Photodynamic therapy of cutaneous T-cell lymphoma cell lines mediated by 5-aminolevulinic acid and derivatives

The delta-amino acid 5-aminolevulinic acid (ALA), is the precursor of the endogenous photosensitiser Protoporphyrin IX (PpIX), and is currently approved for Photodynamic Therapy (PDT) of certain superficial cancers. However, ALA-PDT is not very effective in diseases in which T-cells play a significant role. Cutaneous T-cell lymphomas (CTCL) is a group of non-Hodgkin malignant diseases, which includes mycosis fungoides (MF) and Sézary syndrome (SS). In previous work, we have designed new ALA esters synthesised by three-component Passerini reactions, and some of them showed higher performance as compared to ALA. This work aimed to determine the efficacy as pro-photosensitisers of five new ALA esters of 2-hydroxy-N-arylacetamides (1f, 1 g, 1 h, 1i and 1 k) of higher lipophilicity than ALA in Myla cells of MF and HuT-78 cells of SS. We have also tested its effectiveness against ALA and the already marketed ALA methyl ester (Me-ALA) and ALA hexyl ester (He-ALA). Both cell Myla and SS cells were effectively and equally photoinactivated by ALA-PDT. Besides, the concentration of ALA required to induce half the maximal porphyrin synthesis was 209 μM for Myla and 169 μM for HuT-78 cells. As a criterion of efficacy, we calculated the concentration of the ALA derivatives necessary to induce half the plateau porphyrin values obtained from ALA. These values were achieved at concentrations 4 and 12 times lower compared to ALA, according to the derivative used. For He-ALA, concentrations were 24 to 25 times lower than required for ALA for inducing comparable porphyrin synthesis in both CTCL cells. The light doses for inducing 50% of cell death (LD50) for He-ALA, 1f, 1 g, 1 h and 1i were around 18 and 25 J/cm2 for Myla and HuT-78 cells respectively, after exposure to 0.05 mM concentrations of the compounds. On the other hand, the LD50s for the compound 1 k were 40 and 57 J/cm2 for Myla and HuT-78, respectively. In contrast, 0.05 mM of ALA and Me-ALA did not provoke photokilling since the concentration employed was far below the porphyrin saturation point for these compounds. Our results suggest the potential use of ALA derivatives for topical application in PDT treatment of MF and extracorporeal PDT for the depletion of activated T-cells in SS

A model for examining teacher preparation curricula for inclusion.

There is an increasing need for highly qualified teachers as described by the current legislation in No Child Left Behind (2002). Since this legislative mandate has been enforced, recent initiatives have signaled teacher education programs to examine performance standards in demonstrating preparation of effective teachers for diverse learners. The total number of children with disabilities served over the past eight years has increased at an average of 3.4% each year (Katsiyannis, Zhang, & Conroy, 2003; U.S. Department of Education, 2003). With over 6,000,000 children receiving services across the country, the increased need for well-prepared teachers is critical. Data on increasing teacher shortages in special education (U.S. Department of Education, 2003; Veneri, 1999), as well as a number of studies have amplified various aspects of this dilemma, including causes and possible remedies (Billingsley, 2004; Boe, Cook, Bobbitt, & Terhanian, 1998; Brownell, Bishop, & Sindelar, 2005; Counterpoint, 1999; Menlove, Games, & Galzberg, 2004)

GeantV: Results from the prototype of concurrent vector particle transport simulation in HEP

Full detector simulation was among the largest CPU consumer in all CERN experiment software stacks for the first two runs of the Large Hadron Collider (LHC). In the early 2010's, the projections were that simulation demands would scale linearly with luminosity increase, compensated only partially by an increase of computing resources. The extension of fast simulation approaches to more use cases, covering a larger fraction of the simulation budget, is only part of the solution due to intrinsic precision limitations. The remainder corresponds to speeding-up the simulation software by several factors, which is out of reach using simple optimizations on the current code base. In this context, the GeantV R&D project was launched, aiming to redesign the legacy particle transport codes in order to make them benefit from fine-grained parallelism features such as vectorization, but also from increased code and data locality. This paper presents extensively the results and achievements of this R&D, as well as the conclusions and lessons learnt from the beta prototype.Comment: 34 pages, 26 figures, 24 table

