5,510 research outputs found
Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia.
Vascular endothelial growth factor (VEGF) is produced by most tumour types and stimulates the growth of new blood vessels in the tumour. The expansion of a solid tumour ultimately leads to the development of hypoxic regions, which increases VEGF production and further angiogenesis. In this study, we examined the role of VEGF in the survival of breast tumour cells under hypoxia. Murine 4T1 and human MDA-MB-231 tumour cells were cultured under normoxic and hypoxic growth conditions in the presence or absence of VEGF neutralising antibodies. Apoptosis was assessed in addition to changes in expression of the anti- and pro-apoptotic proteins, Bcl-2 and Bad, respectively. The effect of hypoxia on the novel VEGF receptor, NP1 (neuropilin-1) and the role of the PI3K (phosphatidylinositol-3-kinase) signalling pathway in response to VEGF were examined. VEGF blockade resulted in direct tumour cell apoptosis of both tumour cell lines under normoxia and hypoxia. While blocking VEGF resulted in a downregulation of hypoxia-induced Bcl-2 expression, there was a significant increase in the pro-apoptotic protein Bad relative to cells cultured under hypoxia alone. Both hypoxia and VEGF phosphorylated Akt. Neutralising antibodies to VEGF abrogated this effect, implicating the PI3K pathway in VEGF-mediated cell survival of mammary adenocarcinoma cells. This study demonstrates that VEGF acts as a survival factor not only for endothelial cells as previously thought, but also for some breast tumour cells, protecting them from apoptosis, particularly under hypoxic stress. The data presented provide an additional rationale for combining anti-VEGF strategies with conventional anti-cancer therapies such as chemotherapy and radiotherapy
Squark and slepton masses as probes of supersymmetric SO(10) unification
We carry out an analysis of the non-universal supersymmetry breaking scalar
masses arising in SO(10) supersymmetric unification. By considering patterns of
squark and slepton masses, we derive a set of sum rules for the sfermion masses
which are independent of the manner in which SO(10) breaks to the Standard
Model gauge group via its SU(5) subgroups. The phenomenology arising from such
non-universality is unaffected by the symmetry breaking pattern, so long as the
breaking occurs via any of the SU(5) subgroups of the SO(10) group.Comment: 15 pages using RevTe
Visible Sector Supersymmetry Breaking Revisited
We revisit the possibility of "visible sector" SUSY models: models which are
straightforward renormalizable extensions of the Minimal Supersymmetric
Standard Model (MSSM), where SUSY is broken at tree level. Models of this type
were abandoned twenty years ago due to phenomenological problems, which we
review. We then demonstrate that it is possible to construct simple
phenomenologically viable visible sector SUSY models. Such models are indeed
very constrained, and have some inelegant features. They also have interesting
and distinctive phenomenology. Our models predict light gauginos and very heavy
squarks and sleptons. The squarks and sleptons may not be observable at the
LHC. The LSP is a stable very light gravitino with a significant Higgsino
admixture. The NLSP is mostly Bino. The Higgs boson is naturally heavy. Proton
decay is sufficently and naturally suppressed, even for a cutoff scale as low
as 10^8 GeV. The lightest particle of the O'Raifeartaigh sector (the LOP) is
stable, and is an interesting cold dark matter candidate.Comment: 23 pages, 3 figures, LaTe
General analysis of signals with two leptons and missing energy at the Large Hadron Collider
A signal of two leptons and missing energy is challenging to analyze at the
Large Hadron Collider (LHC) since it offers only few kinematical handles. This
signature generally arises from pair production of heavy charged particles
which each decay into a lepton and a weakly interacting stable particle. Here
this class of processes is analyzed with minimal model assumptions by
considering all possible combinations of spin 0, 1/2 or 1, and of weak
iso-singlets, -doublets or -triplets for the new particles. Adding to existing
work on mass and spin measurements, two new variables for spin determination
and an asymmetry for the determination of the couplings of the new particles
are introduced. It is shown that these observables allow one to independently
determine the spin and the couplings of the new particles, except for a few
cases that turn out to be indistinguishable at the LHC. These findings are
corroborated by results of an alternative analysis strategy based on an
automated likelihood test.Comment: 18 pages, 3 figures, LaTe
Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside Analogues
RNA viruses exhibit extraordinarily high mutation rates during genome replication. Nonnatural ribonucleosides that can increase the mutation rate of RNA viruses by acting as ambiguous substrates during replication have been explored as antiviral agents acting through lethal mutagenesis. We have synthesized novel N-6-substituted purine analogues with ambiguous incorporation characteristics due to tautomerization of the nucleobase. The most potent of these analogues reduced the titer of poliovirus (PV) and coxsackievirus (CVB3) over 1,000-fold during a single passage in HeLa cell culture, with an increase in transition mutation frequency up to 65-fold. Kinetic analysis of incorporation by the PV polymerase indicated that these analogues were templated ambiguously with increased efficiency compared to the known mutagenic nucleoside ribavirin. Notably, these nucleosides were not efficient substrates for cellular ribonucleotide reductase in vitro, suggesting that conversion to the deoxyriboucleoside may be hindered, potentially limiting genetic damage to the host cell. Furthermore, a high-fidelity PV variant (G64S) displayed resistance to the antiviral effect and mutagenic potential of these analogues. These purine nucleoside analogues represent promising lead compounds in the development of clinically useful antiviral therapies based on the strategy of lethal mutagenesis
