Targeting of the MAPK and AKT pathways in conjunctival melanoma shows potential synergy

Purpose: Conjunctival melanoma (CM) is a rare but lethal form of cancer. Similar to cutaneous melanoma, CM frequently carries activating mutations in BRAF and NRAS. We studied whether CM as well as conjunctival benign and premalignant melanocytic lesions express targets in the mitogen-activated protein kinase (MAPK) and AKT pathways, and whether specific inhibitors can suppress CM growth in vitro. Methods: 131 conjunctival lesions obtained from 129 patients were collected. The presence of BRAF V600E mutation and expression of phosphorylated (p)-ERK and p-AKT were assessed by immunohistochemistry. We studied cell proliferation, phosphorylation, cell cycling and apoptosis in three CM cell lines using two BRAF inhibitors (Vemurafenib and Dabrafenib), a MEK inhibitor (MEK162) and an AKT inhibitor (MK2206). Results: The BRAF V600E mutation was present in 19% of nevi and 26% of melanomas, but not in primary acquired melanosis (PAM). Nuclear and cytoplasmic p-ERK and p-AKT were expressed in all conjunctival lesions. Both BRAF inhibitors suppressed growth of both BRAF mutant CM cell lines, but only one induced cell death. MEK162 and MK2206 inhibited proliferation of CM cells in a dose-dependent manner, and the combination of these two drugs led to synergistic growth inhibition and cell death in all CM cell lines. Conclusion: ERK and AKT are constitutively activated in conjunctival nevi, PAM and melanoma. While BRAF inhibitors prohibited cell growth, they were not always cytotoxic. Combining MEK and AKT inhibitors led to more growth inhibition and cell death in CM cells. The combination may benefit patients suffering from metastatic conjunctival melanoma

Alterations to nuclear architecture and genome behavior in senescent cells.

The organization of the genome within interphase nuclei, and how it interacts with nuclear structures is important for the regulation of nuclear functions. Many of the studies researching the importance of genome organization and nuclear structure are performed in young, proliferating, and often transformed cells. These studies do not reveal anything about the nucleus or genome in nonproliferating cells, which may be relevant for the regulation of both proliferation and replicative senescence. Here, we provide an overview of what is known about the genome and nuclear structure in senescent cells. We review the evidence that nuclear structures, such as the nuclear lamina, nucleoli, the nuclear matrix, nuclear bodies (such as promyelocytic leukemia bodies), and nuclear morphology all become altered within growth-arrested or senescent cells. Specific alterations to the genome in senescent cells, as compared to young proliferating cells, are described, including aneuploidy, chromatin modifications, chromosome positioning, relocation of heterochromatin, and changes to telomeres

Infrastructure for Detector Research and Development towards the International Linear Collider

The EUDET-project was launched to create an infrastructure for developing and testing new and advanced detector technologies to be used at a future linear collider. The aim was to make possible experimentation and analysis of data for institutes, which otherwise could not be realized due to lack of resources. The infrastructure comprised an analysis and software network, and instrumentation infrastructures for tracking detectors as well as for calorimetry.Comment: 54 pages, 48 picture

Pion, kaon, proton and anti-proton transverse momentum distributions from p+p and d+Au collisions at sNN=200\sqrt{s_{NN}} = 200 GeV

Identified mid-rapidity particle spectra of $\pi^{\pm}$, $K^{\pm}$, and $p(\bar{p})$ from 200 GeV p+p and d+Au collisions are reported. A time-of-flight detector based on multi-gap resistive plate chamber technology is used for particle identification. The particle-species dependence of the Cronin effect is observed to be significantly smaller than that at lower energies. The ratio of the nuclear modification factor ($R_{dAu}$) between protons $(p+\bar{p})$ and charged hadrons ($h$) in the transverse momentum range $1.2<{p_{T}}<3.0$ GeV/c is measured to be $1.19\pm0.05$(stat)$\pm0.03$(syst) in minimum-bias collisions and shows little centrality dependence. The yield ratio of $(p+\bar{p})/h$ in minimum-bias d+Au collisions is found to be a factor of 2 lower than that in Au+Au collisions, indicating that the Cronin effect alone is not enough to account for the relative baryon enhancement observed in heavy ion collisions at RHIC.Comment: 6 pages, 4 figures, 1 table. We extended the pion spectra from transverse momentum 1.8 GeV/c to 3. GeV/

