Untangling the ATR-CHEK1 network for prognostication, prediction and therapeutic target validation in breast cancer

Background: ATR-Chk1 signalling network is critical for genomic stability. ATR-Chk1 may be deregulated in breast cancer and have prognostic, predictive and therapeutic significance. Patients and methods: We investigated ATR and phosphorylated CHK1Ser345 protein (pChk1) expression in 1712 breast cancers (Nottingham Tenovus series). ATR and Chk1 mRNA were evaluated in 1950 breast cancers (METABRIC cohort). Pre-clinically, biological consequences of ATR gene knockdown or ATR inhibition by small molecule inhibitor (VE-821) were investigated in MCF-7 and MDA-MB-231 breast cancer cell lines and in non-tumorigenic breast epithelial cells (MCF10A). Results: High ATR and high cytoplasmic pChk1 expression was significantly associated with higher tumour stage, higher mitotic index, pleomorphism and lymphovascular invasion. In univariate analysis, high ATR and high cytoplasmic pChk1 protein expression was associated with shorter breast cancer specific survival (BCSS). In multivariate analysis, high ATR remains an independent predictor of adverse outcome. At the mRNA level, high Chk1 remains associated with aggressive phenotypes including lymph node positivity, high grade, Her-2 overexpression, triple-negative phenotype and molecular classes associated with aggressive behaviour and shorter survival.. Pre-clinically, Chk1 phosphorylation at serine 345 following replication stress (induced by gemcitabine or hydroxyurea treatment) was impaired in ATR knockdown and in VE-821 treated breast cancer cells. Doxycycline inducible knockdown of ATR suppressed growth, which was restored when ATR was re-expressed. Similarly, VE-821 treatment resulted in a dose dependent suppression of cancer cell growth and survival (MCF7 and MDA-MB-231) but had no effect on non-tumorigenic breast epithelial cells (MCF10A). Conclusions: We provides evidence that ATR and Chk1 are promising biomarkers and rational drug target for personalized therapy in breast cancer

Assessing Specific Cognitive Deficits Associated with Dementia in Older Adults with Down Syndrome: Use and Validity of the Arizona Cognitive Test Battery (ACTB)

BACKGROUND: Down syndrome is associated with specific cognitive deficits. Alongside this, older adults with Down syndrome are a high risk group for dementia. The Arizona Cognitive Test Battery (ACTB), a cognitive assessment battery specifically developed for use with individuals with Down syndrome, has been proposed for use as outcome measures for clinical trials in this population. It has not been validated in older adults with Down syndrome. This study aims to assess the use and validity of the ACTB in older adults with Down syndrome. METHODS: Participants with Down syndrome aged 45 and over were assessed using the ACTB, standard tabletop tests and informant ratings. RESULTS: Assessment outcomes of 49 participants were analysed. Of these, 19 (39%) had a diagnosis of dementia or possible dementia. Most participants were able to attempt most of the tasks, although some tasks had high floor effects (including CANTAB Intra-Extra Dimensional shift stages completed and Modified Dots Task). Of the ACTB tasks, statistically significant differences were observed between the dementia and no dementia groups on CANTAB Simple Reaction Time median latency, NEPSY Visuomotor Precision-Car and Motorbike and CANTAB Paired Associates Learning stages completed. No significant differences were observed for CANTAB Intra-Extra Dimensional Shift, Modified Dots Task, Finger Sequencing, NEPSY Visuomotor precision-Train and Car and CANTAB Paired Associates Learning first trial memory score. Several of the tasks in the ACTB can be used in older adults with Down syndrome and have mild to moderate concurrent validity when compared to tabletop tests and informant ratings, although this varies on a test by test basis. CONCLUSIONS: Overall, scores for a number of tests in the ACTB were similar when comparing dementia and no dementia groups of older adults with Down syndrome, suggesting that it would not be an appropriate outcome measure of cognitive function for clinical trials of dementia treatments without further modification and validation

