The angiopoietin-Tie signaling system is a vascular-specific receptor tyrosine kinase pathway that is essential for normal vascular development. Although the basic functioning of the pathway is ...understood, many uncertainties remain about the role of certain members of the pathway, particularly angiopoietin-2 (Ang2), in pathological vascular remodeling and angiogenesis. We summarize the components of the angiopoietin-Tie pathway and then focus on studies that highlight the role of Ang2 in disease settings, including cancer and inflammation. The expression of Ang2 is elevated in many cancers and types of inflammation, which prompted the development of specific reagents to block its interaction with the Tie2 receptor. The application of these reagents in preclinical models of inflammation and cancer has begun to elucidate the role of Ang2 in vascular remodeling and disease pathogenesis and has led to emerging clinical tests of Ang2 inhibitors.
Tumour angiogenesis has become an important target for antitumour therapy, with most current therapies aimed at blocking the VEGF pathway. However, not all tumours are responsive to VEGF blockers, ...and some tumours that are responsive initially may become resistant during the course of treatment, thus there is a need to explore other angiogenesis signalling pathways. Recently, the Delta-Notch pathway, and particularly the ligand Delta-like 4 (Dll4), was identified as a new target in tumour angiogenesis. An important feature in angiogenesis is the manifold ways in which the VEGF and Delta-Notch pathways interact. The emerging picture is that the VEGF pathway acts as a potent upstream activating stimulus for angiogenesis, whereas Delta-Notch helps to guide cell fate decisions that appropriately shape the activation. Here we review the two signalling pathways and what is currently known about the ways in which they interact during tumour angiogenesis.
Genetic deletion studies have shown that haploinsufficiency of Delta-like ligand (Dll) 4, a transmembrane ligand for the Notch family of receptors, results in major vascular defects and embryonic ...lethality. To better define the role of Dll4 during vascular growth and differentiation, we selected the postnatal retina as a model because its vasculature develops shortly after birth in a highly stereotypic manner, during which time it is accessible to experimental manipulation. We report that Dll4 expression is dynamically regulated by VEGF in the retinal vasculature, where it is most prominently expressed at the leading front of actively growing vessels. Deletion of a single Dll4 allele or pharmacologic inhibition of Dll4/Notch signaling by intraocular administration of either soluble Dll4-Fc or a blocking antibody against Dll4 all produced the same set of characteristic abnormalities in the developing retinal vasculature, most notably enhanced angiogenic sprouting and increased endothelial cell proliferation, resulting in the formation of a denser and more highly interconnected superficial capillary plexus. In a model of ischemic retinopathy, Dll4 blockade also enhanced angiogenic sprouting and regrowth of lost retinal vessels while suppressing ectopic pathological neovascularization. Our data demonstrate that Dll4 is induced by VEGF as a negative feedback regulator and acts to prevent overexuberant angiogenic sprouting, promoting the timely formation of a well differentiated vascular network.
We developed regression equations to predict fine particulate matter (PM
2.5) at air monitoring locations in the New York City region using data on nearby traffic and land use patterns. Three-year ...averages (1999–2001) of PM
2.5 at US Environmental Protection Agency (EPA) monitors in the 28 counties including and surrounding New York City were calculated using daily data from the EPA's Air Quality Subsystem. As the secondary contribution to PM
2.5 concentrations is lowest in the winter, we also calculated and modeled average winter 2000 PM
2.5 to conduct a preliminary evaluation of model sensitivity to source contribution. Candidate predictor variables included traffic, land use, census and emissions data from local, state and national sources and were tabulated for a series of circular buffer regions at varying distances around the monitors using a geographic information system. In total, more than 25 variables at 5 different buffer distances were considered for inclusion in the model. Before evaluating the variables we removed several samples from the modeling for validation. For comparison and validation purposes we computed both a model using data for the full 28-county region as well as a more urbanized 9-county region. We found that traffic within a buffer of 300 or 500
m explains the greatest proportion of variance (37–44%) in all 3 models. Measures of urbanization, specifically population density, explain a significant amount of the residual variation (7–18%) after including a traffic variable. Finally, a measure of industrial land use further improves the 28-county and 9-county models based on the 3-yr annual averages, explaining an additional 4% and 11% of the variation, respectively, while vegetative land use improves the winter model explaining an additional 6%. The final models predicted well at validation locations. In total, the final land use regression models explain between 61% and 64% of the variation in PM
2.5.
The epidermal growth factor receptor (EGFR) is a clinically validated target in head and neck squamous cell carcinoma (HNSCC), where EGFR-blocking antibodies are approved for first-line treatment. ...However, as with other targeted therapies, intrinsic/acquired resistance mechanisms limit efficacy. In the FaDu HNSCC xenograft model, we show that combined blockade of EGFR and ERBB3 promotes rapid tumor regression, followed by the eventual outgrowth of resistant cells. RNA sequencing revealed that resistant cells express FGFR3-TACC3 fusion proteins, which were validated as drivers of the resistant phenotype by several approaches, including CRISPR-mediated inactivation of FGFR3-TACC3 fusion genes. Interestingly, analysis of signaling in resistant cell lines demonstrated that FGFR3-TACC3 fusion proteins promote resistance by preferentially substituting for EGFR/RAS/ERK signaling rather than ERBB3/PI3K/AKT signaling. Furthermore, although FGFR3-TACC3 fusion proteins promote resistance of additional EGFR-dependent HNSCC and lung cancer cell lines to EGFR blockade, they are unable to compensate for inhibition of PI3K signaling in PIK3CA-mutant HNSCC cell lines. Validation of FGFR3-TACC3 fusion proteins as endogenous drivers of resistance in our screen provides strong evidence that these fusions are capable of substituting for EGFR signaling. Thus, FGFR3-TACC3 fusion proteins may represent a novel mechanism of acquired resistance in EGFR-dependent cancers of multiple cell lineages.
