Arsenic trioxide down-regulates antiapoptotic genes and induces cell death in mycosis fungoides tumors in a mouse model

Background: Mycosis fungoides (MF) is the most frequent cutaneous T-cell lymphoma (CTCL). Arsenic trioxide (As2O3) has recently been shown to be effective against leukemias, so we studied whether As2O3 induces apoptosis of CTCL cells in vitro. We further investigated if As2O3 is effective in a MF mouse model. Material and methods: Annexin V/7-amino-actinomycin-D stainings were carried out to investigate if As2O3 induced apoptosis of CTCL cell lines. To study the underlying mechanisms, the effects of As2O3 on various transcription factors and apoptosis regulating proteins were analyzed by western blots, electrophoretic mobility shift assays and transcription factor enzyme-linked immunosorbent assays. The ability of As2O3 to induce tumor regression was investigated in a MF mouse model. Results: As2O3-induced apoptosis was paralleled by a reduction of the DNA-binding activities of transcription factors of the NFkB and signal transducer and activator of transcription gene families and reduced expression of the antiapoptotic proteins bcl-1, bcl-xL and mcl-1. Local injections of 200 μM As2O3 into tumors caused complete remissions in five of six mice and one partial remission. Conclusions: As2O3 induced apoptosis of CTCL cells by the down-regulation of transcription factors that stimulate the expression of antiapoptotic genes. Local injection of As2O3 into MF tumor-bearing mice resulted in tumor regressio

Single flux quantum circuits with damping based on dissipative transmission lines

We propose and demonstrate the functioning of a special Rapid Single Flux Quantum (RSFQ) circuit with frequency-dependent damping. This damping is achieved by shunting individual Josephson junctions by pieces of open-ended RC transmission lines. Our circuit includes a toggle flip-flop cell, Josephson transmission lines transferring single flux quantum pulses to and from this cell, as well as DC/SFQ and SFQ/DC converters. Due to the desired frequency-dispersion in the RC line shunts which ensures sufficiently low noise at low frequencies, such circuits are well-suited for integrating with the flux/phase Josephson qubit and enable its efficient control.Comment: 6 pages incl. 6 figure

Effects of oxidized lipids (4,5 (E)-epoxy-2(E)-heptenal and 4,5 (E)-epoxy-2 (E) -decenal) and lysine reaction products on zinc and calcium utilization: assays in Caco-2 cells

The influence of the presence of brown products from the reaction between two oxidized lipids (4,5 (E)-epoxy-2(E)-heptenal, EH, and 4,5 (E)-epoxy-2 (E)-decenal, ED) and lysine (EH-L and ED-L) on zinc and calcium utilization was studied, and compared with a fructosyl-lysine mixture (F-L). Assays were carried out in Caco-2 cells grown in bicameral chambers. The Zn transported across the cell monolayer was significantly lower in the presence of the EH-L, ED-L and F-L samples, specially with EH-L. Significant decreases in Zn uptake were also observed, with no differences between samples. However, calcium transport was not modified. Thus, the assayed lipid-aminoacid brown products seem to have negative effects on Zn availability, whereas Ca availability appears to be unaffected.Se estudió la influencia de la presencia de productos obtenidos en la reacción de dos lípidos oxidados (4,5(E)-epoxy-2(E)- heptenal, EH, y 4,5(E)-epoxy-2(E)-decenal, ED) con el aminoácido lisina (EH-L y ED-L), sobre la absorción de zinc y calcio, comparándolos frente a una mezcla de fructosil-lisina (F-L). Los ensayos se realizaron con células Caco-2 sembradas en placas bicamerales. La adición de las muestras EH-L, ED-L y F-L al medio de cultivo supuso una reducción significativa en el Zn transportado a través de la monocapa de células, mucho más marcada ante la presencia de EH-L. También se redujo significativamente la captación celular de Zn, sin diferencias entre las distintas muestras ensayadas. Sin embargo, el transporte de Ca no se vio modificado. Por lo tanto, los productos pardos lípido-aminoacídicos ensayados parecen afectar negativamente la disponibilidad del Zn, sin tener efectos notables sobre la del Ca.Peer reviewe

Differentiation of irradiation and cetuximab induced skin reactions in patients with locally advanced head and neck cancer undergoing radioimmunotherapy: the HICARE protocol (Head and neck cancer: ImmunoChemo and Radiotherapy with Erbitux) – a multicenter phase IV trial

