: minor change
Albedo and Reflection Spectra of Extrasolar Giant Planets
We generate theoretical albedo and reflection spectra for a full range of
extrasolar giant planet (EGP) models, from Jovian to 51-Pegasi class objects.
Our albedo modeling utilizes the latest atomic and molecular cross sections, a
Mie theory treatment of extinction by condensates, a variety of particle size
distributions, and an extension of the Feautrier radiative transfer method
which allows for a general treatment of the scattering phase function. We find
that due to qualitative similarities in the compositions and spectra of objects
within each of five broad effective temperature ranges, it is natural to
establish five representative EGP albedo classes: a ``Jovian'' class (T K; Class I) with tropospheric ammonia clouds, a ``water
cloud'' class (T K; Class II) primarily affected by
condensed HO, a ``clear'' class (T K; Class III)
which lacks clouds, and two high-temperature classes: Class IV (900 K
T 1500 K) for which alkali metal absorption
predominates, and Class V (T 1500 K and/or low surface
gravity ( 10 cm s)) for which a high silicate layer
shields a significant fraction of the incident radiation from alkali metal and
molecular absorption. The resonance lines of sodium and potassium are expected
to be salient features in the reflection spectra of Class III, IV, and V
objects. We derive Bond albedos and effective temperatures for the full set of
known EGPs and explore the possible effects of non-equilibrium condensed
products of photolysis above or within principal cloud decks. As in Jupiter,
such species can lower the UV/blue albedo substantially, even if present in
relatively small mixing ratios.Comment: revised LaTeX manuscript accepted to Ap.J.; also available at
http://jupiter.as.arizona.edu/~burrows/paper
Protocolised non-invasive compared with invasive weaning from mechanical ventilation for adults in intensive care : the Breathe RCT
Background:
Invasive mechanical ventilation (IMV) is a life-saving intervention. Following resolution of the condition that necessitated IMV, a spontaneous breathing trial (SBT) is used to determine patient readiness for IMV discontinuation. In patients who fail one or more SBTs, there is uncertainty as to the optimum management strategy.
Objective:
To evaluate the clinical effectiveness and cost-effectiveness of using non-invasive ventilation (NIV) as an intermediate step in the protocolised weaning of patients from IMV.
Design:
Pragmatic, open-label, parallel-group randomised controlled trial, with cost-effectiveness analysis.
Setting:
A total of 51 critical care units across the UK.
Participants:
Adult intensive care patients who had received IMV for at least 48 hours, who were categorised as ready to wean from ventilation, and who failed a SBT.
Interventions:
Control group (invasive weaning): patients continued to receive IMV with daily SBTs. A weaning protocol was used to wean pressure support based on the patient’s condition. Intervention group (non-invasive weaning): patients were extubated to NIV. A weaning protocol was used to wean inspiratory positive airway pressure, based on the patient’s condition.
Main outcome measures:
The primary outcome measure was time to liberation from ventilation. Secondary outcome measures included mortality, duration of IMV, proportion of patients receiving antibiotics for a presumed respiratory infection and health-related quality of life.
Results:
A total of 364 patients (invasive weaning, n = 182; non-invasive weaning, n = 182) were randomised. Groups were well matched at baseline. There was no difference between the invasive weaning and non-invasive weaning groups in median time to liberation from ventilation {invasive weaning 108 hours [interquartile range (IQR) 57–351 hours] vs. non-invasive weaning 104.3 hours [IQR 34.5–297 hours]; hazard ratio 1.1, 95% confidence interval [CI] 0.89 to 1.39; p = 0.352}. There was also no difference in mortality between groups at any time point. Patients in the non-invasive weaning group had fewer IMV days [invasive weaning 4 days (IQR 2–11 days) vs. non-invasive weaning 1 day (IQR 0–7 days); adjusted mean difference –3.1 days, 95% CI –5.75 to –0.51 days]. In addition, fewer non-invasive weaning patients required antibiotics for a respiratory infection [odds ratio (OR) 0.60, 95% CI 0.41 to 1.00; p = 0.048]. A higher proportion of non-invasive weaning patients required reintubation than those in the invasive weaning group (OR 2.00, 95% CI 1.27 to 3.24). The within-trial economic evaluation showed that NIV was associated with a lower net cost and a higher net effect, and was dominant in health economic terms. The probability that NIV was cost-effective was estimated at 0.58 at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year.
Conclusions:
A protocolised non-invasive weaning strategy did not reduce time to liberation from ventilation. However, patients who underwent non-invasive weaning had fewer days requiring IMV and required fewer antibiotics for respiratory infections.
Future work:
In patients who fail a SBT, which factors predict an adverse outcome (reintubation, tracheostomy, death) if extubated and weaned using NIV?
Trial registration:
Current Controlled Trials ISRCTN15635197.
Funding:
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 48. See the NIHR Journals Library website for further project information
23 High Redshift Supernovae from the IfA Deep Survey: Doubling the SN Sample at z>0.7
We present photometric and spectroscopic observations of 23 high redshift
supernovae spanning a range of z=0.34-1.03, 9 of which are unambiguously
classified as Type Ia. These supernovae were discovered during the IfA Deep
Survey, which began in September 2001 and observed a total of 2.5 square
degrees to a depth of approximately m=25-26 in RIZ over 9-17 visits, typically
every 1-3 weeks for nearly 5 months, with additional observations continuing
until April 2002. We give a brief description of the survey motivations,
observational strategy, and reduction process. This sample of 23 high-redshift
supernovae includes 15 at z>0.7, doubling the published number of objects at
these redshifts, and indicates that the evidence for acceleration of the
universe is not due to a systematic effect proportional to redshift. In
combination with the recent compilation of Tonry et al. (2003), we calculate
cosmological parameter density contours which are consistent with the flat
universe indicated by the CMB (Spergel et al. 2003). Adopting the constraint
that Omega_total = 1.0, we obtain best-fit values of (Omega_m,
Omega_Lambda)=(0.33, 0.67) using 22 SNe from this survey augmented by the
literature compilation. We show that using the empty-beam model for
gravitational lensing does not eliminate the need for Omega_Lambda > 0.
