Low doses of cisplatin or gemcitabine plus Photofrin/photodynamic therapy: Disjointed cell cycle phase-related activity accounts for synergistic outcome in metastatic non-small cell lung cancer cells (H1299).

We compared the effects of monotherapy (photodynamic therapy or chemotherapy) versus combination therapy (photodynamic therapy plus a specific drug) on the non-small cell lung cancer cell line H1299. Our aim was to evaluate whether the additive/synergistic effects of combination treatment were such that the cytostatic dose could be reduced without affecting treatment efficacy. Photodynamic therapy was done by irradiating Photofrin-preloaded H1299 p53/p16-null cells with a halogen lamp equipped with a bandpass filter. The cytotoxic drugs used were cis-diammine-dichloroplatinum [II] (CDDP or cisplatin) and 2',2'-difluoro-2'-deoxycytidine (gemcitabine). Various treatment combinations yielded therapeutic effects (trypan blue dye exclusion test) ranging from additive to clearly synergistic, the most effective being a combination of photodynamic therapy and CDDP. To gain insight into the cellular response mechanisms underlying favorable outcomes, we analyzed the H1299 cell cycle profiles and the expression patterns of several key proteins after monotherapy. In our conditions, we found that photodynamic therapy with Photofrin targeted G0-G1 cells, thereby causing cells to accumulate in S phase. In contrast, low-dose CDDP killed cells in S phase, thereby causing an accumulation of G0-G1 cells (and increased p21 expression). Like photodynamic therapy, low-dose gemcitabine targeted G0-G1 cells, which caused a massive accumulation of cells in S phase (and increased cyclin A expression). Although we observed therapeutic reinforcement with both drugs and photodynamic therapy, reinforcement was more pronounced when the drug (CDDP) and photodynamic therapy exert disjointed phase-related cytotoxic activity. Thus, if photodynamic therapy is appropriately tuned, the dose of the cytostatic drug can be reduced without compromising the therapeutic response

Comparing small area techniques for estimating poverty measures: the case study of Austria and Spain

The Europe 2020 Strategy has formulated key policy objectives or so-called "headline targets" which the European Union as a whole and Member States are individually committed to achieving by 2020. One of the five headline targets is directly related to the key quality aspects of life, namely social inclusion; within these targets, the European Union Statistics on Income and Living Condition (EU-SILC) headline indicators atriskof-poverty or social exclusion and its components will be included in the budgeting of structural funds, one of the main instruments through which policy targets are attained. For this purpose, Directorate-General Regional Policy of the European Commission is aiming to use sub-national/regional level data (NUTS 2). Starting from this, the focus of the present paper is on the "regional dimension" of well-being. We propose to adopt a methodology based on the Empirical Best Linear Unbiased Predictor (EBLUP) with an extension to the spatial dimension (SEBLUP); moreover, we compare this small area technique with the cumulation method. The application is conducted on the basis of EU-SILC data from Austria and Spain. Results report that, in general, estimates computed with the cumulation method show standard errors which are smaller than those computed with EBLUP or SEBLUP. The gain of pooling SILC data over three years is, therefore, relevant, and may allow researchers to prefer this method

Cophylogeny reconstruction via an approximate bayesian computation

Despite an increasingly vast literature on cophylogenetic reconstructions for studying host-parasite associations, understanding the common evolutionary history of such systems remains a problem that is far from being solved. Most algorithms for host-parasite reconciliation use an event-based model, where the events include in general (a subset of) cospeciation, duplication, loss, and host switch. All known parsimonious event-based methods then assign a cost to each type of event in order to find a reconstruction of minimum cost. The main problem with this approach is that the cost of the events strongly influences the reconciliation obtained. Some earlier approaches attempt to avoid this problem by finding a Pareto set of solutions and hence by considering event costs under some minimization constraints. To deal with this problem, we developed an algorithm, called Coala, for estimating the frequency of the events based on an approximate Bayesian computation approach. The benefits of this method are 2-fold: (i) it provides more confidence in the set of costs to be used in a reconciliation, and (ii) it allows estimation of the frequency of the events in cases where the data set consists of trees with a large number of taxa. We evaluate our method on simulated and on biological data sets. We show that in both cases, for the same pair of host and parasite trees, different sets of frequencies for the events lead to equally probable solutions. Moreover, often these solutions differ greatly in terms of the number of inferred events. It appears crucial to take this into account before attempting any further biological interpretation of such reconciliations. More generally, we also show that the set of frequencies can vary widely depending on the input host and parasite trees. Indiscriminately applying a standard vector of costs may thus not be a good strategy

On the construction of model Hamiltonians for adiabatic quantum computation and its application to finding low energy conformations of lattice protein models

In this report, we explore the use of a quantum optimization algorithm for obtaining low energy conformations of protein models. We discuss mappings between protein models and optimization variables, which are in turn mapped to a system of coupled quantum bits. General strategies are given for constructing Hamiltonians to be used to solve optimization problems of physical/chemical/biological interest via quantum computation by adiabatic evolution. As an example, we implement the Hamiltonian corresponding to the Hydrophobic-Polar (HP) model for protein folding. Furthermore, we present an approach to reduce the resulting Hamiltonian to two-body terms gearing towards an experimental realization.Comment: 35 pages, 8 figure

Wt-p53 action in human leukaemia cell lines corresponding to different stages of differentiation.

