33 research outputs found
Combined PDGFR and HDAC inhibition overcomes PTEN disruption in Chordoma
Background: The majority of chordomas show activation of the platelet-derived growth factor receptor (PDGFR). Based on in vitro intertumoral variation in response to recombinant PDGF protein and PDGFR inhibition, and variable tumor response to imatinib, we hypothesized that chordomas resistant to PDGFR inhibition may possess downstream activation of the pathway. Methods: Molecular profiling was performed on 23 consecutive chordoma primary tissue specimens. Primary cultures established from 20 of the 23 specimens, and chordoma cell lines, UCH-1 and UCH-2, were used for in vitro experiments. Results: Loss of heterozygosity (LOH) at the phosphatase and tensin homolog (PTEN) locus was observed in 6 specimens (26%). PTEN disruption statistically correlated with increased Ki-67 proliferation index, an established marker of poor outcome for chordoma. Compared to wild type, PTEN deficient chordomas displayed increased proliferative rate, and responded less favorably to PDGFR inhibition. PTEN gene restoration abrogated this growth advantage. Chordomas are characterized by intratumoral hypoxia and local invasion, and histone deacetylase (HDAC) inhibitors are capable of attenuating both hypoxic signaling and cell migration. The combination of PDGFR and HDAC inhibition effectively disrupted growth and invasion of PTEN deficient chordoma cells. Conclusions: Loss of heterozygosity of the PTEN gene seen in a subset of chordomas is associated with aggressive in vitro behavior and strongly correlates with increased Ki-67 proliferative index. Combined inhibition of PDGFR and HDAC attenuates proliferation and invasion in chordoma cells deficient for PTEN
Surgical treatment of intracranial aneurysms: six-year experience in Belo Horizonte, MG, Brazil
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Multi-model evaluation of the sensitivity of the global energy budget and hydrological cycle to resolution
This study undertakes a multi-model comparison with the aim to describe and quantify systematic changes of the global energy and water budgets when the horizontal resolution of atmospheric models is increased and to identify common factors of these changes among models. To do so, we analyse an ensemble of twelve atmosphere-only and six coupled GCMs, with different model formulations and with resolutions spanning those of state-of-the-art coupled GCMs, i.e. from resolutions coarser than 100 km to resolutions finer than 25 km. The main changes in the global energy budget with resolution are a systematic increase in outgoing longwave radiation and decrease in outgoing shortwave radiation due to changes in cloud properties, and a systematic increase in surface latent heat flux; when resolution is increased from 100 to 25 km, the magnitude of the change of those fluxes can be as large as 5 W m−2. Moreover, all but one atmosphere-only model simulate a decrease of the poleward energy transport at higher resolution, mainly explained by a reduction of the equator-to-pole tropospheric temperature gradient. Regarding hydrological processes, our results are the following: (1) there is an increase of global precipitation with increasing resolution in all models (up to 40 × 103 km3 year−1) but the partitioning between land and ocean varies among models; (2) the fraction of total precipitation that falls on land is on average 10% larger at higher resolution in grid point models, but it is smaller at higher resolution in spectral models; (3) grid points models simulate an increase of the fraction of land precipitation due to moisture convergence twice as large as in spectral models; (4) grid point models, which have a better resolved orography, show an increase of orographic precipitation of up to 13 × 103 km3 year−1 which explains most of the change in land precipitation; (5) at the regional scale, precipitation pattern and amplitude are improved with increased resolution due to a better simulated seasonal mean circulation. We discuss our results against several observational estimates of the Earth's energy budget and hydrological cycle and show that they support recent high estimates of global precipitation
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Recent progress in understanding and predicting Atlantic decadal climate variability
Recent Atlantic climate prediction studies are an exciting new contribution to an extensive body of research on Atlantic decadal variability and predictability that has long emphasized the unique role of the Atlantic Ocean in modulating the surface climate. We present a survey of the foundations and frontiers in our understanding of Atlantic variability mechanisms, the role of the Atlantic Meridional Overturning Circulation (AMOC), and our present capacity for putting that understanding into practice in actual climate prediction systems
Management of pediatric intracranial gunshot wounds: predictors of favorable clinical outcome and a new proposed treatment paradigm
Collagen matrix duraplasty for posterior fossa surgery: evaluation of surgical technique in 52 adult patients
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The resolution sensitivity of Northern Hemisphere blocking in four 25-km atmospheric global circulation models
The aim of this study is to investigate if the representation of Northern Hemisphere blocking is sensitive to resolution in current-generation atmospheric global circulation models (AGCMs). An evaluation is conducted of how well atmospheric blocking is represented in four AGCMs whose horizontal resolution is increased from a grid spacing of more than 100 km to about 25 km. It is shown that Euro-Atlantic blocking is simulated overall more credibly at higher resolution (i.e., in better agreement with a 50-yr reference blocking climatology created from the reanalyses ERA-40 and ERA-Interim). The improvement seen with resolution depends on the season and to some extent on the model considered. Euro-Atlantic blocking is simulated more realistically at higher resolution in winter, spring, and autumn, and robustly so across the model ensemble. The improvement in spring is larger than that in winter and autumn. Summer blocking is found to be better simulated at higher resolution by one model only, with little change seen in the other three models. The representation of Pacific blocking is not found to systematically depend on resolution. Despite the improvements seen with resolution, the 25-km models still exhibit large biases in Euro-Atlantic blocking. For example, three of the four 25-km models underestimate winter northern European blocking frequency by about one-third. The resolution sensitivity and biases in the simulated blocking are shown to be in part associated with the mean-state biases in the models' midlatitude circulation
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