ABCB1 Overexpression Is a key initiator of resistance to tyrosine kinase inhibitors in CML cell lines

The tyrosine kinase inhibitor (TKI) imatinib has resulted in excellent responses in the majority of Chronic Myeloid Leukaemia (CML) patients; however, resistance is observed in 20-30% of patients. More recently, resistance to the second generation TKIs, nilotinib and dasatinib, has also been observed albeit at a lower incidence. ABCB1 has previously been implicated in TKI export and its overexpression linked to TKI resistance. In this study the dynamics of nilotinib resistance was studied in CML cell lines with particular focus on ABCB1 expression levels during development of resistance. Results revealed ABCB1 overexpression is likely an important initiator of nilotinib resistance in vitro. ABCB1 overexpression was also observed in cell lines as an intermediate step during development of resistance to imatinib and dasatinib in vitro. We conclude that ABCB1 overexpression may provide an initial platform to facilitate development of additional mechanisms for resistance to TKIs. This provides a rationale for investigating this phenomenon in patients undergoing TKI therapy.Laura N. Eadie, Timothy P. Hughes, Deborah L. Whit

C5AC_5^A axial form factor from bubble chamber experiments

A careful reanalysis of both Argonne National Laboratory and Brookhaven National Laboratory data for weak single pion production is done. We consider deuteron nuclear effects and normalization (flux) uncertainties in both experiments. We demonstrate that these two sets of data are in good agreement. For the dipole parametrization of $C_5^A(Q^2)$, we obtain $C_5^A(0)=1.19\pm 0.08$, $M_A=0.94\pm 0.03$ GeV. As an application we present the discussion of the uncertainty of the neutral current 1$\pi^0$ production cross section, important for the T2K neutrino oscillation experiment.Comment: 16 pages, 8 figures, 2 table

Could psoralen plus ultraviolet A1 (“PUVA1”) work? Depth penetration achieved by phototherapy lamps

Funding: PhD Studentship UK EPRSC EP/N509759/1.Psoralen and ultraviolet A (PUVA) is useful in treating various hand and foot skin diseases.1 Most cases of psoriasis respond well to phototherapy or PUVA. However, for some diseases, such as palmoplantar pustular psoriasis, PUVA is not always sufficient to produce therapeutic effect. If PUVA fails, it is sometimes necessary to progress to other treatments such as Grenz ray therapy (where available),2 systemic retinoid or systemic immunosuppression. Could “PUVA1” (psoralen combined with ultraviolet A1 long wavelength ultraviolet A [UVA]) work in cases where conventional PUVA (psoralen plus broadband UVA) has been inadequate?PostprintPeer reviewe

ABCC6 plays a significant role in the transport of nilotinib and dasatinib, and contributes to TKI resistance in vitro, in both cell lines and primary patient mononuclear cells

ATP Binding Cassette family efflux proteins ABCB1 and ABCG2 have previously been demonstrated to interact with Tyrosine Kinase Inhibitors (TKIs); however, evidence for the interaction of other potentially relevant drug transporters with TKIs is lacking. Through Taqman transporter array technology we assessed the impact of nilotinib on mRNA expression of ABC transporters, with ABCC6 identified as a transporter of interest. Additionally, increased expression of ABCC6 mRNA was observed during in vitro development of nilotinib resistance in BCR-ABL1-expressing cell lines. K562 cells exposed to gradually increasing concentrations of nilotinib (to 2 μM) expressed up to 57-fold higher levels of ABCC6 mRNA when compared with control cells (p = 0.002). Analogous results were observed in nilotinib resistant K562-Dox cells (up to 33-fold higher levels of ABCC6, p = 0.002). IC50 experiments were conducted on patient mononuclear cells in the absence and presence of three ABCC6 inhibitors: indomethacin, probenecid and pantoprazole. Results demonstrated that all three inhibitors significantly reduced nilotinib IC50 (p<0.001) indicating ABCC6 is likely involved in nilotinib transport. Cell line data confirmed these findings. Similar results were obtained for dasatinib, but not imatinib. Combined, these studies suggest that nilotinib and dasatinib are likely substrates of ABCC6 and to our knowledge, this is the first report of ABCC6 involvement in TKI transport. In addition, ABCC6 overexpression may also contribute to nilotinib and dasatinib resistance in vitro. With nilotinib and dasatinib now front line therapy options in the treatment of CML, concomitant administration of ABCC6 inhibitors may present an attractive option to enhance TKI efficacy.Laura N. Eadie, Phuong Dang, Jarrad M. Goyne, Timothy P. Hughes, Deborah L. Whit

Fitting Parton Distribution Data with Multiplicative Normalization Uncertainties

We consider the generic problem of performing a global fit to many independent data sets each with a different overall multiplicative normalization uncertainty. We show that the methods in common use to treat multiplicative uncertainties lead to systematic biases. We develop a method which is unbiased, based on a self--consistent iterative procedure. We demonstrate the use of this method by applying it to the determination of parton distribution functions with the NNPDF methodology, which uses a Monte Carlo method for uncertainty estimation.Comment: 33 pages, 5 figures: published versio

Direct CP violation for Bˉs0→K0π+π−\bar{B}_{s}^{0}\to K^{0}\pi^{+}\pi^{-} decay in QCD factorization

In the framework of QCD factorization, based on the first order of isospin violation, we study direct CP violation in the decay of $\bar{B}_{s}^{0} \to K^{0}\rho^{0}(\omega)\to K^{0}\pi^{+}\pi^{-}$ including the effect of $\rho-\omega$ mixing. We find that the CP violating asymmetry is large via $\rho-\omega$ mixing mechanism when the invariant mass of the $\pi^{+}\pi^{-}$ pair is in the vicinity of the $\omega$ resonance. For the decay of $\bar{B}_{s}^{0} \to K^{0}\rho^{0}(\omega)\to K^{0}\pi^{+}\pi^{-}$, the maximum CP violating asymmetries can reach about 46%. We also discuss the possibility to observe the predicted CP violating asymmetries at the LHC

