Superior antitumoral activity of dimerized targeted single-chain TRAIL fusion proteins under retention of tumor selectivity

Although targeting of the death receptors (DRs) DR4 and DR5 still appears a suitable antitumoral strategy, the limited clinical responses to recombinant soluble TNF-related apoptosis inducing ligand (TRAIL) necessitate novel reagents with improved apoptotic activity/tumor selectivity. Apoptosis induction by a single-chain TRAIL (scTRAIL) molecule could be enhanced >10-fold by generation of epidermal growth factor receptor (EGFR)-specific scFv-scTRAIL fusion proteins. By forcing dimerization of scFv-scTRAIL based on scFv linker modification, we obtained a targeted scTRAIL composed predominantly of dimers (Db-scTRAIL), exceeding the activity of nontargeted scTRAIL ∼100-fold on Huh-7 hepatocellular and Colo205 colon carcinoma cells. Increased activity of Db-scTRAIL was also demonstrated on target-negative cells, suggesting that, in addition to targeting, oligomerization equivalent to an at least dimeric assembly of standard TRAIL per se enhances apoptosis signaling. In the presence of apoptosis sensitizers, such as the proteasomal inhibitor bortezomib, Db-scTRAIL was effective at picomolar concentrations in vitro (EC50 ∼2 × 10−12 M). Importantly, in vivo, Db-scTRAIL was well tolerated and displayed superior antitumoral activity in mouse xenograft (Colo205) tumor models. Our results show that both targeting and controlled dimerization of scTRAIL fusion proteins provides a strategy to enforce apoptosis induction, together with retained tumor selectivity and good in vivo tolerance

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Association of GATA3, P53, Ki67 status and vascular peritumoral invasion are strongly prognostic in luminal breast cancer

International audienceIntroduction: Breast cancers are traditionally divided into hormone-receptor positive and negative cases. This classification helps to guide patient management. However, a subgroup of hormone-receptor positive patients relapse irrespective of hormonal therapy. Gene expression profiling has classified breast tumours into five major subtypes with significant different outcome. The two luminal subtypes, A and B, show high expression of ESR1, GATA3 and FOXA1 genes. Prognostic biomarkers for oestrogen receptor (ER)-positive cases include progesterone receptor (PR) and androgen receptor (AR), and proteins related to proliferation or apoptotic resistance. The aim of this study was to identify the best predictors of success of hormonal therapy.Methods: By immunohistochemistry we studied 10 markers in a consecutive series of 832 cases of breast carcinoma treated at the Paoli-Calmettes Institute from 1990 to 2002 and deposited onto tissue microarrays (TMA). These markers were luminal-related markers ER, PR, AR, FOXA1 and GATA3 transcription factors, proliferation-related Ki67 and CCND1, ERBB2, anti-apoptotic BCL2 and P53. We also measured vascular peritumoural invasion (VPI), size, grade and lymph node involvement. For 143 cases, gene expression profiles were available. Adjuvant chemotherapy and hormonal therapy were given to high- and low-risk patients, respectively. The 162 events observed and taken into account were metastases.Results: Molecular expression of the 10 parameters and subtype with ER status were strongly correlated. Of the 67 luminal A cases of this series, 63 were ER-positive. Multivariate analyses showed the highly significant prognostic value of VPI (hazard ratio (HR) = 2.47), Ki67 (HR = 2.9), P53 (HR = 2.9) and GATA3 (HR = 0.5) for the 240 patients who received hormonal therapy.Conclusions: A panel of three antibodies (Ki67, P53 and GATA3) associated with VPI can significantly improve the traditional prognosticators in predicting outcome for ER-positive breast cancer patients receiving hormonal therapy

Stock price reaction to profit warnings: The role of time-varying betas

This study investigates the role of time-varying betas, event-induced variance and conditional heteroskedasticity in the estimation of abnormal returns around important news announcements. Our analysis is based on the stock price reaction to profit warnings issued by a sample of firms listed on the Hong Kong Stock Exchange. The standard event study methodology indicates the presence of price reversal patterns following both positive and negative warnings. However, incorporating time-varying betas, event-induced variance and conditional heteroskedasticity in the modelling process results in post-negative-warning price patterns that are consistent with the predictions of the efficient market hypothesis. These adjustments also cause the statistical significance of some post-positive-warning cumulative abnormal returns to disappear and their magnitude to drop to an extent that minor transaction costs would eliminate the profitability of the contrarian strategy

Quality assurance in psychiatry: quality indicators and guideline implementation

In many occasions, routine mental health care does not correspond to the standards that the medical profession itself puts forward. Hope exists to improve the outcome of severe mental illness by improving the quality of mental health care and by implementing evidence-based consensus guidelines. Adherence to guideline recommendations should reduce costly complications and unnecessary procedures. To measure the quality of mental health care and disease outcome reliably and validly, quality indicators have to be available. These indicators of process and outcome quality should be easily measurable with routine data, should have a strong evidence base, and should be able to describe quality aspects across all sectors over the whole disease course. Measurement-based quality improvement will not be successful when it results in overwhelming documentation reducing the time for clinicians for active treatment interventions. To overcome difficulties in the implementation guidelines and to reduce guideline non-adherence, guideline implementation and quality assurance should be embedded in a complex programme consisting of multifaceted interventions using specific psychological methods for implementation, consultation by experts, and reimbursement of documentation efforts. There are a number of challenges to select appropriate quality indicators in order to allow a fair comparison across different approaches of care. Carefully used, the use of quality indicators and improved guideline adherence can address suboptimal clinical outcomes, reduce practice variations, and narrow the gap between optimal and routine care

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Search for high-mass resonances decaying to dilepton final states in pp collisions at s√=7 TeV with the ATLAS detector

The ATLAS detector at the Large Hadron Collider is used to search for high-mass resonances decaying to an electron-positron pair or a muon-antimuon pair. The search is sensitive to heavy neutral Z′ gauge bosons, Randall-Sundrum gravitons, Z * bosons, techni-mesons, Kaluza-Klein Z/γ bosons, and bosons predicted by Torsion models. Results are presented based on an analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.9 fb−1 in the e + e − channel and 5.0 fb−1 in the μ + μ −channel. A Z ′ boson with Standard Model-like couplings is excluded at 95 % confidence level for masses below 2.22 TeV. A Randall-Sundrum graviton with coupling k/MPl=0.1 is excluded at 95 % confidence level for masses below 2.16 TeV. Limits on the other models are also presented, including Technicolor and Minimal Z′ Models

Search for the neutral Higgs bosons of the minimal supersymmetric standard model in pp collisions at root s=7 TeV with the ATLAS detector

A search for neutral Higgs bosons of the Minimal Supersymmetric Standard Model (MSSM) is reported. The analysis is based on a sample of proton-proton collisions at a centre-of-mass energy of 7TeV recorded with the ATLAS detector at the Large Hadron Collider. The data were recorded in 2011 and correspond to an integrated luminosity of 4.7 fb-1 to 4.8 fb-1. Higgs boson decays into oppositely-charged muon or τ lepton pairs are considered for final states requiring either the presence or absence of b-jets. No statistically significant excess over the expected background is observed and exclusion limits at the 95% confidence level are derived. The exclusion limits are for the production cross-section of a generic neutral Higgs boson, φ, as a function of the Higgs boson mass and for h/A/H production in the MSSM as a function of the parameters mA and tan β in the mhmax scenario for mA in the range of 90GeV to 500 GeV. Copyright CERN