Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth

Targeted cancer therapies, which act on specific cancer-associated molecular targets, are predominantly inhibitors of oncogenic kinases. While these drugs have achieved some clinical success, the inactivation of kinase signaling via stimulation of endogenous phosphatases has received minimal attention as an alternative targeted approach. Here, we have demonstrated that activation of the tumor suppressor protein phosphatase 2A (PP2A), a negative regulator of multiple oncogenic signaling proteins, is a promising therapeutic approach for the treatment of cancers. Our group previously developed a series of orally bioavailable small molecule activators of PP2A, termed SMAPs. We now report that SMAP treatment inhibited the growth of KRAS-mutant lung cancers in mouse xenografts and transgenic models. Mechanistically, we found that SMAPs act by binding to the PP2A Aα scaffold subunit to drive conformational changes in PP2A. These results show that PP2A can be activated in cancer cells to inhibit proliferation. Our strategy of reactivating endogenous PP2A may be applicable to the treatment of other diseases and represents an advancement toward the development of small molecule activators of tumor suppressor proteins

The dependence of dijet production on photon virtuality in ep collisions at HERA

The dependence of dijet production on the virtuality of the exchanged photon, Q^2, has been studied by measuring dijet cross sections in the range 0 < Q^2 < 2000 GeV^2 with the ZEUS detector at HERA using an integrated luminosity of 38.6 pb^-1. Dijet cross sections were measured for jets with transverse energy E_T^jet > 7.5 and 6.5 GeV and pseudorapidities in the photon-proton centre-of-mass frame in the range -3 < eta^jet <0. The variable xg^obs, a measure of the photon momentum entering the hard process, was used to enhance the sensitivity of the measurement to the photon structure. The Q^2 dependence of the ratio of low- to high-xg^obs events was measured. Next-to-leading-order QCD predictions were found to generally underestimate the low-xg^obs contribution relative to that at high xg^obs. Monte Carlo models based on leading-logarithmic parton-showers, using a partonic structure for the photon which falls smoothly with increasing Q^2, provide a qualitative description of the data.Comment: 35 pages, 6 eps figures, submitted to Eur.Phys.J.

Beauty photoproduction measured using decays into muons in dijet events in ep collisions at s\sqrt{s}=318 GeV

The photoproduction of beauty quarks in events with two jets and a muon has been measured with the ZEUS detector at HERA using an integrated luminosity of 110 pb$^{- 1}$. The fraction of jets containing b quarks was extracted from the transverse momentum distribution of the muon relative to the closest jet. Differential cross sections for beauty production as a function of the transverse momentum and pseudorapidity of the muon, of the associated jet and of $x_{\gamma}^{jets}$, the fraction of the photon's momentum participating in the hard process, are compared with MC models and QCD predictions made at next-to-leading order. The latter give a good description of the data.Comment: 32 pages, 6 tables, 7 figures Table 6 and Figure 7 revised September 200

Search for a narrow charmed baryonic state decaying to D^*+/- p^-/+ in ep collisions at HERA

A resonance search has been made in the D^*+/- p^-/+ invariant-mass spectrum with the ZEUS detector at HERA using an integrated luminosity of 126 pb^-1. The decay channels D^*+ -> D^0 pi^+_s -> (K^- pi^+) pi^+_s and D^*+ -> D^0 pi^+_s -> (K^- pi^+ pi^+ pi^-) pi^+_s (and the corresponding antiparticle decays) were used to identify D^*+/- mesons. No resonance structure was observed in the D^*+/- p^-/+ mass spectrum from more than 60000 reconstructed D^*+/- mesons. The results are not compatible with a report of the H1 Collaboration of a charmed pentaquark, Theta^0_c.Comment: 22 pages, 7 figures, 1 table; minor text revisions; 2 references adde

High ultraviolet C resistance of marine Planctomycetes

Planctomycetes are bacteria with particular characteristics such as internal membrane systems encompassing intracellular compartments, proteinaceous cell walls, cell division by yeast-like budding and large genomes. These bacteria inhabit a wide range of habitats, including marine ecosystems, in which ultra-violet radiation has a potential harmful impact in living organisms. To evaluate the effect of ultra-violet C on the genome of several marine strains of Planctomycetes, we developed an easy and fast DNA diffusion assay in which the cell wall was degraded with papain, the wall-free cells were embedded in an agarose microgel and lysed. The presence of double strand breaks and unwinding by single strand breaks allow DNA diffusion, which is visible as a halo upon DNA staining. The number of cells presenting DNA diffusion correlated with the dose of ultra-violet C or hydrogen peroxide. From DNA damage and viability experiments, we found evidence indicating that some strains of Planctomycetes are significantly resistant to ultra-violet C radiation, showing lower sensitivity than the known resistant Arthrobacter sp. The more resistant strains were those phylogenetically closer to Rhodopirellula baltica, suggesting that these species are adapted to habitats under the influence of ultra-violet radiation. Our results provide evidence indicating that the mechanism of resistance involves DNA damage repair and/or other DNA ultra-violet C-protective mechanism.This research was supported by the European Regional Development Fund (ERDF) through the COMPETE-Operational Competitiveness Programme and national funds through FCT-Foundation for Science and Technology, under the projects Pest-C/BIA/UI4050/2011 and PEst-C/MAR/LA0015/2013. We are grateful to Catia Moreira for helping with the extraction of the pigments.info:eu-repo/semantics/publishedVersio