A Measurement of Rb using a Double Tagging Method

The fraction of Z to bbbar events in hadronic Z decays has been measured by the OPAL experiment using the data collected at LEP between 1992 and 1995. The Z to bbbar decays were tagged using displaced secondary vertices, and high momentum electrons and muons. Systematic uncertainties were reduced by measuring the b-tagging efficiency using a double tagging technique. Efficiency correlations between opposite hemispheres of an event are small, and are well understood through comparisons between real and simulated data samples. A value of Rb = 0.2178 +- 0.0011 +- 0.0013 was obtained, where the first error is statistical and the second systematic. The uncertainty on Rc, the fraction of Z to ccbar events in hadronic Z decays, is not included in the errors. The dependence on Rc is Delta(Rb)/Rb = -0.056*Delta(Rc)/Rc where Delta(Rc) is the deviation of Rc from the value 0.172 predicted by the Standard Model. The result for Rb agrees with the value of 0.2155 +- 0.0003 predicted by the Standard Model.Comment: 42 pages, LaTeX, 14 eps figures included, submitted to European Physical Journal

Measurement of the B+ and B-0 lifetimes and search for CP(T) violation using reconstructed secondary vertices

The lifetimes of the B+ and B-0 mesons, and their ratio, have been measured in the OPAL experiment using 2.4 million hadronic Z(0) decays recorded at LEP. Z(0) --> b (b) over bar decays were tagged using displaced secondary vertices and high momentum electrons and muons. The lifetimes were then measured using well-reconstructed charged and neutral secondary vertices selected in this tagged data sample. The results aretau(B+) = 1.643 +/- 0.037 +/- 0.025 pstau(Bo) = 1.523 +/- 0.057 +/- 0.053 pstau(B+)/tau(Bo) = 1.079 +/- 0.064 +/- 0.041,where in each case the first error is statistical and the second systematic.A larger data sample of 3.1 million hadronic Z(o) decays has been used to search for CP and CPT violating effects by comparison of inclusive b and (b) over bar hadron decays, No evidence fur such effects is seen. The CP violation parameter Re(epsilon(B)) is measured to be Re(epsilon(B)) = 0.001 +/- 0.014 +/- 0.003and the fractional difference between b and (b) over bar hadron lifetimes is measured to(Delta tau/tau)(b) = tau(b hadron) - tau((b) over bar hadron)/tau(average) = -0.001 +/- 0.012 +/- 0.008

Neurofilament light as a blood biomarker for neurodegeneration in Down syndrome.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.BACKGROUND: Down syndrome (DS) may be considered a genetic form of Alzheimer's disease (AD) due to universal development of AD neuropathology, but diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. A potential biomarker is neurofilament light (NF-L), due to its association with axonal damage in neurodegenerative conditions. METHODS: We measured blood NF-L concentrations in 100 adults with DS using Simoa NF-light® assays, and we examined relationships with age as well as cross-sectional and longitudinal dementia diagnosis. RESULTS: NF-L concentrations increased with age (Spearman's rho = 0.789, p < 0.001), with a steep increase after age 40, and they were predictive of dementia status (p = 0.022 adjusting for age, sex, and APOE4), but they showed no relationship with long-standing epilepsy or premorbid ability. Baseline NF-L concentrations were associated with longitudinal dementia status. CONCLUSIONS: NF-L is a biomarker for neurodegeneration in DS with potential for use in future clinical trials to prevent or delay dementia.This work was funded by a Wellcome Trust Strategic Award (grant number 098330/Z/12/Z) conferred upon The London Down Syndrome (LonDownS) Consortium (Chief Investigator, Andre Strydom)

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

Down syndrome, caused by an extra copy of chromosome 21, is associated with a greatly increased risk of early onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP), an Alzheimer risk factor, although the possession of extra copies of other chromosome 21 genes may also play a role. Further study of the mechanisms underlying the development of Alzheimer disease in Down syndrome could provide insights into the mechanisms that cause dementia in the general population

Measurement of the W+W−γW^{+}W^{-} \gamma Cross-section and First direct Limits on Anomalous Electroweak Quartic Gauge Couplings

A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W+W- events accompanied by hard photon radiation produced in e+e- collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183pb^-1 of data recorded at root{s}=189GeV. From these data, 17 W+W-gamma candidates are selected with photon energy greater than 10GeV, consistent with the Standard Model expectation. These events are used to measure the e+e- to W+W-gamma cross-section within a set of geometric and kinematic cuts; sigma{W+W-gamma} = 136+-37+-8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the {W+ W- gamma gamma} and {W+ W- gamma Z0} vertices: -0.070GeV^{-2} < a_0/Lambda^2 < 0.070GeV^{-2}, -0.13GeV^{-2} < a_c/Lambda^2 < 0.19GeV^{-2}, -0.61GeV^{-2} < a_n/Lambda^2 < 0.57GeV^{-2}, where Lambda represents the energy scale for new physics.A study of W + W − events accompanied by hard photon radiation produced in e + e − collisions at LEP is presented. Events consistent with two on-shell W-bosons and an isolated photon are selected from 183 pb −1 of data recorded at s =189 GeV. From these data, 17 W + W − γ candidates are selected with photon energy greater than 10 GeV, consistent with the Standard Model expectation. These events are used to measure the e + e − →W + W − γ cross-section within a set of geometric and kinematic cuts, σ ̂ WW γ =136±37±8 fb, where the first error is statistical and the second systematic. The photon energy spectrum is used to set the first direct, albeit weak, limits on possible anomalous contributions to the W + W − γγ and W + W − γ Z 0 vertices: −0.070 GeV −

