Imatinib mesylate is considered standard of care for first-line treatment of chronic phase chronic myeloid leukemia (CML-CP). In the phase III, randomized, open-label International Randomized Study ...of Interferon vs STI571 (IRIS) trial, previously untreated CML-CP patients were randomized to imatinib (n=553) or interferon-alpha (IFN) plus cytarabine (n=553). This 6-year update focuses on patients randomized to receive imatinib as first-line therapy for newly diagnosed CML-CP. During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC). The toxicity profile was unchanged. The cumulative best complete cytogenetic response (CCyR) rate was 82%; 63% of all patients randomized to receive imatinib and still on study treatment showed CCyR at last assessment. The estimated event-free survival at 6 years was 83%, and the estimated rate of freedom from progression to AP and BC was 93%. The estimated overall survival was 88% -- or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML.
We evaluated homologous recombination deficient (HRD) phenotypes in epithelial ovarian cancer (EOC) considering BRCA1, BRCA2, and RAD51C in a large well-annotated patient set. We evaluated EOC ...patients for germline deleterious mutations (n = 899), somatic mutations (n = 279) and epigenetic alterations (n = 482) in these genes using NGS and genome-wide methylation arrays. Deleterious germline mutations were identified in 32 (3.6%) patients for BRCA1, in 28 (3.1%) for BRCA2 and in 26 (2.9%) for RAD51C. Ten somatically sequenced patients had deleterious alterations, six (2.1%) in BRCA1 and four (1.4%) in BRCA2. Fifty two patients (10.8%) had methylated BRCA1 or RAD51C. HRD patients with germline or somatic alterations in any gene were more likely to be high grade serous, have an earlier diagnosis age and have ovarian and/or breast cancer family history. The HRD phenotype was most common in high grade serous EOC. Identification of EOC patients with an HRD phenotype may help tailor specific therapies.
The Community Earth System Model Version 2 (CESM2) Danabasoglu, G.; Lamarque, J.‐F.; Bacmeister, J. ...
Journal of advances in modeling earth systems,
February 2020, Letnik:
12, Številka:
2
Journal Article
Recenzirano
Odprti dostop
An overview of the Community Earth System Model Version 2 (CESM2) is provided, including a discussion of the challenges encountered during its development and how they were addressed. In addition, an ...evaluation of a pair of CESM2 long preindustrial control and historical ensemble simulations is presented. These simulations were performed using the nominal 1° horizontal resolution configuration of the coupled model with both the “low‐top” (40 km, with limited chemistry) and “high‐top” (130 km, with comprehensive chemistry) versions of the atmospheric component. CESM2 contains many substantial science and infrastructure improvements and new capabilities since its previous major release, CESM1, resulting in improved historical simulations in comparison to CESM1 and available observations. These include major reductions in low‐latitude precipitation and shortwave cloud forcing biases; better representation of the Madden‐Julian Oscillation; better El Niño‐Southern Oscillation‐related teleconnections; and a global land carbon accumulation trend that agrees well with observationally based estimates. Most tropospheric and surface features of the low‐ and high‐top simulations are very similar to each other, so these improvements are present in both configurations. CESM2 has an equilibrium climate sensitivity of 5.1–5.3 °C, larger than in CESM1, primarily due to a combination of relatively small changes to cloud microphysics and boundary layer parameters. In contrast, CESM2's transient climate response of 1.9–2.0 °C is comparable to that of CESM1. The model outputs from these and many other simulations are available to the research community, and they represent CESM2's contributions to the Coupled Model Intercomparison Project Phase 6.
Plain Language Summary
The Community Earth System Model (CESM) is an open‐source, comprehensive model used in simulations of the Earth's past, present, and future climates. The newest version, CESM2, has many new technical and scientific capabilities ranging from a more realistic representation of Greenland's evolving ice sheet, to the ability to model in detail how crops interact with the larger Earth system, to improved representation of clouds and rain, and to the addition of wind‐driven waves on the model's ocean surface. The data sets from a large set of simulations that include integrations for the preindustrial conditions (1850s) and for the 1850‐2014 historical period are available to the community, representing CESM2's contributions to the Coupled Model Intercomparison Project Phase 6 (CMIP6).