The use of dipeptide derivatives of 5-aminolaevulinic acid promotes their entry to tumor cells and improves tumor selectivity of photodynamic therapy

The use of endogenous protoporphyrin IX generated after administration of 5-aminolaevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). However, the bioavailability of ALA is limited by its hydrophilic properties and limited cell uptake. A promising approach to optimize the efficacy of ALA-PDT is to deliver ALA in the form of prodrugs to mask its hydrophilic nature. The aim of this work was to evaluate the potential of two ALA dipeptide derivatives, N-acetyl terminated leucinyl-ALA methyl ester (Ac-Leu-ALA-Me) and phenylalanyl-ALA methyl ester (Ac-Phe-ALA-Me), for their use in PDT of cancer, by investigating the generation of protoporphyrin IX in an oncogenic cell line (PAM212-Ras), and in a subcutaneous tumor model. In our in vitro studies, both derivatives were more effective than ALA in PDT treatment, at inducing the same protoporphyrin IX levels but at 50- to 100-fold lower concentrations, with the phenylalanyl derivative being the most effective. The efficient release of ALA from Ac-Phe-ALA-Me appears to be consistent with the reported substrate and inhibitor preferences of acylpeptide hydrolase. In vivo studies revealed that topical application of the peptide prodrug Ac-Phe-ALA-Me gave greater selectivity than with ALA itself, and induced tumor photodamage, whereas systemic administration improved ALA-induced porphyrin generation in terms of equivalent doses administered, without induction of toxic effects. Our data support the possibility of using particularly Ac-Phe-ALA-Me both for topical treatment of basal cell carcinomas and for systemic administration. Further chemical fine-tuning of this prodrug template should yield additional compounds for enhanced ALA-PDT with potential for translation to the clinic

Search for non-relativistic Magnetic Monopoles with IceCube

The IceCube Neutrino Observatory is a large Cherenkov detector instrumenting $1\,\mathrm{km}^3$ of Antarctic ice. The detector can be used to search for signatures of particle physics beyond the Standard Model. Here, we describe the search for non-relativistic, magnetic monopoles as remnants of the GUT (Grand Unified Theory) era shortly after the Big Bang. These monopoles may catalyze the decay of nucleons via the Rubakov-Callan effect with a cross section suggested to be in the range of $10^{-27}\,\mathrm{cm^2}$ to $10^{-21}\,\mathrm{cm^2}$. In IceCube, the Cherenkov light from nucleon decays along the monopole trajectory would produce a characteristic hit pattern. This paper presents the results of an analysis of first data taken from May 2011 until May 2012 with a dedicated slow-particle trigger for DeepCore, a subdetector of IceCube. A second analysis provides better sensitivity for the brightest non-relativistic monopoles using data taken from May 2009 until May 2010. In both analyses no monopole signal was observed. For catalysis cross sections of $10^{-22}\,(10^{-24})\,\mathrm{cm^2}$ the flux of non-relativistic GUT monopoles is constrained up to a level of $\Phi_{90} \le 10^{-18}\,(10^{-17})\,\mathrm{cm^{-2}s^{-1}sr^{-1}}$ at a 90% confidence level, which is three orders of magnitude below the Parker bound. The limits assume a dominant decay of the proton into a positron and a neutral pion. These results improve the current best experimental limits by one to two orders of magnitude, for a wide range of assumed speeds and catalysis cross sections.Comment: 20 pages, 20 figure

A combined maximum-likelihood analysis of the high-energy astrophysical neutrino flux measured with IceCube