τ\tau decays with neutral kaons

The branching ratio of the tau lepton to a neutral K meson is measured from a sample of approximately 200,000 tau decays recorded by the OPAL detector at centre-of-mass energies near the Z0 resonance. The measurement is based on two samples which identify one-prong tau decays with KL and KS mesons. The combined branching ratios are measured to be B(tau- -->pi- K0bar nutau) = (9.33+-0.68+-0.49)x10^-3 B(tau- -->pi- K0bar [>=1pi0] nutau) = (3.24+-0.74+-0.66)x10^-3 B(tau- -->K- K0bar [>=0pi0] nutau) = (3.30+-0.55+-0.39)x10^-3 where the first error is statistical and the second systematic.The branching ratio of the tau lepton to a neutral K meson is measured from a sample of approximately 200,000 tau decays recorded by the OPAL detector at centre-of-mass energies near the Z0 resonance. The measurement is based on two samples which identify one-prong tau decays with KL and KS mesons. The combined branching ratios are measured to be B(tau- -->pi- K0bar nutau) = (9.33+-0.68+-0.49)x10^-3 B(tau- -->pi- K0bar [>=1pi0] nutau) = (3.24+-0.74+-0.66)x10^-3 B(tau- -->K- K0bar [>=0pi0] nutau) = (3.30+-0.55+-0.39)x10^-3 where the first error is statistical and the second systematic

Transverse and Longitudinal Bose Einstein Correlations in hadronic Z0Z^0 Decays

Bose-Einstein correlations in pairs of identical charged pions produced in asample of 4.3 million Z0 hadronic decays are studied as a function of the threecomponents of the momentum difference, transverse ("out" and "side") andlongitudinal with respect to the thrust direction of the event. A significantdifference between the transverse, r_t_side, and longitudinal, r_l, dimensionsis observed, indicating that the emitting source of identical pions, asobserved in the Longitudinally CoMoving System, has an elongated shape. This isobserved with a variety of selection techniques. Specifically, the values ofthe parameters obtained by fitting the extended Goldhaber parametrisation tothe correlation function C'= C^{DATA}}/C^{MC} for two-jet events, selected withthe Durham algorithm and resolution parameter ycut=0.04, arer_t_out=(0.647+-0.011(stat})+0.022-0.124(syst)) fm,r_t_side=(0.809+-0.009(stat)+0.019-0.032}(syst)) fm, r_l=(0.989+-0.011(stat)+0.030-0.015(syst})) fm andr_l/r_t_side=1.222+- 0.027(stat})+0.075-0.012(syst). The results are discussedin the context of a recent model of Bose-Einstein correlations based on stringfragmentation.Bose-Einstein correlations in pairs of identical charged pions produced in a sample of 4.3 million Z0 hadronic decays are studied as a function of the three components of the momentum difference, transverse ("out" and "side") and longitudinal with respect to the thrust direction of the event. A significant difference between the transverse, r_t_side, and longitudinal, r_l, dimensions is observed, indicating that the emitting source of identical pions, as observed in the Longitudinally CoMoving System, has an elongated shape. This is observed with a variety of selection techniques. Specifically, the values of the parameters obtained by fitting the extended Goldhaber parametrisation to the correlation function C'= C^{DATA}}/C^{MC} for two-jet events, selected with the Durham algorithm and resolution parameter ycut=0.04, are r_t_out=(0.647+-0.011(stat})+0.022-0.124(syst)) fm, r_t_side=(0.809+-0.009(stat)+0.019-0.032}(syst)) fm, r_l=(0.989+-0.011(stat)+0.030-0.015(syst})) fm and r_l/r_t_side=1.222+-0.027(stat})+0.075-0.012(syst). The results are discussed in the context of a recent model of Bose-Einstein correlations based on string fragmentation