Measurement of the B0-anti-B0-Oscillation Frequency with Inclusive Dilepton Events

The $B^0$-$\bar B^0$ oscillation frequency has been measured with a sample of 23 million \B\bar B pairs collected with the BABAR detector at the PEP-II asymmetric B Factory at SLAC. In this sample, we select events in which both B mesons decay semileptonically and use the charge of the leptons to identify the flavor of each B meson. A simultaneous fit to the decay time difference distributions for opposite- and same-sign dilepton events gives $\Delta m_d = 0.493 \pm 0.012{(stat)}\pm 0.009{(syst)}$ ps$^{-1}$.Comment: 7 pages, 1 figure, submitted to Physical Review Letter

Azimuthal anisotropy and correlations in p+p, d+Au and Au+Au collisions at 200 GeV

We present the first measurement of directed flow ($v_1$) at RHIC. $v_1$ is found to be consistent with zero at pseudorapidities $\eta$ from -1.2 to 1.2, then rises to the level of a couple of percent over the range $2.4 < |\eta| < 4$. The latter observation is similar to data from NA49 if the SPS rapidities are shifted by the difference in beam rapidity between RHIC and SPS. Back-to-back jets emitted out-of-plane are found to be suppressed more if compared to those emitted in-plane, which is consistent with {\it jet quenching}. Using the scalar product method, we systematically compared azimuthal correlations from p+p, d+Au and Au+Au collisions. Flow and non-flow from these three different collision systems are discussed.Comment: Quark Matter 2004 proceeding, 4 pages, 3 figure

Azimuthal anisotropy: the higher harmonics

We report the first observations of the fourth harmonic (v_4) in the azimuthal distribution of particles at RHIC. The measurement was done taking advantage of the large elliptic flow generated at RHIC. The integrated v_4 is about a factor of 10 smaller than v_2. For the sixth (v_6) and eighth (v_8) harmonics upper limits on the magnitudes are reported.Comment: 4 pages, 6 figures, contribution to the Quark Matter 2004 proceeding

All-optical switching and strong coupling using tunable whispering-gallery-mode microresonators

We review our recent work on tunable, ultrahigh quality factor whispering-gallery-mode bottle microresonators and highlight their applications in nonlinear optics and in quantum optics experiments. Our resonators combine ultra-high quality factors of up to Q = 3.6 \times 10^8, a small mode volume, and near-lossless fiber coupling, with a simple and customizable mode structure enabling full tunability. We study, theoretically and experimentally, nonlinear all-optical switching via the Kerr effect when the resonator is operated in an add-drop configuration. This allows us to optically route a single-wavelength cw optical signal between two fiber ports with high efficiency. Finally, we report on progress towards strong coupling of single rubidium atoms to an ultra-high Q mode of an actively stabilized bottle microresonator.Comment: 20 pages, 24 figures. Accepted for publication in Applied Physics B. Changes according to referee suggestions: minor corrections to some figures and captions, clarification of some points in the text, added references, added new paragraph with results on atom-resonator interactio

Strange Resonance Production in p+p and Au+Au Collisions at RHIC Energies

Resonance yields and spectra from elementary p+p and Au+Au collisions at $\sqrt{s_{\rm NN}} =$ 200 GeV from the STAR experiment at RHIC are presented and discussed in terms of chemical and thermal freeze-out conditions. Thermal models do not adequately describe the yields of the resonance production in central Au+Au collisions. The approach to include elastic hadronic interactions between chemical freeze-out and thermal freeze-out suggests a time of $\Delta \tau>$5 fm/c.Comment: 4 pages, 7 figures, proceedings of the Quark Matter 2004, in Oakland, California, to be published in Journal of Physics G: Nuclear and Particle Physic