Evidence for an extraterrestrial flux of high-energy neutrinos has now been found in multiple searches with the IceCube detector. The first solid evidence was provided by a search for neutrino events with deposited energies $\gtrsim30$ TeV and interaction vertices inside the instrumented volume. Recent analyses suggest that the extraterrestrial flux extends to lower energies and is also visible with throughgoing, $\nu_\mu$-induced tracks from the Northern hemisphere. Here, we combine the results from six different IceCube searches for astrophysical neutrinos in a maximum-likelihood analysis. The combined event sample features high-statistics samples of shower-like and track-like events. The data are fit in up to three observables: energy, zenith angle and event topology. Assuming the astrophysical neutrino flux to be isotropic and to consist of equal flavors at Earth, the all-flavor spectrum with neutrino energies between 25 TeV and 2.8 PeV is well described by an unbroken power law with best-fit spectral index $-2.50\pm0.09$ and a flux at 100 TeV of $\left(6.7_{-1.2}^{+1.1}\right)\cdot10^{-18}\,\mathrm{GeV}^{-1}\mathrm{s}^{-1}\mathrm{sr}^{-1}\mathrm{cm}^{-2}$. Under the same assumptions, an unbroken power law with index $-2$ is disfavored with a significance of 3.8 $\sigma$ ($p=0.0066\%$) with respect to the best fit. This significance is reduced to 2.1 $\sigma$ ($p=1.7\%$) if instead we compare the best fit to a spectrum with index $-2$ that has an exponential cut-off at high energies. Allowing the electron neutrino flux to deviate from the other two flavors, we find a $\nu_e$ fraction of $0.18\pm0.11$ at Earth. The sole production of electron neutrinos, which would be characteristic of neutron-decay dominated sources, is rejected with a significance of 3.6 $\sigma$ ($p=0.014\%$).Comment: 16 pages, 10 figures; accepted for publication in The Astrophysical Journal; updated one referenc

The IceCube Neutrino Observatory - Contributions to ICRC 2015 Part II: Atmospheric and Astrophysical Diffuse Neutrino Searches of All Flavors

Papers on atmospheric and astrophysical diffuse neutrino searches of all flavors submitted to the 34th International Cosmic Ray Conference (ICRC 2015, The Hague) by the IceCube Collaboration.Comment: 66 pages, 36 figures, Papers submitted to the 34th International Cosmic Ray Conference, The Hague 2015, v2 has a corrected author lis

Improved limits on dark matter annihilation in the Sun with the 79-string IceCube detector and implications for supersymmetry

We present an improved event-level likelihood formalism for including neutrino telescope data in global fits to new physics. We derive limits on spin-dependent dark matter-proton scattering by employing the new formalism in a re-analysis of data from the 79-string IceCube search for dark matter annihilation in the Sun, including explicit energy information for each event. The new analysis excludes a number of models in the weak-scale minimal supersymmetric standard model (MSSM) for the first time. This work is accompanied by the public release of the 79-string IceCube data, as well as an associated computer code for applying the new likelihood to arbitrary dark matter models.Comment: 24 pages, 8 figs, 1 table. Contact authors: Pat Scott & Matthias Danninger. Likelihood tool available at http://nulike.hepforge.org. v2: small updates to address JCAP referee repor

Determining neutrino oscillation parameters from atmospheric muon neutrino disappearance with three years of IceCube DeepCore data

We present a measurement of neutrino oscillations via atmospheric muon neutrino disappearance with three years of data of the completed IceCube neutrino detector. DeepCore, a region of denser instrumentation, enables the detection and reconstruction of atmospheric muon neutrinos between 10 GeV and 100 GeV, where a strong disappearance signal is expected. The detector volume surrounding DeepCore is used as a veto region to suppress the atmospheric muon background. Neutrino events are selected where the detected Cherenkov photons of the secondary particles minimally scatter, and the neutrino energy and arrival direction are reconstructed. Both variables are used to obtain the neutrino oscillation parameters from the data, with the best fit given by $\Delta m^2_{32}=2.72^{+0.19}_{-0.20}\times 10^{-3}\,\mathrm{eV}^2$ and $\sin^2\theta_{23} = 0.53^{+0.09}_{-0.12}$ (normal mass hierarchy assumed). The results are compatible and comparable in precision to those of dedicated oscillation experiments.Comment: 10 pages, 7 figure