Recent studies support the potential application of the wt-p53 gene in cancer therapy. Expression of exogenous wt-p53 suppresses a variety of leukaemia phenotypes by acting on cell survival, proliferation and/or differentiation. As for tumour gene therapy, the final fate of the neoplastic cells is one of the most relevant points. We examined the effects of exogenous wt-p53 gene expression in several leukaemia cell lines to identify p53-responsive leukaemia. The temperature-sensitive p53Val135 mutant or the human wt-p53 cDNA was transduced in leukaemia cell lines representative of different acute leukaemia FAB subtypes, including M1 (KG1), M2 (HL-60), M3 (NB4), M5 (U937) and M6 (HEL 92.1.7), as well as blast crisis of chronic myelogenous leukaemia (BC-CML: K562, BV173) showing diverse differentiation features. By morphological, molecular and biochemical analyses, we have shown that exogenous wt-p53 gene expression induces apoptosis only in cells corresponding to M1, M2 and M3 of the FAB classification and in BC-CML showing morphological and cytochemical features of undifferentiated blast cells. In contrast, it promotes differentiation in the others. Interestingly, cell responsiveness was independent of the vector used and the status of the endogenous p53 gene

Thermo-hydraulic modeling of the ITER radial neutron camera

The ITER Radial Neutron Camera (RNC) is a diagnostic system designed as a multichannel detection system to measure the uncollided neutron flux from the plasma, generated in the tokamak vacuum vessel, providing information on neutron emissivity profile. The RNC consists of array of cylindrical collimators located in two diagnostic structures: the ex-port system and the in-port system. The in-port system, contains the diamond detectors which need a temperature protection. Feasibility study of the efficiency of the cooling system for the In-port Detector Modules of the RNC during baking process was the main goal of thermo-hydraulic numerical modeling. The paper presents the concept of the cooling system layout and the original way of integration of numerical thermo-hydraulic analyses of the in-port detector cassette. Due to the large extent of the detector cassette it is impossible to include all relevant thermal and hydraulic effects in one global model with sufficient level of details. Thus the modelling strategy is based on the concept of three stage modelling from details to global model. The presented paper includes results of numerical calculations made with ANSYS Fluent software in order to provide the final answer, including calculation of heat loads in the detector cassette from adjacent walls during baking and normal operation conditions

European divertor target concepts for DEMO: Design rationales and high heat flux performance

The divertor target plates are the most thermally loaded in-vessel components in a fusion reactor where high heat fluxes are produced on the plasma-facing components (PFCs) by intense plasma bombardment, radiation and nuclear heating. For reliable exhaust of huge thermal power, robust and durable divertor target PFCs with a sufficiently large heat removal capability and lifetime has to be developed. Since 2014 in the framework of the preconceptual design activities of the EUROfusion DEMO project, integrated R&D efforts have been made in the subproject ‘Target development’ of the work package ‘Divertor’ to develop divertor target PFCs for DEMO. Recently, the first R&D phase was concluded where six (partly novel) target PFC concepts were developed and evaluated by means of non-destructive inspections and high-heat-flux fatigue testing. In this paper, the major achievements of the first phase activities in this subproject are presented focusing on the design rationales of the target PFC concepts, technology options employed for small-scale mock-up fabrication and the results of the first round high-heat-flux qualification test campaign. It is reported that the mock-ups of three PFC concepts survived up to 500 loading cycles at 20 MW/m² (with hot water cooling at 130 °C) without any discernable indication of degradation in performance or structural integrity

Nuclear Analyses for the Assessment of the Loads on the ITER Radial Neutron Camera In-Port System and Evaluation of Its Measurement Performances

The radial neutron camera (RNC) is a key ITER diagnostic system designed to measure the uncollided 14- and 2.5-MeV neutrons from deuterium-tritium (DT) and deuterium-deuterium (DD) fusion reactions, through an array of detectors covering a full poloidal plasma section along collimated lines of sight (LoS). Its main objective is the assessment of the neutron emissivity/alpha source profile and the total neutron source strength, providing spatially resolved measurements of several parameters needed for fusion power estimation, plasma control, and plasma physics studies. The present RNC layout is composed of two fan-shaped collimating structures viewing the plasma radially through vertical slots in the diagnostic shielding module (DSM) of ITER Equatorial Port 1 (EP01): the ex-port subsystem and the in-port one. The ex-port subsystem, devoted to the plasma core coverage, extends from the Port Interspace to the Bioshield Plug: it consists of a massive shielding unit hosting two sets of collimators lying on different toroidal planes, leading to a total of 16 interleaved LoS. The in-port system consists of a cassette, integrated inside the port plug DSM, containing two detectors per each of the six LoS looking at the plasma edges. The in-port system must guarantee the required measurement performances in critical operating conditions in terms of high radiation levels, given its proximity to the plasma neutron source. This article presents an updated neutronic analysis based on the latest design of the in-port system and port plug. It has been performed by means of the Monte Carlo MCNP code and provides nuclear loads on the in-port RNC during normal operating conditions (NOC) and inputs for the measurement performance analysis