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Vascular endothelial growth factor receptor-2 (VEGFR2) is the main pro-angiogenic receptor expressed by endothelial cells (ECs). Using surface plasmon resonance, immunoprecipitation, enzymatic digestion, immunofluorescence and cross-linking experiments with specific sugar-binding lectins, we demonstrated that VEGFR2 bears both α,1-fucose and α(2,6)-linked sialic acid (NeuAc). However, only the latter is required for VEGF binding to VEGFR2 and consequent VEGF-dependent VEGFR2 activation and motogenic response in ECs. Notably, downregulation of β-galactoside α(2,6)-sialyltransferase expression by short hairpin RNA transduction inhibits VEGFR2 α(2,6) sialylation that is paralleled by an increase of β-galactoside α(2,3)-sialyltransferase expression. This results in an ex-novo α(2,3)-NeuAc sialylation of the receptor that functionally replaces the lacking α(2,6)-NeuAc, thus allowing VEGF/VEGFR2 interaction. In keeping with the role of VEGFR2 sialylation in angiogenesis, the α(2,6)-NeuAc-binding lectin Sambucus nigra (SNA) prevents VEGF-dependent VEGFR2 autophosphorylation and EC motility, proliferation and motogenesis. In addition, SNA exerts a VEGF-antagonist activity in tridimensional angiogenesis models in vitro and in the chick-embryo chorioallantoic membrane neovascularization assay and mouse matrigel plug assay in vivo . In conclusion, VEGFR2-associated NeuAc plays an important role in modulating VEGF/VEGFR2 interaction, EC pro-angiogenic activation and neovessel formation. VEGFR2 sialylation may represent a target for the treatment of angiogenesis-dependent diseases.

To date, the mutational status of EGFR and PTEN has been shown as relevant for favoring pro- or anti-tumor functions of STAT3 in human glioblastoma multiforme (GBM). We have screened genomic data from 154 patients and have identified a strong positive correlation between STAT3 and HDAC7 expression. In the current work we show the existence of a subpopulation of patients overexpressing HDAC7 and STAT3 that has particularly poor clinical outcome. Surprisingly, the somatic mutation rate of both STAT3 and HDAC7 was insignificant in GBM comparing with EGFR, PTEN or TP53 . Depletion of HDAC7 in a range of GBM cells induced the expression of tyrosine kinase JAK1 and the tumor suppressor AKAP12. Both proteins synergistically sustained the activity of STAT3 by inducing its phosphorylation (JAK1) and protein expression (AKAP12). In absence of HDAC7, activated STAT3 was responsible for significant imbalance of secreted pro-/anti-angiogenic factors. This inhibited the migration and sprouting of endothelial cells in paracrine fashion in vitro as well as angiogenesis in vivo . In a murine model of GBM, induced HDAC7-silencing decreased the tumor burden by threefold. The current data show for the first time that silencing HDAC7 can reset the tumor suppressor activity of STAT3, independently of the EGFR/PTEN/TP53 background of the GBM. This effect could be exploited to overcome tumor heterogeneity and provide a new rationale behind the development of specific HDAC7 inhibitors for clinical use.

Angiogenesis is the process of generating new capillary blood vessels. Uncontrolled endothelial cell proliferation is observed in tumor neovascularization and in angioproliferative diseases. Tumors cannot growth as a mass above few mm3 unless a new blood supply is induced. It derives that the control of the neovascularization process may affect tumor growth and may represent a novel approach to tumor therapy. Angiogenesis is controlled by a balance between proangiogenic and antiangiogenic factors. The angiogenic switch represents the net result of the activity of angiogenic stimulators and inhibitors, suggesting that counteracting even a single major angiogenic factor could shift the balance towards inhibition. Heparan sulfate proteoglycans are involved in the modulation of the neovascularization that takes place in different physiological and pathological conditions. This modulation occurs through the interaction with angiogenic growth factors or with negative regulators of angiogenesis. Thus, the study of the biochemical bases of this interaction may help to design glycosaminoglycan analogs endowed with angiostatic properties. The purpose of this review is to provide an overview of the structure / function of heparan sulfate proteoglycans in endothelial cells and to summarize the angiostatic properties of synthetic heparin-like compounds, chemically modified heparins, and biotechnological heparins.

Serology has become an increasingly important tool for the surveillance of a wide range of infectious diseases. It has been particularly useful to monitor malaria transmission in elimination settings where existing metrics such as parasite prevalence and incidence of clinical cases are less sensitive. Seroconversion rates, based on antibody prevalence to Plasmodium falciparum asexual blood-stage antigens, provide estimates of transmission intensity that correlate with entomological inoculation rates but lack precision in settings where seroprevalence is still high. Here we present a new and widely applicable method, based on cross-sectional data on individual antibody levels. We evaluate its use as a sero-surveillance tool in a Tanzanian setting with declining malaria prevalence. We find that the newly developed mathematical models produce more precise estimates of transmission patterns, are robust in high transmission settings and when sample sizes are small and provide a powerful tool for serological evaluation of malaria transmission intensity.