The prognostic value of dobutamine stress echocardiography amongst British Indian Asian and Afro-Caribbean patients: a comparison with European white patients

Background The incidence of cardiovascular disease is considerably disparate among different racial and ethnic populations. While dobutamine stress echocardiography (DSE) has been shown to be useful in Caucasian patients, its role among ethnic minority groups remains unclear. This study aimed to investigate the prognostic importance of DSE in three ethnic groups in the UK. Methods DSE was performed on 6231 consecutive patients. After exclusions, 5329 patients formed the study (2676 [50.2 %] Indian Asian, 2219 [41.6 %] European white and 434 [8.1 %] Afro-Caribbean). Study outcome measures were non-fatal cardiac events (NFCE) and all-cause mortality. Results There were 849 (15.9 %) NFCE and 1365 (25.6 %) deaths over a median follow-up period of 4.6 years. In total 1174 (22 %) patients had inducible myocardial ischaemia during DSE, 859 (16.1 %) had fixed wall motion abnormalities and 3645 (68.4 %) patients had a normal study. Ethnicity did not predict events. Among the three ethnic groups, ischaemia on DSE was associated with 2 to 2.5 times the risk of non-fatal cardiac events and 1.2 to 1.4 times the risk of all-cause mortality. Peak wall motion score index was the strongest independent predictor of non-fatal cardiac events and all-cause mortality in all groups. The C statistic for the prediction of NFCE and all-cause mortality were significantly higher when DSE parameters were added to the standard risk factors for all ethnic groups. Conclusions DSE is a strong predictor of NFCE and all-cause mortality and provides predictive information beyond that provided by standard risk factors in three major racial and ethnic groups. No major differences among racial and ethnic groups in the predictive value of DSE was detected

Murine Models and Cell Lines for the Investigation of Pheochromocytoma: Applications for Future Therapies?

Pheochromocytomas (PCCs) are slow-growing neuroendocrine tumors arising from adrenal chromaffin cells. Tumors arising from extra-adrenal chromaffin cells are called paragangliomas. Metastases can occur up to approximately 60% or even more in specific subgroups of patients. There are still no well-established and clinically accepted “metastatic” markers available to determine whether a primary tumor is or will become malignant. Surgical resection is the most common treatment for non-metastatic PCCs, but no standard treatment/regimen is available for metastatic PCC. To investigate what kind of therapies are suitable for the treatment of metastatic PCC, animal models or cell lines are very useful. Over the last two decades, various mouse and rat models have been created presenting with PCC, which include models presenting tumors that are to a certain degree biochemically and/or molecularly similar to human PCC, and develop metastases. To be able to investigate which chemotherapeutic options could be useful for the treatment of metastatic PCC, cell lines such as mouse pheochromocytoma (MPC) and mouse tumor tissue (MTT) cells have been recently introduced and they both showed metastatic behavior. It appears these MPC and MTT cells are biochemically and molecularly similar to some human PCCs, are easily visualized by different imaging techniques, and respond to different therapies. These studies also indicate that some mouse models and both mouse PCC cell lines are suitable for testing new therapies for metastatic PCC

The interaction of bacterial pathogens with platelets.

In recent years, the frequency of serious cardiovascular infections such as endocarditis has increased, particularly in association with nosocomially acquired antibiotic-resistant pathogens. Growing evidence suggests a crucial role for the interaction of bacteria with human platelets in the pathogenesis of cardiovascular infections. Here, we review the nature of the interactions between platelets and bacteria, and the role of these interactions in the pathogenesis of endocarditis and other cardiovascular diseases

Search for Resonance Decays to Lepton+jet at DESY HERA and Limits on Leptoquarks

A search for narrow-width resonances that decay into electron+jet or neutrino+jet has been performed with the ZEUS detector at the DESY ep collider HERA operating at center-of-mass energies of 300 and 318 GeV. An integrated e+p luminosity of 114.8 pb-1 and e-p luminosity of 16.7 pb-1 were used. No evidence for any resonance was found. Limits were derived on the Yukawa coupling λ as a function of the mass of a hypothetical resonance that has arbitrary decay branching ratios into eq or vq. These limits also apply to squarks predicted by R-parity-violating supersymmetry. Limits for the production of leptoquarks described by the Buchmüller-Rückl-Wyler model were also derived for masses up to 400 GeV. For λ = 0.1, leptoquark masses up to 290 GeV are excluded