Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.

BACKGROUND: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS: We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION: Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies. FUNDING: This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US)

Azimuthal anisotropy and correlations at large transverse momenta in p+pp+p and Au+Au collisions at sNN\sqrt{s_{_{NN}}}= 200 GeV

Results on high transverse momentum charged particle emission with respect to the reaction plane are presented for Au+Au collisions at $\sqrt{s_{_{NN}}}$= 200 GeV. Two- and four-particle correlations results are presented as well as a comparison of azimuthal correlations in Au+Au collisions to those in $p+p$ at the same energy. Elliptic anisotropy, $v_2$, is found to reach its maximum at $p_t \sim 3$ GeV/c, then decrease slowly and remain significant up to $p_t\approx 7$ -- 10 GeV/c. Stronger suppression is found in the back-to-back high-$p_t$ particle correlations for particles emitted out-of-plane compared to those emitted in-plane. The centrality dependence of $v_2$ at intermediate $p_t$ is compared to simple models based on jet quenching.Comment: 4 figures. Published version as PRL 93, 252301 (2004

Azimuthal anisotropy in Au+Au collisions at sqrtsNN = 200 GeV

The results from the STAR Collaboration on directed flow (v_1), elliptic flow (v_2), and the fourth harmonic (v_4) in the anisotropic azimuthal distribution of particles from Au+Au collisions at sqrtsNN = 200 GeV are summarized and compared with results from other experiments and theoretical models. Results for identified particles are presented and fit with a Blast Wave model. Different anisotropic flow analysis methods are compared and nonflow effects are extracted from the data. For v_2, scaling with the number of constituent quarks and parton coalescence is discussed. For v_4, scaling with v_2^2 and quark coalescence is discussed.Comment: 26 pages. As accepted by Phys. Rev. C. Text rearranged, figures modified, but data the same. However, in Fig. 35 the hydro calculations are corrected in this version. The data tables are available at http://www.star.bnl.gov/central/publications/ by searching for "flow" and then this pape

CASTLEGUARD : anonymised data streams with guaranteed differential privacy

Data streams are commonly used by data controllers to outsource the processing of real-time data to third-party data processors. Data protection legislation and best practice in data management support the view that data controllers are responsible for providing a guarantee of privacy for user data contained within published data streams. Continuously Anonymising STreaming data via adaptive cLustEring (CASTLE) is an established method for anonymising data streams with a guarantee of k-anonymity. However, k-anonymity has been shown to be a weak privacy guarantee that has vulnerabilities in practical applications. In this paper we propose Continuously Anonymising STreaming data via adaptive cLustEring with GUAR-anteed Differential privacy (CASTLEGUARD), a data stream anonymisation algorithm that provides a reliable guarantee of k-anonymity, l-diversity and differential privacy to data subjects. We analyse CASTLEGUARD to show that, through safe k-anonymisation and β-sampling, the proposed approach satisfies differentially private k-anonymity. Further, we demonstrate the efficacy of the approach in the context of machine learning, presenting experimental analysis to demonstrate that it can be used to protect the individual privacy of users whilst maintaining the utility of a data stream

Multistrange baryon production in Au-Au collisions at root s(NN)=130 GeV

The transverse mass spectra and midrapidity yields for Xis and Omegas are presented. For the 10% most central collisions, the (Xi) over bar (+)/h(-) ratio increases from the Super Proton Synchrotron to the Relativistic Heavy Ion Collider energies while the Xi(-)/h(-) stays approximately constant. A hydrodynamically inspired model fit to the Xi spectra, which assumes a thermalized source, seems to indicate that these multistrange particles experience a significant transverse flow effect, but are emitted when the system is hotter and the flow is smaller than values obtained from a combined fit to pi, K, p, and Lambdas

Multistrange baryon elliptic flow in Au plus Au collisions at root(NN)-N-S=200 GeV

We report on the first measurement of elliptic flow nu(2)(p(T)) of multistrange baryons Xi(-)+Xi(+) and Omega(-)+Omega(+) in heavy-ion collisions. In minimum-bias Au+Au collisions at root s(NN)=200 GeV, a significant amount of elliptic flow, comparable to other nonstrange baryons, is observed for multistrange baryons which are expected to be particularly sensitive to the dynamics of the partonic stage of heavy-ion collisions. The p(T) dependence of nu(2) of the multistrange baryons confirms the number of constituent quark scaling previously observed for lighter hadrons. These results support the idea that a substantial fraction of the observed collective motion is developed at the early partonic stage in ultrarelativistic nuclear collisions at the Relativistic Heavy Ion Collider

Incident energy dependence of p(t) correlations at relativistic energies

Journals published by the American Physical Society can be found at http://publish.aps.org/We present results for two-particle transverse momentum correlations, , as a function of event centrality for Au+Au collisions at root SNN = 20, 62, 130, and 200 GeV at the BNL Relativistic Heavy Ion Collider. We observe correlations decreasing with centrality that are similar at all four incident energies. The correlations multiplied by the multiplicity density increase with incident energy, and the centrality dependence may show evidence of processes such as thermalization, jet production, or the saturation of transverse flow. The square root of the correlations divided by the event-wise average transverse momentum per event shows little or no beam energy dependence and generally agrees with previous measurements made at the CERN Super Proton Synchrotron