Experience from this survey indicates great potential for similar large-scale
surveys while also revealing the limitations of performing surveys for z>1 SNe
from the ground.Comment: 67 pages, 12 figures, 12 tables, accepted for publication in the
Astrophysical Journa
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Increased burden of familial-associated early-onset cancer risk among minority americans compared to non-latino whites
Background: The role of race/ethnicity in genetic predisposition of early-onset cancers can be estimated by comparing family-based cancer concordance rates among ethnic groups. Methods: We used linked California health registries to evaluate the relative cancer risks for first-degree relatives of patients diagnosed between ages 0 and 26, and the relative risks of developing distinct second primary malignancies (SPMs). From 1989 to 2015, we identified 29,631 cancer patients and 62,863 healthy family members. We calculated the standardized incident ratios (SIRs) of early-onset primary cancers diagnosed in proband siblings and mothers, as well as SPMs detected among early-onset patients. Analyses were stratified by self-identified race/ethnicity. Results: Given probands with cancer, there were increased relative risks of any cancer for siblings and mothers (SIR = 3.32; 95% confidence interval [CI]: 2.85–3.85) and of SPMs (SIR = 7.27; 95% CI: 6.56–8.03). Given a proband with solid cancer, both Latinos (SIR = 4.98; 95% CI: 3.82–6.39) and non-Latino Blacks (SIR = 7.35; 95% CI: 3.36–13.95) exhibited significantly higher relative risk of any cancer in siblings and mothers when compared to non-Latino White subjects (SIR = 3.02; 95% CI: 2.12–4.16). For hematologic cancers, higher familial risk was evident for Asian/Pacific Islanders (SIR = 7.56; 95% CI: 3.26–14.90) compared to non-Latino whites (SIR = 2.69; 95% CI: 1.62–4.20). Conclusions: The data support a need for increased attention to the genetics of early-onset cancer predisposition and environmental factors in race/ethnic minority families in the United States.</p
Impact of an invasive alien plant on litter decomposition along a latitudinal gradient
Invasive alien plant effects on ecosystem functions are often difficult to predict across environmental gradients due to the context-dependent interactions between the invader and the recipient communities. Adopting a functional trait-based framework could provide more mechanistic predictions for invasive species' impacts. In this study, we contrast litter decomposition rates among communities with and without the invasive plant Impatiens glandulifera in five regions along a 1600 km long latitudinal gradient in Europe. Across this gradient, four functional traits, namely leaf dry matter content (LDMC), specific leaf area (SLA), stem-specific density (SSD), and plant height, are correlated to rates of litter decomposition of standardized rooibos (labile), green tea (recalcitrant), and I. glandulifera litter. Our results show that both invaded and non-invaded plant communities had a higher expression of acquisitive traits (low LDMC and SSD, high SLA) with increasing temperature along the latitudinal gradient, partly explaining the variation in decomposition rates along the gradient. At the same time, invasion shifted community trait composition toward more acquisitive traits across the latitudinal gradient. These trait changes partly explained the increased litter decomposition rates of the labile litter fraction of rooibos and I. glandulifera litter in invaded communities, a shift that was most evident in the warmer study regions. Plant available nitrogen was lower in invaded communities, likely due to high nutrient uptake by I. glandulifera. Meanwhile, the coldest study region was characterized by a reversed effect of invasion on decomposition rates. Here, community traits related to low litter quality and potential allelopathic effects of the invader resulted in reduced litter decomposition rates, suggesting a threshold temperature at which invader effects on litter decomposition turn positive. This study therefore illustrates how functional trait changes toward acquisitive traits can help explain invader-induced changes in ecosystem functions such as increased litter decomposition
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Characterization of subsurface media from locations up- and down-gradient of a uranium-contaminated aquifer.
The processing of sediment to accurately characterize the spatially-resolved depth profiles of geophysical and geochemical properties along with signatures of microbial density and activity remains a challenge especially in complex contaminated areas. This study processed cores from two sediment boreholes from background and contaminated core sediments and surrounding groundwater. Fresh core sediments were compared by depth to capture the changes in sediment structure, sediment minerals, biomass, and pore water geochemistry in terms of major and trace elements including pollutants, cations, anions, and organic acids. Soil porewater samples were matched to groundwater level, flow rate, and preferential flows and compared to homogenized groundwater-only samples from neighboring monitoring wells. Groundwater analysis of nearby wells only revealed high sulfate and nitrate concentrations while the same analysis using sediment pore water samples with depth was able to suggest areas high in sulfate- and nitrate-reducing bacteria based on their decreased concentration and production of reduced by-products that could not be seen in the groundwater samples. Positive correlations among porewater content, total organic carbon, trace metals and clay minerals revealed a more complicated relationship among contaminant, sediment texture, groundwater table, and biomass. The fluctuating capillary interface had high concentrations of Fe and Mn-oxides combined with trace elements including U, Th, Sr, Ba, Cu, and Co. This suggests the mobility of potentially hazardous elements, sediment structure, and biogeochemical factors are all linked together to impact microbial communities, emphasizing that solid interfaces play an important role in determining the abundance of bacteria in the sediments
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