Provenance studies demonstrate the important control of plate boundary mountain building on continental sediment routing systems. Less well understood is if subsidence and uplift in cratons also has ...the potential to affect the organization of sediment routing systems on continental scales. New detrital zircon provenance data from the Michigan Basin in the Midcontinent of North America preserve evidence of intrabasin provenance heterogeneity in Cambrian, Ordovician, and middle Devonian strata. These results suggest that cratonic basins serve as effective sediment barriers that prevent mixing within and across basins from 10 to 100 s of millions of years. Internal sediment mixing, sorting, and dispersal may be achieved by a combination of sedimentary processes and inherited low relief topography. These observations are consistent with provenance data sets from eastern Laurentian Midcontinent basins that show locally and regionally variable provenance signatures during the early Paleozoic. By the late Devonian, provenance signatures throughout the basins homogenized, consistent with the emergence of transcontinental sediment transport systems associated with Appalachian orogenesis at the plate margin. These results demonstrate the importance of cratonic basins on local and regional sediment routing systems suggesting that these features may impede the integration of continental-scale sediment routings systems, particularly during periods of plate margin quiescence.
Unresectable hepatocellular carcinoma is extremely difficult to treat. TheraSphere consists of yttrium-90 (a pure beta emitter) microspheres, which are injected into the hepatic arteries. This ...article reviews the safety and survival of patients with hepatocellular carcinoma who were treated with yttrium-90 microspheres. Eighty patients were selected from a database of 108 yttrium-90 microsphere-treated patients and were staged by using Child-Pugh, Okuda, and Cancer of the Liver Italian Program scoring systems. Patients were treated with local, regional, and whole-liver approaches. Survival from first treatment was analyzed with Kaplan-Meier and Cox regression methods. Adverse events and complications of treatment were coded by using the Southwest Oncology Group toxicity scoring system. Patients received liver doses ranging from 47 to 270 Gy. Thirty-two patients (40%) received more than 1 treatment. Survival correlated with pretreatment Cancer of the Liver Italian Program scores (
P = .002), as well as with the individual Cancer of the Liver Italian Program components, Child-Pugh class, alpha-fetoprotein levels, and percentage of tumor replacement. Patients classified as Okuda stage I (n = 54) and II (n = 26) had median survival durations and 1-year survival rates of 628 days and 63%, and 384 days and 51%, respectively (
P = .02). One patient died of liver failure judged as possibly related to treatment. Thus, in selected patients with hepatocellular carcinoma, yttrium-90 microsphere treatment is safe and well tolerated. On the basis of these results, a randomized controlled trial is warranted comparing yttrium-90 microsphere treatment with transarterial chemoembolization by using the Cancer of the Liver Italian Program system for prospective stratified randomization.
Angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF) are endothelial cell-specific growth factors. Direct comparison of transgenic mice overexpressing these factors in the skin ...revealed that the VEGF-induced blood vessels were leaky, whereas those induced by Ang1 were nonleaky. Moreover, vessels in Ang1-overexpressing mice were resistant to leaks caused by inflammatory agents. Coexpression of Ang1 and VEGF had an additive effect on angiogenesis but resulted in leakage-resistant vessels typical of Ang1. Ang1 therefore may be useful for reducing microvascular leakage in diseases in which the leakage results from chronic inflammation or elevated VEGF and, in combination with VEGF, for promoting growth of nonleaky vessels.
Measurements of liquid-liquid phase transition temperatures (cloud points) of mixtures of a protein (lysozyme) and a polymer, poly(ethylene glycol) (PEG) show that the addition of low molecular ...weight PEG stabilizes the mixture whereas high molecular weight PEG was destabilizing. We demonstrate that this behavior is inconsistent with an entropic lysozyme-PEG depletion interaction and suggest that an energetic lysozyme-PEG attraction is responsible. In order to independently characterize the lysozyme-PEG interactions, light scattering experiments on the same mixtures were performed to measure second and third virial coefficients. These measurements indicate that PEG induces repulsion between lysozyme molecules, contrary to the depletion prediction. Furthermore, it is shown that third virial terms must be included in the mixture's free energy in order to qualitatively capture our data.
In this work we study the potential for utilizing the scattering of polarized neutrons from nuclei whose spin has been modulated using nuclear magnetic resonance (NMR). From first principles, we ...present an in-depth development of the differential scattering cross-sections that would arise in such measurements from a hypothetical target system containing nuclei with non- zero spins. In particular, we investigate the modulation of the polarized scattering cross-sections following the application of radio frequency pulses that impart initial transverse rotations to selected sets of spin-1/2 nuclei. The long-term aim is to provide a foundational treatment of the scattering cross section associated with enhancing scattering signals from selected nuclei using NMR techniques, thus employing minimal chemical or isotopic alterations, so as to advance knowledge of macromolecular or liquid structure.
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