1,075 research outputs found
Inhibition of the hypoxia-inducible factor pathway by a G-quadruplex binding small molecule.
The hypoxia-inducible transcription factor (HIF) co-ordinates the response of tumours to low oxygen by stimulating genes involved in metabolism and angiogenesis. HIF pathway activation is associated with decreased progression-free survival and increased mortality; compounds that target this pathway are potential agents for the treatment of a range of solid tumour malignancies. Renal cancers are likely to be particularly sensitive to inhibition of the HIF pathway since ~80% show constitutive activation of HIF. We have previously described the di-substituted naphthalene derivative, CL67, which binds to a G-quadruplex higher-order structure in the HIF promoter sequence in vitro. We show here that CL67 blocks HIF expression leading to inhibition of HIF-transactivation and down-regulation of downstream target genes and proteins in renal carcinoma cell lines and in a mouse xenograft model of renal cancer. This inhibition is independent of pathways that control HIF abundance through oxygen-dependant degradation and oxygen dependant HIF sub-unit expression
Dasatinib inhibits CXCR4 signaling in chronic lymphocytic leukaemia cells and impairs migration towards CXCL12
Chemokines and their ligands play a critical role in enabling chronic lymphocytic leukaemia (CLL) cells access to protective microenvironmental niches within tissues, ultimately resulting in chemoresistance and relapse: disruption of these signaling pathways has become a novel therapeutic approach in CLL. The tyrosine kinase inhibitor dasatinib inhibits migration of several cell lines from solid-organ tumours, but effects on CLL cells have not been reported. We studied the effect of clinically achievable concentrations of dasatinib on signaling induced by the chemokine CXCL12 through its' receptor CXCR4, which is highly expressed on CLL cells. Dasatinib pre-treatment inhibited Akt and ERK phosphorylation in CLL cells upon stimulation with CXCL12. Dasatinib also significantly diminished the rapid increase in actin polymerisation observed in CLL cells following CXCL12 stimulation. Moreover, the drug significantly inhibited chemotaxis in a transwell assay, and reduced the percentage of cells able to migrate beneath a CXCL12-expressing murine stromal cell line. Dasatinib also abrogated the anti-apoptotic effect of prolonged CXCL12 stimulation on cultured CLL cells. These data suggest that dasatinib, akin to other small molecule kinase inhibitors targeting the B-cell receptor signaling pathway, may redistribute CLL cells from protective tissue niches to the peripheral blood, and support the investigation of dasatinib in combination strategies
Digital strategies to a local cultural tourism development: Project e-Carnide
Digital humanities and smart economy strategies are being seen as an important link between tourism and cultural heritage, as they may contribute to differentiate the audiences and to provide different approaches. Carnide is a peripheral neighbourhood of Lisbon with an elderly population, visible traces of rurality, and strong cultural and religious traditions. The academic project e-Carnide concerns its tangible and intangible cultural heritage and the data dissemination through a website and a mobile app, with textual and visual information. The project aims to analyse the impact of technological solutions on cultural tourism development in a sub-region, involving interdisciplinary research in heritage, history of art, ethnography, design communication and software engineering and the collaboration between the university and local residents in a dynamic and innovative way. Framed by a theoretical approach about the role of smart economy for the cultural tourism development in peripheral areas, this paper focuses on a case study, dealing with documents, interviews and observations, in order to understand how the e-Carnide project evolves. The study comprises an analysis about the strengths, weaknesses, opportunities and threats (SWOT analysis) of the project in view to realize its social and cultural implications and to appreciate how it can be applied in other similar and enlarged projects. Results of the research indicates that the new technological strategies can promote the involvement of the population in the knowledge of its own heritage as a factor of cultural and creative tourism development centred on an authentic and immersive experience of the places
Search for rare quark-annihilation decays, B --> Ds(*) Phi
We report on searches for B- --> Ds- Phi and B- --> Ds*- Phi. In the context
of the Standard Model, these decays are expected to be highly suppressed since
they proceed through annihilation of the b and u-bar quarks in the B- meson.
Our results are based on 234 million Upsilon(4S) --> B Bbar decays collected
with the BABAR detector at SLAC. We find no evidence for these decays, and we
set Bayesian 90% confidence level upper limits on the branching fractions BF(B-
--> Ds- Phi) Ds*- Phi)<1.2x10^(-5). These results
are consistent with Standard Model expectations.Comment: 8 pages, 3 postscript figues, submitted to Phys. Rev. D (Rapid
Communications
Observation and study of baryonic B decays: B -> D(*) p pbar, D(*) p pbar pi, and D(*) p pbar pi pi
We present a study of ten B-meson decays to a D(*), a proton-antiproton pair,
and a system of up to two pions using BaBar's data set of 455x10^6 BBbar pairs.
