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 $p \to K^{+} \overline{\nu}$. 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 s=\sqrt{s}=10 and 14 TeV without and with missing ETE_T

We examine the supersymmetry (SUSY) reach of the CERN LHC operating at $\sqrt{s}=10$ 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 $2\to n$ Standard Model (SM) processes. We show that SUSY discovery is possible even before the detectors are understood well enough to utilize either $E_T^{\rm miss}$ or electrons in the signal. We evaluate the early SUSY reach of the LHC at $\sqrt{s}=10$ TeV by examining multi-muon plus $\ge4$ jets and also dijet events with {\it no} missing $E_T$ cuts and show that the greatest reach in terms of $m_{1/2}$ occurs in the dijet channel. The reach in multi-muons is slightly smaller in $m_{1/2}$, but extends to higher values of $m_0$. 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 $E_T$ cuts for $\sqrt{s}=10$ and 14 TeV, and plot the reach for integrated luminosities ranging up to 3000 fb$^{-1}$ at the SLHC. For $\sqrt{s}=10$ TeV, the LHC reach extends to $m_{gluino}=1.9, 2.3, 2.8$ and 2.9 TeV for $m_{squark}\sim m_{gluino}$ and integrated luminosities of 10, 100, 1000 and 3000 fb$^{-1}$, respectively. For $\sqrt{s}=14$ 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