1,485 research outputs found
Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas
FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K-mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox-breaking RAF inhibitor (PLX8394) has been designed. Here, we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenibresistant BRAF splice variant-expressing tumors and reduced splice variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test the efficacy of therapeutic agents. © 2017 American Association for Cancer Research
Disrupted Maturation of the Microbiota and Metabolome among Extremely Preterm Infants with Postnatal Growth Failure
Growth failure during infancy is a major global problem that has adverse effects on long-term health and neurodevelopment. Preterm infants are disproportionately affected by growth failure and its effects. Herein we found that extremely preterm infants with postnatal growth failure have disrupted maturation of the intestinal microbiota, characterized by persistently low diversity, dominance of pathogenic bacteria within the Enterobacteriaceae family, and a paucity of strictly anaerobic taxa including Veillonella relative to infants with appropriate postnatal growth. Metabolomic profiling of infants with growth failure demonstrated elevated serum acylcarnitines, fatty acids, and other byproducts of lipolysis and fatty acid oxidation. Machine learning algorithms for normal maturation of the microbiota and metabolome among infants with appropriate growth revealed a pattern of delayed maturation of the microbiota and metabolome among infants with growth failure. Collectively, we identified novel microbial and metabolic features of growth failure in preterm infants and potentially modifiable targets for intervention
Kinetics and cellular site of glycolipid loading control
CD1d-restricted natural killer T cells (NKT cells) possess a wide range of effector and regulatory
activities that are related to their ability to secrete both T helper 1 (Th1) cell- and Th2 cell-type
cytokines. We analyzed presentation of NKT cell activating α galactosylceramide (αGalCer) analogs
that give predominantly Th2 cell-type cytokine responses to determine how ligand structure controls
the outcome of NKT cell activation. Using a monoclonal antibody specific for αGalCer-CD1d
complexes to visualize and quantitate glycolipid presentation, we found that Th2 cell-type cytokinebiasing
ligands were characterized by rapid and direct loading of cell-surface CD1d proteins.
Complexes formed by association of these Th2 cell-type cytokine-biasing αGalCer analogs with
CD1d showed a distinctive exclusion from ganglioside-enriched, detergent-resistant plasma
membrane microdomains of antigen-presenting cells. These findings help to explain how subtle
alterations in glycolipid ligand structure can control the balance of proinflammatory and antiinflammatory
activities of NKT cells
The First Empirical Mass Loss Law for Population II Giants
Using the Spitzer IRAC camera we have obtained mid-IR photometry of the red
giant branch stars in the Galactic globular cluster 47 Tuc. About 100 stars
show an excess of mid-infrared light above that expected from their
photospheric emission. This is plausibly due to dust formation in mass flowing
from these stars. This mass loss extends down to the level of the horizontal
branch and increases with luminosity. The mass loss is episodic, occurring in
only a fraction of stars at a given luminosity. Using a simple model and our
observations we derive mass loss rates for these stars. Finally, we obtain the
first empirical mass loss formula calibrated with observations of Population II
stars. The dependence on luminosity of our mass loss rate is considerably
shallower than the widely used Reimers Law. The results presented here are the
first from our Spitzer survey of a carefully chosen sample of 17 Galactic
Globular Clusters, spanning the entire metallicity range from about one
hundredth up to almost solar
Global rise in human infectious disease outbreaks
To characterize the change in frequency of infectious disease outbreaks over time worldwide, we encoded and analysed a novel 33-year dataset (1980–2013) of 12 102 outbreaks of 215 human infectious diseases, comprising more than 44 million cases occuring in 219 nations. We merged these records with ecological characteristics of the causal pathogens to examine global temporal trends in the total number of outbreaks, disease richness (number of unique diseases), disease diversity (richness and outbreak evenness) and per capita cases. Bacteria, viruses, zoonotic diseases (originating in animals) and those caused by pathogens transmitted by vector hosts were responsible for the majority of outbreaks in our dataset. After controlling for disease surveillance, communications, geography and host availability, we find the total number and diversity of outbreaks, and richness of causal diseases increased significantly since 1980 (p < 0.0001). When we incorporate Internet usage into the model to control for biased reporting of outbreaks (starting 1990), the overall number of outbreaks and disease richness still increase significantly with time (p < 0.0001), but per capita cases decrease significantly (p = 0.005). Temporal trends in outbreaks differ based on the causal pathogen's taxonomy, host requirements and transmission mode. We discuss our preliminary findings in the context of global disease emergence and surveillance
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