Geo-neutrinos: A systematic approach to uncertainties and correlations

Geo-neutrinos emitted by heat-producing elements (U, Th and K) represent a unique probe of the Earth interior. The characterization of their fluxes is subject, however, to rather large and highly correlated uncertainties. The geochemical covariance of the U, Th and K abundances in various Earth reservoirs induces positive correlations among the associated geo-neutrino fluxes, and between these and the radiogenic heat. Mass-balance constraints in the Bulk Silicate Earth (BSE) tend instead to anti-correlate the radiogenic element abundances in complementary reservoirs. Experimental geo-neutrino observables may be further (anti)correlated by instrumental effects. In this context, we propose a systematic approach to covariance matrices, based on the fact that all the relevant geo-neutrino observables and constraints can be expressed as linear functions of the U, Th and K abundances in the Earth's reservoirs (with relatively well-known coefficients). We briefly discuss here the construction of a tentative "geo-neutrino source model" (GNSM) for the U, Th, and K abundances in the main Earth reservoirs, based on selected geophysical and geochemical data and models (when available), on plausible hypotheses (when possible), and admittedly on arbitrary assumptions (when unavoidable). We use then the GNSM to make predictions about several experiments ("forward approach"), and to show how future data can constrain - a posteriori - the error matrix of the model itself ("backward approach"). The method may provide a useful statistical framework for evaluating the impact and the global consistency of prospective geo-neutrino measurements and Earth models.Comment: 17 pages, including 4 figures. To appear on "Earth, Moon, and Planets," Special Issue on "Neutrino Geophysics," Proceedings of Neutrino Science 2005 (Honolulu, Hawaii, Dec. 2005

Neutrino Oscillations and the Supernova 1987A Signal

We study the impact of neutrino oscillations on the interpretation of the supernova (SN) 1987A neutrino signal by means of a maximum-likelihood analysis. We focus on oscillations between $\overline\nu_e$ with $\overline\nu_\mu$ or $\overline\nu_\tau$ with those mixing parameters that would solve the solar neutrino problem. For the small-angle MSW solution ($\Delta m^2\approx10^{-5}\,\rm eV^2$, $\sin^22\Theta_0\approx0.007$), there are no significant oscillation effects on the Kelvin-Helmholtz cooling signal; we confirm previous best-fit values for the neutron-star binding energy and average spectral $\overline\nu_e$ temperature. There is only marginal overlap between the upper end of the 95.4\% CL inferred range of $\langle E_{\overline\nu_e}\rangle$ and the lower end of the range of theoretical predictions. Any admixture of the stiffer $\overline\nu_\mu$ spectrum by oscillations aggravates the conflict between experimentally inferred and theoretically predicted spectral properties. For mixing parameters in the neighborhood of the large-angle MSW solution ($\Delta m^2\approx10^{-5}\,\rm eV^2$, $\sin^22\Theta_0\approx0.7$) the oscillations in the SN are adiabatic, but one needs to include the regeneration effect in the Earth which causes the Kamiokande and IMB detectors to observe different $\overline\nu_e$ spectra. For the solar vacuum solution ($\Delta m^2\approx10^{-10}\,\rm eV^2$, $\sin^22\Theta_0\approx1$) the oscillations in the SN are nonadiabatic; vacuum oscillations take place between the SN and the detector. If either of the large-angle solutions were borne out by the upcoming round of solar neutrino experiments, one would have to conclude that the SN~1987A $\overline\nu_\mu$ and/or $\overline\nu_e$ spectra had been much softer than predicted by currentComment: Final version with very minor wording changes, to be published in Phys. Rev.

A combined analysis of short-baseline neutrino experiments in the (3+1) and (3+2) sterile neutrino oscillation hypotheses

We investigate adding two sterile neutrinos to resolve the apparent tension existing between short-baseline neutrino oscillation results and CPT-conserving, four-neutrino oscillation models. For both (3+1) and (3+2) models, the level of statistical compatibility between the combined dataset from the null short-baseline experiments Bugey, CHOOZ, CCFR84, CDHS, KARMEN, and NOMAD, on the one hand; and the LSND dataset, on the other, is computed. A combined analysis of all seven short-baseline experiments, including LSND, is also performed, to obtain the favored regions in neutrino mass and mixing parameter space for both models. Finally, four statistical tests to compare the (3+1) and the (3+2) hypotheses are discussed. All tests show that (3+2) models fit the existing short-baseline data significantly better than (3+1) models.Comment: 16 pages, 15 figures. Added NOMAD data to the analysis, one statistical test, and two figures. References and text added. Version submitted to PR

Search for very high energy gamma-rays from WIMP annihilations near the Sun with the Milagro Detector

The neutralino, the lightest stable supersymmetric particle, is a strong theoretical candidate for the missing astronomical ``dark matter''. A profusion of such neutralinos can accumulate near the Sun when they lose energy upon scattering and are gravitationally captured. Pair-annihilations of those neutralinos may produce very high energy (VHE, above $100 GeV$) gamma-rays. Milagro is an air shower array which uses the water Cherenkov technique to detect extensive air showers and is capable of observing VHE gamma-rays from the direction of the Sun with an angular resolution of $0.75^{\circ}$. Analysis of Milagro data with an exposure to the Sun of 1165 hours presents the first attempt to detect TeV gamma-rays produced by annihilating neutralinos captured by the Solar system and shows no statistically significant signal. Resulting limits that can be set on gamma-ray flux due to near-Solar neutralino annihilations and on neutralino cross-section are presented