KIT is the major oncogenic driver of gastrointestinal stromal tumors (GIST). Imatinib, sunitinib, and regorafenib are approved therapies; however, efficacy is often limited by the acquisition of ...polyclonal secondary resistance mutations in KIT, with those located in the activation (A) loop (exons 17/18) being particularly problematic. Here, we explore the KIT-inhibitory activity of ponatinib in preclinical models and describe initial characterization of its activity in patients with GIST.
The cellular and in vivo activities of ponatinib, imatinib, sunitinib, and regorafenib against mutant KIT were evaluated using an accelerated mutagenesis assay and a panel of engineered and GIST-derived cell lines. The ponatinib-KIT costructure was also determined. The clinical activity of ponatinib was examined in three patients with GIST previously treated with all three FDA-approved agents.
In engineered and GIST-derived cell lines, ponatinib potently inhibited KIT exon 11 primary mutants and a range of secondary mutants, including those within the A-loop. Ponatinib also induced regression in engineered and GIST-derived tumor models containing these secondary mutations. In a mutagenesis screen, 40 nmol/L ponatinib was sufficient to suppress outgrowth of all secondary mutants except V654A, which was suppressed at 80 nmol/L. This inhibitory profile could be rationalized on the basis of structural analyses. Ponatinib (30 mg daily) displayed encouraging clinical activity in two of three patients with GIST.
Ponatinib possesses potent activity against most major clinically relevant KIT mutants and has demonstrated preliminary evidence of activity in patients with refractory GIST. These data strongly support further evaluation of ponatinib in patients with GIST.
Recent foodborne illness outbreaks have heightened pressures on growers to deter wildlife from farms, jeopardizing conservation efforts. However, it remains unclear which species, particularly birds, ...pose the greatest risk to food safety. Using >11,000 pathogen tests and 1565 bird surveys covering 139 bird species from across the western United States, we examined the importance of 11 traits in mediating wild bird risk to food safety. We tested whether traits associated with pathogen exposure (e.g., habitat associations, movement, and foraging strategy) and pace‐of‐life (clutch size and generation length) mediated foodborne pathogen prevalence and proclivities to enter farm fields and defecate on crops. Campylobacter spp. were the most prevalent enteric pathogen (8.0%), while Salmonella and Shiga‐toxin producing Escherichia coli (STEC) were rare (0.46% and 0.22% prevalence, respectively). We found that several traits related to pathogen exposure predicted pathogen prevalence. Specifically, Campylobacter and STEC‐associated virulence genes were more often detected in species associated with cattle feedlots and bird feeders, respectively. Campylobacter was also more prevalent in species that consumed plants and had longer generation lengths. We found that species associated with feedlots were more likely to enter fields and defecate on crops. Our results indicated that canopy‐foraging insectivores were less likely to deposit foodborne pathogens on crops, suggesting growers may be able to promote pest‐eating birds and birds of conservation concern (e.g., via nest boxes) without necessarily compromising food safety. As such, promoting insectivorous birds may represent a win‐win‐win for bird conservation, crop production, and food safety. Collectively, our results suggest that separating crop production from livestock farming may be the best way to lower food safety risks from birds. More broadly, our trait‐based framework suggests a path forward for co‐managing wildlife conservation and food safety risks in farmlands by providing a strategy for holistically evaluating the food safety risks of wild animals, including under‐studied species.
