No abstract

Therapeutic targeting of the beta-adrenergic receptors has recently shown remarkable efficacy in the treatment of benign vascular tumors such as infantile hemangiomas. As infantile hemangiomas are reported to express high levels of beta adrenergic receptors, we examined the expression of these receptors on more aggressive vascular tumors such as hemangioendotheliomas and angiosarcomas, revealing beta 1, 2, and 3 receptors were indeed present and therefore aggressive vascular tumors may similarly show increased susceptibility to the inhibitory effects of beta blockade. Using a panel of hemangioendothelioma and angiosarcoma cell lines, we demonstrate that beta adrenergic inhibition blocks cell proliferation and induces apoptosis in a dose dependent manner. Beta blockade is selective for vascular tumor cells over normal endothelial cells and synergistically effective when combined with standard chemotherapeutic or cytotoxic agents. We demonstrate that inhibition of beta adrenergic signaling induces large scale changes in the global gene expression patterns of vascular tumors, including alterations in the expression of established cell cycle and apoptotic regulators. Using in vivo tumor models we demonstrate that beta blockade shows remarkable efficacy as a single agent in reducing the growth of angiosarcoma tumors. In summary, these experiments demonstrate the selective cytotoxicity and tumor suppressive ability of beta adrenergic inhibition on malignant vascular tumors and have laid the groundwork for a promising treatment of angiosarcomas in humans.

Infantile hemangiomas (IHs) are non-malignant, largely cutaneous vascular tumors affecting approximately 5–10% of children to varying degrees. During the first year of life, these tumors are strongly proliferative, reaching an average size ranging from 2 to 20 cm. These lesions subsequently stabilize, undergo a spontaneous slow involution and are fully regressed by 5 to 10 years of age. Systemic treatment of infants with the non-selective β-adrenergic receptor blocker, propranolol, has demonstrated remarkable efficacy in reducing the size and appearance of IHs. However, the mechanism by which this occurs is largely unknown. In this study, we sought to understand the molecular mechanisms underlying the effectiveness of β blocker treatment in IHs. Our data reveal that propranolol treatment of IH endothelial cells, as well as a panel of normal primary endothelial cells, blocks endothelial cell proliferation, migration, and formation of the actin cytoskeleton coincident with alterations in vascular endothelial growth factor receptor-2 (VEGFR-2), p38 and cofilin signaling. Moreover, propranolol induces major alterations in the protein levels of key cyclins and cyclin-dependent kinase inhibitors, and modulates global gene expression patterns with a particular affect on genes involved in lipid/sterol metabolism, cell cycle regulation, angiogenesis and ubiquitination. Interestingly, the effects of propranolol were endothelial cell-type independent, affecting the properties of IH endothelial cells at similar levels to that observed in neonatal dermal microvascular and coronary artery endothelial cells. This data suggests that while propranolol markedly inhibits hemangioma and normal endothelial cell function, its lack of endothelial cell specificity hints that the efficacy of this drug in the treatment of IHs may be more complex than simply blockage of endothelial function as previously believed.

Aims. We study the photospheric magnetic field of ∼2000 active regions over solar cycle 23 to search for parameters that may be indicative of energy build-up and its subsequent release as a solar flare in the corona. Methods. We extract three sets of parameters: (1) snapshots in space and time: total flux, magnetic gradients, and neutral lines; (2) evolution in time: flux evolution; and (3) structures at multiple size scales: wavelet analysis. This work combines standard pattern recognition and classification techniques via a relevance vector machine to determine (i.e., classify) whether a region is expected to flare (≥C1.0 according to GOES). We consider classification performance using all 38 extracted features and several feature subsets. Classification performance is quantified using both the true positive rate (the proportion of flares correctly predicted) and the true negative rate (the proportion of non-flares correctly classified). Additionally, we compute the true skill score which provides an equal weighting to true positive rate and true negative rate and the Heidke skill score to allow comparison to other flare forecasting work. Results. We obtain a true skill score of ∼0.5 for any predictive time window in the range 2 to 24 h, with a true positive rate of ∼0.8 and a true negative rate of ∼0.7. These values do not appear to depend on the predictive time window, although the Heidke skill score (<0.5) does. Features relating to snapshots of the distribution of magnetic gradients show the best predictive ability over all predictive time windows. Other gradient-related features and the instantaneous power at various wavelet scales also feature in the top five (of 38) ranked features in predictive power. It has always been clear that while the photospheric magnetic field governs the coronal non-potentiality (and hence likelihood of producing a solar flare), photospheric magnetic field information alone is not sufficient to determine this in a unique manner. Furthermore we are only measuring proxies of the magnetic energy build up. We are still lacking observational details on why energy is released at any particular point in time. We may have discovered the natural limit of the accuracy of flare predictions from these large scale studies.

We study the prediction of solar flare size and time-to-flare using 38 features describing magnetic complexity of the photospheric magnetic field. This work uses support vector regression to formulate a mapping from the 38-dimensional feature space to a continuous-valued label vector representing flare size or timeto-flare. When we consider flaring regions only, we find an average error in estimating flare size of approximately half a geostationary operational environmental satellite (GOES ) class. When we additionally consider non-flaring regions, we find an increased average error of approximately 3/4 a GOES class. We also consider thresholding the regressed flare size for the experiment containing both flaring and non-flaring regions and find a true positive rate of 0.69 and a true negative rate of 0.86 for flare prediction. The results for both of these size regression experiments are consistent across a wide range of predictive time windows, indicating that the magnetic complexity features may be persistent in appearance long before flare activity. This is supported by our larger error rates of some 40 hr in the time-to-flare regression problem. The 38 magnetic complexity features considered here appear to have discriminative potential for flare size, but their persistence in time makes them less discriminative for the time-to-flare problem.