725 research outputs found
Differential chemosensitivity to antifolate drugs between RAS and BRAF melanoma cells.
BACKGROUND:
The importance of the genetic background of cancer cells for the individual susceptibility to cancer treatments is increasingly apparent. In melanoma, the existence of a BRAF mutation is a main predictor for successful BRAF-targeted therapy. However, despite initial successes with these therapies, patients relapse within a year and have to move on to other therapies. Moreover, patients harbouring a wild type BRAF gene (including 25% with NRAS mutations) still require alternative treatment such as chemotherapy. Multiple genetic parameters have been associated with response to chemotherapy, but despite their high frequency in melanoma nothing is known about the impact of BRAF or NRAS mutations on the response to chemotherapeutic agents.
METHODS:
Using cell proliferation and DNA methylation assays, FACS analysis and quantitative-RT-PCR we have characterised the response of a panel of NRAS and BRAF mutant melanoma cell lines to various chemotherapy drugs, amongst them dacarbazine (DTIC) and temozolomide (TMZ) and DNA synthesis inhibitors.
RESULTS:
Although both, DTIC and TMZ act as alkylating agents through the same intermediate, NRAS and BRAF mutant cells responded differentially only to DTIC. Further analysis revealed that the growth-inhibitory effects mediated by DTIC were rather due to interference with nucleotide salvaging, and that NRAS mutant melanoma cells exhibit higher activity of the nucleotide synthesis enzymes IMPDH and TK1. Importantly, the enhanced ability of RAS mutant cells to use nucleotide salvaging resulted in resistance to DHFR inhibitors.
CONCLUSION:
In summary, our data suggest that the genetic background in melanoma cells influences the response to inhibitors blocking de novo DNA synthesis, and that defining the RAS mutation status could be used to stratify patients for the use of antifolate drugs
Screening attendance, age group and diabetic retinopathy level at first screen
AIMS:
To report on the relationships between age at diagnosis of diabetes, time from registration with the screening programme to first diabetic eye screening and severity of diabetic retinopathy.
METHODS:
Data were extracted from four English screening programmes and from the Scottish, Welsh and Northern Irish programmes. Time from diagnosis of diabetes to first screening and age at diagnosis were calculated.
RESULTS:
Time from registration with the screening programme to first screening episode is strongly related to age at registration. Within 18 months of registration 89% of 3958 young people under 18 years of age and 81% of 391 293 people over 35 years of age were seen. In 19 058 people between 18 and 34 years of age, 80% coverage was not reached until 2 years and 9 months. The time from diagnosis of diabetes to first screening is positively associated with severity of disease (P < 0.0001).
CONCLUSIONS:
This report is the first that to demonstrate that those in the 18-34 year age group are least likely to attend promptly for screening after registration with a higher risk of referable diabetic retinopathy being present at the time of first screen. Date of diagnosis should be recorded and prodigious efforts made to screen all people promptly after diagnosis. Screening programmes should collect data on those who have not attended within one year of registration
Observation of a Narrow Resonance of Mass 2.46 GeV/c^2 Decaying to D_s^*+ pi^0 and Confirmation of the D_sJ^* (2317) State
Using 13.5 inverse fb of e+e- annihilation data collected with the CLEO II
detector we have observed a narrow resonance in the Ds*+pi0 final state, with a
mass near 2.46 GeV. The search for such a state was motivated by the recent
discovery by the BaBar Collaboration of a narrow state at 2.32 GeV, the
DsJ*(2317)+ that decays to Ds+pi0. Reconstructing the Ds+pi0 and Ds*+pi0 final
states in CLEO data, we observe peaks in both of the corresponding
reconstructed mass difference distributions, dM(Dspi0)=M(Dspi0)-M(Ds) and
dM(Ds*pi0)=M(Ds*pi0)-M(Ds*), both of them at values near 350 MeV. We interpret
these peaks as signatures of two distinct states, the DsJ*(2317)+ plus a new
state, designated as the DsJ(2463)+. Because of the similar dM values, each of
these states represents a source of background for the other if photons are
lost, ignored or added. A quantitative accounting of these reflections confirms
that both states exist. We have measured the mean mass differences
= 350.0 +/- 1.2 [stat] +/- 1.0 [syst] MeV for the DsJ*(2317) state, and
= 351.2 +/- 1.7 [stat] +/- 1.0 [syst] MeV for the new DsJ(2463)+
state. We have also searched, but find no evidence, for decays of the two
states via the channels Ds*+gamma, Ds+gamma, and Ds+pi+pi-. The observations of
the two states at 2.32 and 2.46 GeV, in the Ds+pi0 and Ds*+pi0 decay channels
respectively, are consistent with their interpretations as (c anti-strange)
mesons with orbital angular momentum L=1, and spin-parities of 0+ and 1+.Comment: 16 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLNS, version to be published in Physical
