MEK Inhibition Enhances Paclitaxel-induced Tumor Apoptosis

The anti-cancer drug paclitaxel (Taxol) alters microtubule assembly and activates pro-apoptotic signaling pathways. Previously, we and others found that paclitaxel activates endogenous JNK in tumor cells, and the activation of JNK contributes to tumor cell apoptosis. Here we find that paclitaxel activates the prosurvival MEK/ERK pathway, which conversely may compromise the efficacy of paclitaxel. Hence, a combination treatment of paclitaxel and MEK inhibitors was pursued to determine whether this treatment could lead to enhanced apoptosis. The inhibition of MEK/ERK with a pharmacologic inhibitor, U0126, together with paclitaxel resulted in a dramatic enhancement of apoptosis that is four times more than the additive value of the two drugs alone. Enhanced apoptosis was verified by the terminal transferase-mediated dUTP nick end labeling assay, by an enzyme-linked immunosorbent assay for histone-associated DNA fragments, and by flow cytometric analysis for DNA content. Specificity of the pharmacologic inhibitor was confirmed by the use of (a) a second MEK/ERK inhibitor and (b) a transdominant-negative MEK. Enhanced apoptosis was verified in breast, ovarian, and lung tumor cell lines, suggesting this effect is not cell type-specific. This is the first report of enhanced apoptosis detected in the presence of paclitaxel and MEK inhibition and suggests a new anticancer strategy

Real and Virtual Compton Scattering off the Nucleon

A review is given of the very recent developments in the fields of real and virtual Compton scattering off the nucleon. Both real and virtual Compton scattering reactions are discussed at low outgoing photon energy where one accesses polarizabilities of the nucleon. The real Compton scattering at large momentum transfer is discussed which is asymptotically a tool to obtain information on the valence quark wave function of the nucleon. The rapid developments in deeply virtual Compton scattering and associated meson electroproduction reactions at high energy, high photon virtuality and small momentum transfer to the nucleon are discussed. A unified theoretical description of those processes has emerged over the last few years, which gives access to new, generalized parton distributions. The experimental status and perspectives in these fields are also discussed.Comment: 25 pages, 17 figure

IL-10 Regulates Il12b Expression via Histone Deacetylation: Implications for Intestinal Macrophage Homeostasis

To prevent excessive inflammatory responses to commensal microbes, intestinal macrophages unlike their systemic counterparts do not produce inflammatory cytokines in response to enteric bacteria. Consequently, loss of macrophage tolerance to the enteric microbiota plays a central role in the pathogenesis of the inflammatory bowel diseases. Therefore, we examined whether the hyporesponsive phenotype of intestinal macrophages is programmed by prior exposure to the microbiota. IL-10, but not in vivo exposure to the microbiota, programs intestinal macrophage tolerance, as wild-type (WT) colonic macrophages from germ free and specific-pathogen free (SPF) derived mice produce IL-10 but not IL-12 p40 when activated with enteric bacteria. Basal and activated IL-10 expression is mediated through a MyD88 dependent pathway. Conversely, colonic macrophages from germ free and SPF derived colitis-prone Il10−/− mice demonstrated robust production of IL-12 p40. Next, mechanisms through which IL-10 inhibits Il12b expression were investigated. While Il12b mRNA was transiently induced in LPS-activated WT bone marrow derived macrophages (BMDMs), expression persisted in Il10−/− BMDMs. There were no differences in nucleosome remodeling, mRNA stability, NF-κB activation or MAPK signaling to explain prolonged transcription of Il12b in Il10−/− BMDMs. However, acetylated histone H4 (AcH4) transiently associated with the Il12b promoter in WT BMDMs, whereas association of these factors was prolonged in Il10−/− BMDMs. Experiments utilizing histone deacetylase (HDAC) inhibitors and HDAC3 shRNA indicate that HDAC3 is involved in histone deacetylation of the Il12b promoter by IL-10. These results suggest that histone deacetylation on the Il12b promoter by HDAC3 mediates homeostatic effects of IL-10 in macrophages

Operation and performance of the ATLAS semiconductor tracker

The semiconductor tracker is a silicon microstrip detector forming part of the inner tracking system of the ATLAS experiment at the LHC. The operation and performance of the semiconductor tracker during the first years of LHC running are described. More than 99% of the detector modules were operational during this period, with an average intrinsic hit efficiency of (99.74±0.04)%. The evolution of the noise occupancy is discussed, and measurements of the Lorentz angle, δ-ray production and energy loss presented. The alignment of the detector is found to be stable at the few-micron level over long periods of time. Radiation damage measurements, which include the evolution of detector leakage currents, are found to be consistent with predictions and are used in the verification of radiation background simulations

El Pueblo : diario republicano de Valencia: El Pueblo : diario republicano de Valencia - Año XVI Número 6292 - 1909 septiembre 22 (22/09/1909)

Optical pumping of hot LO phonons in GaAs has been studied as a function of the excitation photon frequency. The experimental results are in good agreement with a model calculation which includes both inter- and intra-valley electron-phonon scatterings. The GAMMA-L and GAMMA-X intervalley electron-phonon interactions in GaAs have been estimated