Key Points
Community Earth System Model Version 2 includes many substantial science and infrastructure improvements since its previous version
Preindustrial control and historical simulations were performed with low‐top and high‐top with comprehensive chemistry atmospheric models
Comparisons to observations are improved relative to previous versions, including major reductions in radiation and precipitation biases
We present an analysis of , O iii88, N ii122, and far-infrared (FIR) fine-structure line observations obtained with Herschel/PACS, for ∼240 local luminous infrared galaxies (LIRGs) in the Great ...Observatories All-sky LIRG Survey. We find pronounced declines ("deficits") of line-to-FIR continuum emission for N ii122, , and as a function of FIR color and infrared luminosity surface density, . The median electron density of the ionized gas in LIRGs, based on the N ii122/N ii205 ratio, is = 41 cm−3. We find that the dispersion in the deficit of LIRGs is attributed to a varying fractional contribution of photodissociation regions (PDRs) to the observed emission, f( ) = / , which increases from ∼60% to ∼95% in the warmest LIRGs. The / ratio is tightly correlated with the PDR gas kinetic temperature in sources where is not optically thick or self-absorbed. For each galaxy, we derive the average PDR hydrogen density, , and intensity of the interstellar radiation field, G, in units of and find G/ ratios of ∼0.1-50 cm3, with ULIRGs populating the upper end of the distribution. There is a relation between G/ and , showing a critical break at 5 × 1010 L kpc−2. Below , G/ remains constant, 0.32 cm3, and variations in are driven by the number density of star-forming regions within a galaxy, with no change in their PDR properties. Above , G/ increases rapidly with , signaling a departure from the typical PDR conditions found in normal star-forming galaxies toward more intense/harder radiation fields and compact geometries typical of starbursting sources.
In Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over time, perhaps because degeneration of nigrostrial neurons causes progressive loss of aromatic l-amino acid ...decarboxylase (AADC), the enzyme that converts levodopa into dopamine. In a primate model of PD, intrastriatal infusion of an adeno-associated viral type 2 vector containing the human AADC gene (AAV-hAADC) results in robust response to low-dose levodopa without the side effects associated with higher doses. These data prompted a clinical trial.
Patients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer (18)Ffluoro-L-m-tyrosine (FMT) were performed as a measure of gene expression.
The gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased "on" time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort.
This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson's Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.
CONTEXT: The urban heat island (UHI) is a well-documented pattern of warming in cities relative to rural areas. Most UHI research utilizes remote sensing methods at large scales, or climate sensors ...in single cities surrounded by standardized land cover. Relatively few studies have explored continental-scale climatic patterns within common urban microenvironments such as residential landscapes that may affect human comfort. OBJECTIVES: We tested the urban homogenization hypothesis which states that structure and function in cities exhibit ecological “sameness” across diverse regions relative to the native ecosystems they replaced. METHODS: We deployed portable micrometeorological sensors to compare air temperature and humidity in residential yards and native landscapes across six U.S. cities that span a range of climates (Phoenix, AZ; Los Angeles, CA; Minneapolis-St. Paul, MN; Boston, MA; Baltimore, MD; and Miami, FL). RESULTS: Microclimate in residential ecosystems was more similar among cities than among native ecosystems, particularly during the calm morning hours. Maximum regional actual evapotranspiration (AET) was related to the morning residential microclimate effect. Residential yards in cities with maximum AET <50–65 cm/year (Phoenix and Los Angeles) were generally cooler and more humid than nearby native shrublands during summer mornings, while yards in cities above this threshold were generally warmer (Baltimore and Miami) and drier (Miami) than native forests. On average, temperature and absolute humidity were ~6 % less variable among residential ecosystems than among native ecosystems from diverse regions. CONCLUSIONS: These data suggest that common residential land cover and structural characteristics lead to microclimatic convergence across diverse regions at the continental scale.