BACKGROUND: In order to improve the clinical outcome of patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical and molecular differentiation between radiogenic skin reactions and skin reactions caused by cetuximab which may correlate with outcome, have never been described before. METHODS/DESIGN: The HICARE study is a national, multicenter, prospective phase IV study exploring the different types of skin reactions that occur in patients with LASCCHN undergoing radioimmun(chemo)therapy with the EGFR inhibitor cetuximab. 500 patients with LASCCHN will be enrolled in 40 participating sites in Germany. Primary endpoint is the rate of radiation dermatitis NCI CTCAE grade 3 and 4 (v. 4.02). Radioimmunotherapy will be applied according to SmPC, i.e. cetuximab will be administered as loading dose and then weekly during the radiotherapy. Irradiation will be applied as intensity-modulated radiation therapy (IMRT) or 3D-dimensional radiation therapy. DISCUSSION: The HICARE trial is expected to be one of the largest trials ever conducted in head and neck cancer patients. The goal of the HICARE trial is to differentiate skin reactions caused by radiation from those caused by the monoclonal antibody cetuximab, to evaluate the incidence and severity of these skin reactions and to correlate them with outcome parameters. Besides, the translational research program will help to identify and confirm novel peripheral blood based molecular predictors and surrogates for treatment response and resistance. TRIAL REGISTRATION: Clinical Trial Identifier, NCT01553032 (clinicaltrials.gov) EudraCT number: 2010-019748-3

Jet formation and jet velocity fluctuations in a flue organ pipe

Flow visualization of the initial transient in a small recorderlike flue organ pipe is presented and the various stages of the jet formation are related to measurements of the acoustic response of the pipe. An initial acoustic signal, due to the unsteady volume flow of the jet, appears before the forming jet reaches the labium. This signal can easily be modeled using a low-frequency approximation. The initial trajectory of the jet makes a curve towards the exterior of the pipe. Under certain conditions, the jet may even, at first, miss the labium. This effect is related to the steepness of the pressure rise in the foot of the pipe. The initial impact of the jet with the labium appears to be a crucial factor in the triggering of the transient. Moving the labium towards the exterior of the pipe, using a steep pressure rise or putting ears around the mouth increase the chance that the jet will hit the labium. This initial impact is followed by an impulsive vortex shedding at the labium and subsequently a high-frequency varicoselike oscillation is observed on the jet. This oscillation is also observed without labium. After about three periods of the fundamental mode of the pipe, turbulence appears therefore destroying these coherent structures. Whereas the time dependency of the jet velocity dominates the first stage of the starting transient, the jet velocity fluctuations during steady-state result in a non-negligible damping. This loss mechanism is, for the fundamental mode of our experimental organ pipe, of the same order of magnitude as the radiation or visco-thermal damping.</p

Spatial organization in cyclic Lotka-Volterra systems

We study the evolution of a system of $N$ interacting species which mimics the dynamics of a cyclic food chain. On a one-dimensional lattice with N<5 species, spatial inhomogeneities develop spontaneously in initially homogeneous systems. The arising spatial patterns form a mosaic of single-species domains with algebraically growing size, $\ell(t)\sim t^\alpha$, where $\alpha=3/4$ (1/2) and 1/3 for N=3 with sequential (parallel) dynamics and N=4, respectively. The domain distribution also exhibits a self-similar spatial structure which is characterized by an additional length scale, ${\cal L}(t)\sim t^\beta$, with $\beta=1$ and 2/3 for N=3 and 4, respectively. For $N\geq 5$, the system quickly reaches a frozen state with non interacting neighboring species. We investigate the time distribution of the number of mutations of a site using scaling arguments as well as an exact solution for N=3. Some possible extensions of the system are analyzed.Comment: 18 pages, 10 figures, revtex, also available from http://arnold.uchicago.edu/~ebn

Connecting Berry's phase and the pumped charge in a Cooper pair pump

The properties of the tunnelling-charging Hamiltonian of a Cooper pair pump are well understood in the regime of weak and intermediate Josephson coupling, i.e. when $E_{\mathrm{J}}\lesssim E_{\mathrm{C}}$. It is also known that Berry's phase is related to the pumped charge induced by the adiabatical variation of the eigenstates. We show explicitly that pumped charge in Cooper pair pump can be understood as a partial derivative of Berry's phase with respect to the phase difference $\phi$ across the array. The phase fluctuations always present in real experiments can also be taken into account, although only approximately. Thus the measurement of the pumped current gives reliable, yet indirect, information on Berry's phase. As closing remarks, we give the differential relation between Berry's phase and the pumped charge, and state that the mathematical results are valid for any observable expressible as a partial derivative of the Hamiltonian.Comment: 5 pages, 5 figures, RevTeX, Presentation has been clarifie