Gamma Rays and Neutrinos from SNR RX J1713.7-3946
The supernova paradigm for the origin of galactic cosmic rays can be tested
using multifrequency observations of both non-thermal and thermal emission from
supernova remnants. The smoking gun of hadronic acceleration in these sources
can, however, only be provided by the detection of a high energy neutrino
signal. Here we apply the theory of non-linear particle acceleration at
supernova shocks to the case of the supernova remnant RX J1713.7-3946, which is
becoming the stereotypical example of a possible hadronic accelerator after the
detection of high energy gamma rays by the HESS telescope. Our aim is twofold:
on one hand we want to address the uncertainties in the discrimination between
a hadronic and a leptonic interpretation of the gamma ray emission, mainly
related to the possibility of a statistical uncertainty in the energy
determination of the gamma ray photons in the TeV region. On the other we want
to stress how a km cube neutrino telescope would break the degeneracy and
provide evidence for efficient cosmic ray acceleration in RX J1713.7-3946. A 3
sigma evidence would require about two years of observation.Comment: 11 pages, 3 figures, accepted for publication in Astropaticle Physic
Not Even Decoupling Can Save Minimal Supersymmetric SU(5)
We make explicit the statement that Minimal Supersymmetric SU(5) has been
excluded by the Super-Kamiokande search for the process . This exclusion is made by first placing limits on the colored
Higgs triplet mass, by forcing the gauge couplings to unify. We also show that
taking the superpartners of the first two generations to be very heavy in order
to avoid flavor changing neutral currents, the so-called ``decoupling'' idea,
is insufficient to resurrect the Minimal SUSY SU(5). We comment on various
mechanisms to further suppress proton decay in SUSY SU(5). Finally, we address
the contributions to proton decay from gauge boson exchange in the Minimal SUSY
SU(5) and flipped SU(5) models.Comment: 8 pages, 4 figure
Strong-weak CP hierarchy from non-renormalization theorems
We point out that the hierarchy between the measured values of the CKM phase
and the strong CP phase has a natural origin in supersymmetry with spontaneous
CP violation and low energy supersymmetry breaking. The underlying reason is
simple and elegant: in supersymmetry the strong CP phase is protected by an
exact non-renormalization theorem while the CKM phase is not. We present
explicit examples of models which exploit this fact and discuss corrections to
the non-renormalization theorem in the presence of supersymmetry breaking. This
framework for solving the strong CP problem has generic predictions for the
superpartner spectrum, for CP and flavor violation, and predicts a preferred
range of values for electric dipole moments.Comment: 36 pages, 3 figure
Supersymmetry discovery potential of the LHC at 10 and 14 TeV without and with missing
We examine the supersymmetry (SUSY) reach of the CERN LHC operating at
and 14 TeV within the framework of the minimal supergravity
model. We improve upon previous reach projections by incorporating updated
background calculations including a variety of Standard Model (SM)
processes. We show that SUSY discovery is possible even before the detectors
are understood well enough to utilize either or electrons in
the signal. We evaluate the early SUSY reach of the LHC at TeV by
examining multi-muon plus jets and also dijet events with {\it no}
missing cuts and show that the greatest reach in terms of
occurs in the dijet channel. The reach in multi-muons is slightly smaller in
, but extends to higher values of . We find that an observable
multi-muon signal will first appear in the opposite-sign dimuon channel, but as
the integrated luminosity increases the relatively background-free but
rate-limited same-sign dimuon, and ultimately the trimuon channel yield the
highest reach. We show characteristic distributions in these channels that
serve to distinguish the signal from the SM background, and also help to
corroborate its SUSY origin. We then evaluate the LHC reach in various
no-lepton and multi-lepton plus jets channels {\it including} missing
cuts for and 14 TeV, and plot the reach for integrated
luminosities ranging up to 3000 fb at the SLHC. For TeV,
the LHC reach extends to and 2.9 TeV for
and integrated luminosities of 10, 100, 1000 and
3000 fb, respectively. For TeV, the LHC reach for the same
integrated luminosities is to m_{gluino}=2.4,\3.1, 3.7 and 4.0 TeV.Comment: 34 pages, 25 figures. Revised projections for the SUSY reach for
ab^-1 integrated luminosities, with minor corrections of references and text.
2 figures added. To appear in JHE
First Observation of the Rare Decay Mode K-long -> e+ e-
In an experiment designed to search for and study very rare two-body decay
modes of the K-long, we have observed four examples of the decay K-long -> e+
e-, where the expected background is 0.17+-0.10 events. This observation
translates into a branching fraction of 8.7^{+5.7}_{-4.1} X 10^{-12},
consistent with recent theoretical predictions. This result represents by far
the smallest branching fraction yet measured in particle physics.Comment: 9 pages, 3 figure
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