Here 11 years of surface data (1961–72, excluding 1963) taken at ocean weather ship N (OWS N) are analyzed. OWS N is located in the subtropical eastern Pacific Ocean (140°W, 30°N). Bulk formulas are employed to calculate each component of the surface heat flux (sensible, latent, longwave, and shortwave) from the 3-h measurements of sea surface temperature (SST), air temperature, surface humidity, wind speed, and cloudiness. Analyses are performed on fluxes averaged over daily and monthly intervals. Results indicate a large fraction of the variance in net surface energy flux is associated with anomalies in the latent heat flux; the latter are principally due to variability in the surface wind speed. Cross correlation and regression analyses of monthly anomalies of SST and SST tendency (∂SST/∂t) with the surface heat flux components indicate over 50% of the variance in SST-tendency anomalies is accounted for by local anomalies in thenetsurface energy flux. In the summer, the summed variance in the four components of the surface heat flux is explained almost completely by two modes of variability that are nearly orthogonal. The first (second) mode is defined as the combination of surface flux components that optimally covaries with the SST-tendency anomaly (SST anomaly) and it contains 74% (26%) of thesummedvariance inallof the surface heat flux components. In addition, thenetheat flux anomaly associated with the the SST-tendency anomaly, which results from the summing of the individual components that define the first mode, accounts for virtually all (96%) of the variance in the net surface flux; it is dominated by the latent heat flux component. The second mode is dominated by the variability in the shortwave flux (mainly due to changes in the cloudiness), but the opposing anomalies in latent and longwave flux largely cancel the anomalies in the shortwave. Hence, thenetheat flux associated with the flux components that covary with the SST anomalies is too small to generate significant variability in SST. The physical scenario consistent with the analyses presented is as follows. Throughout the year, variability that is inherent to the atmosphere causes net surface flux anomalies (mainly due to anomalies in evaporation driven by wind speed anomalies) that account for over 50% of the variability in SST. During the summer months, the changes in the SST that are driven by the aforementioned atmospheric variability, in turn, force changes in the lower troposphere (e.g., in the low-level cloudiness) that are announced by a redistribution of the surface heat flux components, though these changes in the lower atmosphere do not further affect the ocean because there is an insignificant change in thenetsurface heat flux. The results obtained from the observations are confirmed using a one-dimensional ocean mixed layer model. Model results also indicate that heat flux anomalies due to entrainment processes act in the same sense as the net surface heat flux anomalies but are small (about 7% of the variance) compared to the surface heat flux anomalies. Anomalies in ocean advection contribute significantly to SST anomalies only during late wintertime and only for seasonally averaged and longer timescales.

Fibroblast growth factor-2 (FGF2) exerts paracrine and autocrine functions on endothelial cells. FGF2-overexpressing murine aortic endothelial cells (FGF2-T-MAE cells) induce opportunistic hemangioendothelioma-like tumors when inoculated in immunodeficient mice. To evaluate the impact of FGF2-mediated activation on gene expression profile in transformed endothelial cells, we performed subtractive suppression hybridization analysis between FGF2-T-MAE cells and parental MAE cells. The two cell populations were compared for differential gene expression also by gene macroarray hybridization with 32P-labeled cDNAs. The two approaches allowed the identification of 27 transcripts whose expression was upregulated by FGF2 in endothelial cells. With the exception of one unknown gene, the differentially expressed transcripts encoded for proteins involved in the modulation of cell cycle, differentiation, and cell adhesion. Among them, the stress-inducible genes A170, GADD45 and GADD153 are upregulated by FGF2 transfection or recombinant growth factor treatment. Their expression was also induced in vascular tumors originated by parental or FGF2-transfected MAE cells in nude mice. This study extends the number of genes involved in tumor angiogenesis and/or endothelial cell transformation, a finding with possible implications for the discovery of novel targets for angiostatic therapy.

Fibroblast growth factor-2 (FGF2) exerts paracrine and autocrine functions on endothelial cells. FGF2-over-expressing murine aortic endothelial cells (FGF2-T-MAE cells) induce opportunistic hemangioendothelioma-like tumors when inoculated in immunodeficient mice. To evaluate the impact of FGF2-mediated activation on gene expression profile in transformed endothelial cells, we performed subtractive suppression hybridization analysis between FGF2-T-MAE cells and parental MAE cells. The two cell populations were compared for differential gene expression also by gene macroarray hybridization with super(32)P-labeled cDNAs. The two approaches allowed the identification of 27 transcripts whose expression was upregulated by FGF2 in endothelial cells. With the exception of one unknown gene, the differentially expressed transcripts encoded for proteins involved in the modulation of cell cycle, differentiation, and cell adhesion. Among them, the stress-inducible genes A170, GADD45 and GADD153 are upregulated by FGF2 transfection or recombinant growth factor treatment. Their expression was also induced in vascular tumors originated by parental or FGF2-transfected MAE cells in nude mice. This study extends the number of genes involved in tumor angiogenesis and/or endothelial cell transformation, a finding with possible implications for the discovery of novel targets for angiostatic therapy.

Coupling between molecules and vacuum photon fields inside an optical cavity has proven to be an effective way to engineer molecular properties, in particular reactivity. To ease the rationalization of cavity induced effects we introduce an ab initio method leading to the first fully consistent molecular orbital theory for quantum electrodynamics environments. Our framework is non-perturbative and explains modifications of the electronic structure due to the interaction with the photon field. In this work, we show that the newly developed orbital theory can be used to predict cavity induced modifications of molecular reactivity and pinpoint classes of systems with significant cavity effects. We also investigate electronic cavity-induced modifications of reaction mechanisms in vibrational strong coupling regimes. Theoretical description of light-matter coupling in the strong-coupling regime is challenging. Here the authors introduce a fully consistent ab-initio method of molecular orbital theory applicable to material systems in quantum electrodynamics environments.