Four of the modes (B0bar -> D0 p anti-p, B0bar -> D*0 p anti-p, B0bar -> D+ p
anti-p pi-, B0bar -> D*+ p anti-p pi-) are studied with improved statistics
compared to previous measurements; six of the modes (B- -> D0 p anti-p pi-, B-
-> D*0 p anti-p pi-, B0bar -> D0 p anti-p pi- pi+, B0bar -> D*0 p anti-p pi-
pi+, B- -> D+ p anti-p pi- pi-, B- -> D*+ p anti-p pi- pi-) are first
observations. The branching fractions for 3- and 5-body decays are suppressed
compared to 4-body decays. Kinematic distributions for 3-body decays show
non-overlapping threshold enhancements in m(p anti-p) and m(D(*)0 p) in the
Dalitz plots. For 4-body decays, m(p pi-) mass projections show a narrow peak
with mass and full width of (1497.4 +- 3.0 +- 0.9) MeV/c2, and (47 +- 12 +- 4)
MeV/c2, respectively, where the first (second) errors are statistical
(systematic). For 5-body decays, mass projections are similar to phase space
expectations. All results are preliminary.Comment: 28 pages, 90 postscript figures, submitted to LP0
In Vivo Evidence of Reduced Integrity of the GrayâWhite Matter Boundary in Autism Spectrum Disorder
Atypical cortical organization and reduced integrity of the grayâwhite matter boundary have been reported by postmortem
studies in individuals with autism spectrum disorder (ASD). However, there are no in vivo studies that examine these
particular features of cortical organization in ASD. Hence, we used structural magnetic resonance imaging to examine
differences in tissue contrast between gray and white matter in 98 adults with ASD and 98 typically developing controls, to
test the hypothesis that individuals with ASD have significantly reduced tissue contrast. More specifically, we examined
contrast as a percentage between gray and white matter tissue signal intensities (GWPC) sampled at the grayâwhite matter
boundary, and across different cortical layers. We found that individuals with ASD had significantly reduced GWPC in
several clusters throughout the cortex (cluster, P < 0.05). As expected, these reductions were greatest when tissue intensities
were sampled close to grayâwhite matter interface, which indicates a less distinct grayâwhite matter boundary in ASD. Our
in vivo findings of reduced GWPC in ASD are therefore consistent with prior postmortem findings of a less well-defined
grayâwhite matter boundary in ASD. Taken together, these results indicate that GWPC might be utilized as an in vivo proxy
measure of atypical cortical microstructural organization in future studies
Observation of associated near-side and away-side long-range correlations in âsNN=5.02ââTeV proton-lead collisions with the ATLAS detector
Two-particle correlations in relative azimuthal angle (ÎÏ) and pseudorapidity (Îη) are measured in âsNN=5.02ââTeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1ââÎŒb-1 of data as a function of transverse momentum (pT) and the transverse energy (ÎŁETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Îη|<5) ânear-sideâ (ÎÏâŒ0) correlation that grows rapidly with increasing ÎŁETPb. A long-range âaway-sideâ (ÎÏâŒÏ) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ÎŁETPb, is found to match the near-side correlation in magnitude, shape (in Îη and ÎÏ) and ÎŁETPb dependence. The resultant ÎÏ correlation is approximately symmetric about Ï/2, and is consistent with a dominant cosâĄ2ÎÏ modulation for all ÎŁETPb ranges and particle pT
Evidence for the h_b(1P) meson in the decay Upsilon(3S) --> pi0 h_b(1P)
Using a sample of 122 million Upsilon(3S) events recorded with the BaBar
detector at the PEP-II asymmetric-energy e+e- collider at SLAC, we search for
the spin-singlet partner of the P-wave chi_{bJ}(1P) states in the
sequential decay Upsilon(3S) --> pi0 h_b(1P), h_b(1P) --> gamma eta_b(1S). We
observe an excess of events above background in the distribution of the recoil
mass against the pi0 at mass 9902 +/- 4(stat.) +/- 2(syst.) MeV/c^2. The width
of the observed signal is consistent with experimental resolution, and its
significance is 3.1sigma, including systematic uncertainties. We obtain the
value (4.3 +/- 1.1(stat.) +/- 0.9(syst.)) x 10^{-4} for the product branching
fraction BF(Upsilon(3S)-->pi0 h_b) x BF(h_b-->gamma eta_b).Comment: 8 pages, 4 postscript figures, submitted to Phys. Rev. D (Rapid
Communications
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