Simulated water quality resulting from three alternative future land-use scenarios for two agricultural watersheds in central Iowa was compared to water quality under current and historic land ...use/land cover to explore both the potential water quality impact of perpetuating current trends and potential benefits of major changes in agricultural practices in the U.S. Corn Belt. The Soil Water Assessment Tool (SWAT) was applied to evaluate the effect of management practices on surface water discharge and annual loads of sediment and nitrate in these watersheds. The agricultural practices comprising Scenario 1, which assumes perpetuation of current trends (conversion to conservation tillage, increase in farm size and land in production, use of currently-employed Best Management Practices (BMPs)) result in simulated increased export of nitrate and decreased export of sediment relative to the present. However, simulations indicate that the substantial changes in agricultural practices envisioned in Scenarios 2 and 3 (conversion to conservation tillage, strip intercropping, rotational grazing, conservation set-asides and greatly extended use of best management practices (BMPs) such as riparian buffers, engineered wetlands, grassed waterways, filter strips and field borders) could potentially reduce current loadings of sediment by 37 to 67 percent and nutrients by 54 to 75 percent. Results from the study indicate that major improvements in water quality in these agricultural watersheds could be achieved if such environmentally-targeted agricultural practices were employed. Traditional approaches to water quality improvement through application of traditional BMPs will result in little or no change in nutrient export and minor decreases in sediment export from Corn Belt watersheds.
During the past decade, cardiothoracic surgery (CTS) education has undergone tremendous change with the advent of new technologies and the implementation of integrated programs, to name a few. The ...goal of this study was to assess how residents' career paths, training, and perceptions changed during this period.
The 2006 to 2014 surveys accompanying the Thoracic Surgery Residents Association/Thoracic Surgery Directors' Association in-training examination taken by CTS residents were analyzed, along with a 2003 survey of graduating CTS residents. Of 2,563 residents surveyed, 2,434 (95%) responded.
During the decade, fewer residents were interested in mixed adult cardiac/thoracic practice (20% in 2014 vs 52% in 2003, p = 0.004), more planned on additional training (10% in 2003 vs 41% to 47% from 2011 to 2014), and the frequent use of simulation increased from 1% in 2009 to 24% in 2012 (p < 0.001). More residents recommended CTS to potential trainees (79% in 2014 vs 65% in 2010, p = 0.007). Job offers increased from a low of 12% in 2008 with three or more offers to 34% in 2014. Debt increased from 0% with more than $200,000 in 2003 to 40% in 2013 (p < 0.001). Compared with residents in traditional programs, more integrated residents in 2014 were interested in adult cardiac surgery (53% vs 31%) and congenital surgery (22% vs 7%), fewer were interested in general thoracic surgery (5% vs 31%, p < 0.001), and more planned on additional training (66% vs 36%, p < 0.001).
With the evolution in CTS over the last decade, residents' training and career paths have changed substantially, with increased specialization and simulation accompanied by increased resident satisfaction and an improved job market.
Luminous z ≥ 7 quasars provide direct probes of the evolution of supermassive black holes (SMBHs) and the intergalactic medium (IGM) during the epoch of reionization (EoR). The Ly damping wing ...absorption imprinted by neutral hydrogen in the IGM can be detected in a single EoR quasar spectrum, allowing the measurement of the IGM neutral fraction toward that line of sight. However, damping wing features have only been detected in two z > 7 quasars in previous studies. In this paper, we present new high-quality optical and near-infrared spectroscopy of the z = 7.00 quasar DES J025216.64-050331.8 obtained with Keck/Near-Infrared Echellette Spectrometer and Gemini/GMOS. By using the Mg ii single-epoch virial method, we find that it hosts a SMBH accreting at an Eddington ratio of λEdd = 0.7 0.1, consistent with the values seen in other luminous z ∼ 7 quasars. Furthermore, the Ly region of the spectrum exhibits a strong damping wing absorption feature. The lack of associated metal absorption in the quasar spectrum indicates that this absorption is imprinted by a neutral IGM. Using a state-of-the-art model developed by Davies et al., we measure a volume-averaged neutral hydrogen fraction at z = 7 of within 68% (95%) confidence intervals when marginalizing over quasar lifetimes of . This is the highest IGM neutral fraction yet measured using reionization-era quasar spectra.