The Human Connectome Project (HCP) seeks to map the structural and functional connections between network elements in the human brain. Magnetoencephalography (MEG) provides a temporally rich source ...of information on brain network dynamics and represents one source of functional connectivity data to be provided by the HCP. High quality MEG data will be collected from 50 twin pairs both in the resting state and during performance of motor, working memory and language tasks. These data will be available to the general community. Additionally, using the cortical parcellation scheme common to all imaging modalities, the HCP will provide processing pipelines for calculating connection matrices as a function of time and frequency. Together with structural and functional data generated using magnetic resonance imaging methods, these data represent a unique opportunity to investigate brain network connectivity in a large cohort of normal adult human subjects. The analysis pipeline software and the dynamic connectivity matrices that it generates will all be made freely available to the research community.
•Millisecond resolution dynamic connectivity will be provided to the HCP using MEG•MEG data will be collected at rest and during motor and cognitive task performance•Task paradigms are matched to tfMRI designs to provide cross-modal information•A number of connectivity metrics will be implemented at both sensor and source levels•Automated processing pipelines will be made publically available
We report on the results from the first six months of the Catalina Real-Time Transient Survey (CRTS). In order to search for optical transients (OTs) with timescales of minutes to years, the CRTS ...analyses data from the Catalina Sky Survey which repeatedly covers 26,000 of square degrees on the sky. The CRTS provides a public stream of transients that are bright enough to be followed up using small telescopes. Since the beginning of the survey, all CRTS transients have been made available to astronomers around the world in real time using HTML tables,RSS feeds, and VOEvents. As part of our public outreach program, the detections are now also available in Keyhole Markup Language through Google Sky. The initial discoveries include over 350 unique OTs rising more than 2 mag from past measurements. Sixty two of these are classified as supernovae (SNe), based on light curves, prior deep imaging and spectroscopic data. Seventy seven are due to cataclysmic variables (CVs; only 13 previously known), while an additional 100 transients were too infrequently sampled to distinguish between faint CVs and SNe. The remaining OTs include active galactic nucleus, blazars, high-proper-motions stars, highly variable stars (such as UV Ceti stars), and transients of an unknown nature. Our results suggest that there is a large population of SNe missed by many current SN surveys because of selection biases. These objects appear to be associated with faint host galaxies. We also discuss the unexpected discovery of white dwarf binary systems through dramatic eclipses.
We present the main results from the second model intercomparison within the GEWEX (Global Energy and Water cycle EXperiment) Atmospheric Boundary Layer Study (GABLS). The target is to examine the ...diurnal cycle over land in today’s numerical weather prediction and climate models for operational and research purposes. The set-up of the case is based on observations taken during the Cooperative Atmosphere-Surface Exchange Study-1999 (CASES-99), which was held in Kansas, USA in the early autumn with a strong diurnal cycle with no clouds present. The models are forced with a constant geostrophic wind, prescribed surface temperature and large-scale divergence. Results from 30 different model simulations and one large-eddy simulation (LES) are analyzed and compared with observations. Even though the surface temperature is prescribed, the models give variable near-surface air temperatures. This, in turn, gives rise to differences in low-level stability affecting the turbulence and the turbulent heat fluxes. The increase in modelled upward sensible heat flux during the morning transition is typically too weak and the growth of the convective boundary layer before noon is too slow. This is related to weak modelled near-surface winds during the morning hours. The agreement between the models, the LES and observations is the best during the late afternoon. From this intercomparison study, we find that modelling the diurnal cycle is still a big challenge. For the convective part of the diurnal cycle, some of the first-order schemes perform somewhat better while the turbulent kinetic energy (TKE) schemes tend to be slightly better during nighttime conditions. Finer vertical resolution tends to improve results to some extent, but is certainly not the solution to all the deficiencies identified.
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