Review D; minor modifications and fixes to typographical errors, plus an
added section on production properties. The main results are unchanged; they
supersede those reported in hep-ex/030501
Measurement of the Charge Asymmetry in
We report on a search for a CP-violating asymmetry in the charmless hadronic
decay B -> K*(892)+- pi-+, using 9.12 fb^-1 of integrated luminosity produced
at \sqrt{s}=10.58 GeV and collected with the CLEO detector. We find A_{CP}(B ->
K*(892)+- pi-+) = 0.26+0.33-0.34(stat.)+0.10-0.08(syst.), giving an allowed
interval of [-0.31,0.78] at the 90% confidence level.Comment: 7 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLNS, submitted to PR
Study of the q^2-Dependence of B --> pi ell nu and B --> rho(omega)ell nu Decay and Extraction of |V_ub|
We report on determinations of |Vub| resulting from studies of the branching
fraction and q^2 distributions in exclusive semileptonic B decays that proceed
via the b->u transition. Our data set consists of the 9.7x10^6 BBbar meson
pairs collected at the Y(4S) resonance with the CLEO II detector. We measure
B(B0 -> pi- l+ nu) = (1.33 +- 0.18 +- 0.11 +- 0.01 +- 0.07)x10^{-4} and B(B0 ->
rho- l+ nu) = (2.17 +- 0.34 +0.47/-0.54 +- 0.41 +- 0.01)x10^{-4}, where the
errors are statistical, experimental systematic, systematic due to residual
form-factor uncertainties in the signal, and systematic due to residual
form-factor uncertainties in the cross-feed modes, respectively. We also find
B(B+ -> eta l+ nu) = (0.84 +- 0.31 +- 0.16 +- 0.09)x10^{-4}, consistent with
what is expected from the B -> pi l nu mode and quark model symmetries. We
extract |Vub| using Light-Cone Sum Rules (LCSR) for 0<= q^2<16 GeV^2 and
Lattice QCD (LQCD) for 16 GeV^2 <= q^2 < q^2_max. Combining both intervals
yields |Vub| = (3.24 +- 0.22 +- 0.13 +0.55/-0.39 +- 0.09)x10^{-3}$ for pi l nu,
and |Vub| = (3.00 +- 0.21 +0.29/-0.35 +0.49/-0.38 +-0.28)x10^{-3} for rho l nu,
where the errors are statistical, experimental systematic, theoretical, and
signal form-factor shape, respectively. Our combined value from both decay
modes is |Vub| = (3.17 +- 0.17 +0.16/-0.17 +0.53/-0.39 +-0.03)x10^{-3}.Comment: 45 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLNS, submitted to PR
Search for CP Violation in D^0--> K_S^0 pi^+pi^-
We report on a search for CP violation in the decay of D0 and D0B to Kshort
pi+pi-. The data come from an integrated luminosity of 9.0 1/fb of e+e-
collisions at sqrt(s) ~ 10 GeV recorded with the CLEO II.V detector. The
resonance substructure of this decay is well described by ten quasi-two-body
decay channels (K*-pi+, K*0(1430)-pi+, K*2(1430)-pi+, K*(1680)-pi+, Kshort rho,
Kshort omega, Kshort f0(980), Kshort f2(1270), Kshort f0(1370), and the ``wrong
sign'' K*+ pi-) plus a small non-resonant component. We observe no evidence for
CP violation in the amplitudes and phases that describe the decay D0 to K_S^0
pi+pi-.Comment: 10 pages, 3 figures, also available at
http://w4.lns.cornell.edu/public/CLNS/, submitted to PR
Measurement of Lepton Momentum Moments in the Decay bar{B} \to X \ell \bar{\nu} and Determination of Heavy Quark Expansion Parameters and |V_cb|
We measure the primary lepton momentum spectrum in B-bar to X l nu decays,
for p_l > 1.5 GeV/c in the B rest frame. From this, we calculate various
moments of the spectrum. In particular, we find R_0 = [int(E_l>1.7)
(dGam/dE_sl)*dE_l] / [int(E_l>1.5) (dGam/dE_sl)*dE_l] = 0.6187 +/- 0.0014_stat
+/- 0.0016_sys and R_1 = [int(E_l>1.5) E_l(dGam/dE_sl)*dE_l] / [int(E_l>1.5)
(dGam/dE_sl)*dE_l] = (1.7810 +/- 0.0007_stat +/- 0.0009_sys) GeV. We use these
moments to determine non-perturbative parameters governing the semileptonic
width. In particular, we extract the Heavy Quark Expansion parameters
Lambda-bar = (0.39 +/- 0.03_stat +/- 0.06_sys +/- 0.12_th) GeV and lambda_1 =
(-0.25 +/- 0.02_stat +/- 0.05_sys +/- 0.14_th) GeV^2. The theoretical
constraints used are evaluated through order 1/M_B^3 in the non-perturbative
expansion and beta_0*alpha__s^2 in the perturbative expansion. We use these
parameters to extract |V_cb| from the world average of the semileptonic width
and find |V_cb| = (40.8 +/- 0.5_Gam-sl +/- 0.4_(lambda_1,Lambda-bar)-exp +/-
0.9_th) x 10^-3. In addition, we extract the short range b-quark mass m_b^1S =
(4.82 +/- 0.07_exp +/- 0.11_th) GeV/c^2. Finally, we discuss the implications
of our measurements for the theoretical understanding of inclusive semileptonic
processes.Comment: 21 pages postscript, also available through
http://w4.lns.cornell.edu/public/CLNS, submitted to PR
Search for the glueball candidates f0(1500) and fJ(1710) in gamma gamma collisions
Data taken with the ALEPH detector at LEP1 have been used to search for gamma
gamma production of the glueball candidates f0(1500) and fJ(1710) via their
decay to pi+pi-. No signal is observed and upper limits to the product of gamma
gamma width and pi+pi- branching ratio of the f0(1500) and the fJ(1710) have
been measured to be Gamma_(gamma gamma -> f0(1500)). BR(f0(1500)->pi+pi-) <
0.31 keV and Gamma_(gamma gamma -> fJ(1710)). BR(fJ(1710)->pi+pi-) < 0.55 keV
at 95% confidence level.Comment: 10 pages, 3 figure
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