A two-stage, stratified, systematic sample design was implemented in the Willamette Valley, Oregon, USA, to quantify wetland and land-use changes from the 1980s to the 1990s. The Stage 1 sample ...(n=711) was drawn from public land survey sections and was stratified by land use and runoff potential. The Stage II sample (n=114) re-sampled the Stage I sample stratified by the amount of hydric soils identified in the Stage 1 sample. Wetland and upland classes were delineated on large-scale aerial photographs, digitized into ARC/Info coverages, and compared to quantify land-cover changes. Total loss of wetlands to uplands during the study period was about 3,800 ha, representing a 2.1 percent wetland loss from the 1980s. The net loss after adjusting for wetland gains was about 2,750 ha. During the study period, 70 percent of the wetland loss was associated with agriculture, six percent was lost to urbanization, and 24 percent was lost to other changes. The loss of wetlands to agriculture and the conversion of wetland types was consistent with a pronounced climatic component related to below-normal precipitation from 1985 to 1994, although continued installation of tile drains and expansion of irrigated agriculture also may have contributed to the changes. The loss of wetlands to agriculture raised questions regarding the effectiveness of current agricultural wetland policy, which appears ill-prepared to protect small wetlands or to deal with loss of wetlands from intensified use of existing farmland. This study identified a larger number and area of wetlands compared with national wetland surveys because of the larger scale data used in this study, the nature of the strata used in the statistical design, and the inclusion of palustrine farmed wetlands in the landuse classification.
A statistically designed survey of lakes and streams conducted by the Environmental Protection Agency in acid-sensitive areas of the United States, the National Surface Water Survey (NSWS), was used ...to identify the role of acidic deposition relative to other factors in causing acidic conditions in an estimated 1180 lakes and 4670 streams. Atmospheric deposition was the dominant source of acid anions in 75 percent of the acidic lakes and 47 percent of the acidic streams. Organic anions were dominant in one-fourth of the acidic lakes and streams; acidic mine drainage was the dominant acid source in 26 percent of the acidic streams. Other causes of acidic conditions were relatively unimportant on a regional scale. Nearly all the deposition-dominated acidic systems were found in six well-delineated subpopulations that represent about one- fourth of the NSWS lake population and one-third of the NSWS stream population.
We present the first observations of foreground Lyα forest absorption from high-redshift galaxies, targeting 24 star-forming galaxies (SFGs) with z ~ 2.3-2.8 within a 5' × 14' region of the COSMOS ...field. The transverse sightline separation is ~2 h-1 Mpc comoving, allowing us to create a tomographic reconstruction of the three-dimensional (3D) Lyα forest absorption field over the redshift range 2.20 ≤ z ≤ 2.45. The resulting map covers 6 h-1 Mpc × 14 h-1 Mpc in the transverse plane and 230 h-1 Mpc along the line of sight with a spatial resolution of ≈3.5 h-1 Mpc, and is the first high-fidelity map of a large-scale structure on ~ Mpc scales at z > 2. Our map reveals significant structures with ≳10 h-1 Mpc extent, including several spanning the entire transverse breadth, providing qualitative evidence for the filamentary structures predicted to exist in the high-redshift cosmic web. Simulated reconstructions with the same sightline sampling, spectral resolution, and signal-to-noise ratio recover the salient structures present in the underlying 3D absorption fields. Using data from other surveys, we identified 18 galaxies with known redshifts coeval with our map volume, enabling a direct comparison with our tomographic map. This shows that galaxies preferentially occupy high-density regions, in qualitative agreement with the same comparison applied to simulations. Our results establish the feasibility of the CLAMATO survey, which aims to obtain Lyα forest spectra for ~1000 SFGs over ~1 deg2 of the COSMOS field, in order to map out the intergalactic medium large-scale structure at 〈z〉 ~ 2.3 over a large volume (100 h-1 Mpc)3.
As part of the Eastern Lake Survey, data on 26 chemical parameters were measured for 768 lakes in the north eastern U.S.A., including all of the New England states together with parts of N.Y., Pa., ...and N.J. A summary of the data obtained is presented in tables and graphs. The results were analysed to examine relationships between physical and chemical variables that might influence the response of the lakes to acid deposition or other perturbations. The data supported the hypothesis that regional lake acidification had occurred in northeastern U.S.A. (see preceding abstract).
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