Personalized medicine support system : resolving conflict in allocation to risk groups and predicting patient molecular response to targeted therapy

Treatment management in cancer patients is largely based on the use of a standardized set of predictive and prognostic factors. The former are used to evaluate specific clinical interventions, and they can be useful for selecting treatments because they directly predict the response to a treatment. The latter are used to evaluate a patient’s overall outcomes, and can be used to identify the risks or recurrence of a disease. Current intelligent systems can be a solution for transferring advancements in molecular biology into practice, especially for predicting the molecular response to molecular targeted therapy and the prognosis of risk groups in cancer medicine. This framework primarily focuses on the importance of integrating domain knowledge in predictive and prognostic models for personalized treatment. Our personalized medicine support system provides the needed support in complex decisions and can be incorporated into a treatment guide for selecting molecular targeted therapies.Haneen Banjar, David Adelson, Fred Brown, and Tamara Leclerc

Design of a low-noise aeroacoustic wind tunnel facility at Brunel University

This paper represents the design principle of a quiet, low turbulence and moderately high speed aeroacoustic wind tunnel which was recently commissioned at Brunel University. A new hemi-anechoic chamber was purposely built to facilitate aeroacoustic measurements. The wind tunnel can achieve a maximum speed of about 80 ms-1. The turbulence intensity of the free jet in the potential core is between 0.1–0.2%. The noise characteristic of the aeroacoustic wind tunnel was validated by three case studies. All of which can demonstrate a very low background noise produced by the bare jet in comparison to the noise radiated from the cylinder rod/flat plate/airfoil in the air stream.The constructions of the aeroacoustic wind tunnel and the hemi-anechoic chamber are financially supported by the School of Engineering and Design at Brunel University

Les effets pro-arythmiques des médicaments

RésuméLes effets pro-arythmiques des médicaments sont fréquents et graves, et sont associés à une surmortalité non négligeable. La polymédication augmente le nombre d’effets indésirables et d’interactions graves voire mortelles. Certains sont facilement évitables. Cependant, au-delà de l’allongement de l’intervalle QT, d’autres mécanismes peuvent avoir un rôle majeur comme les dysfonctions du RyR2, responsable d’arythmie calcium-dépendantes par surcharge calcique intracellulaire, avec apparition de post-dépolarisations tardives, sans modifications de l’intervalle QT. Les bloqueurs des canaux sodiques sont également un problème sérieux de part le risque de démasquer ou d’aggraver une dysfonction du canal sodique chez des patients atteints de syndrome de Brugada asymptomatique ou non. Leur dépistage à un stade précoce du développement des médicaments peut avoir un intérêt majeur.SummaryThe cardiac safety of new and marketed drugs is a major concern for public authorities, patients, physicians as well as pharmaceutical companies. Letal adverse drug reactions are indeed a leading cause of death worldwide and increase at a greater rate than the increase in total hospital admission. The increasing use of polypharmacy in current clinical practice is also associated to a growing number of side effects and interactions leading to fatal adverse events. Measurement of the QT interval is an established, albeit incomplete, approach to assess the proarrhythmic risk of a drug. Ventricular arrhythmia (VA) can be caused by a QT-prolonging drug inducing abnormal repolarization of the action potential (AP) of ventricular cardiomyocytes. Emerging evidence, derived from recent understanding of these mechanisms and of similar mechanisms reported for heart failure (HF), suggest that diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) related to RyR2 dysfunction can induce Ca2+ dependent arrhythmia. In this report, we review mechanisms underlying drug-induced arrhythmogenic effects and Ca2+ dependent arrhythmia, and, for the latter, we discuss some of the issues associated to worsening of cardiac arrhythmias

Modelling predictors of molecular response to frontline imatinib for patients with chronic myeloid leukaemia

BACKGROUND: Treatment of patients with chronic myeloid leukaemia (CML) has become increasingly difficult in recent years due to the variety of treatment options available and challenge deciding on the most appropriate treatment strategy for an individual patient. To facilitate the treatment strategy decision, disease assessment should involve molecular response to initial treatment for an individual patient. Patients predicted not to achieve major molecular response (MMR) at 24 months to frontline imatinib may be better treated with alternative frontline therapies, such as nilotinib or dasatinib. The aims of this study were to i) understand the clinical prediction 'rules' for predicting MMR at 24 months for CML patients treated with imatinib using clinical, molecular, and cell count observations (predictive factors collected at diagnosis and categorised based on available knowledge) and ii) develop a predictive model for CML treatment management. This predictive model was developed, based on CML patients undergoing imatinib therapy enrolled in the TIDEL II clinical trial with an experimentally identified achieving MMR group and non-achieving MMR group, by addressing the challenge as a machine learning problem. The recommended model was validated externally using an independent data set from King Faisal Specialist Hospital and Research Centre, Saudi Arabia. PRINCIPLE FINDINGS: The common prognostic scores yielded similar sensitivity performance in testing and validation datasets and are therefore good predictors of the positive group. The G-mean and F-score values in our models outperformed the common prognostic scores in testing and validation datasets and are therefore good predictors for both the positive and negative groups. Furthermore, a high PPV above 65% indicated that our models are appropriate for making decisions at diagnosis and pre-therapy. Study limitations include that prior knowledge may change based on varying expert opinions; hence, representing the category boundaries of each predictive factor could dramatically change performance of the models.Haneen Banjar, Damith Ranasinghe, Fred Brown, David Adelson, Trent Kroger, Tamara Leclercq, Deborah White, Timothy Hughes, Naeem Chaudhr

Consistent couplings between spin-2 and spin-3 massless fields

We solve the problem of constructing consistent first-order cross-interactions between spin-2 and spin-3 massless fields in flat spacetime of arbitrary dimension n > 3 and in such a way that the deformed gauge algebra is non-Abelian. No assumptions are made on the number of derivatives involved in the Lagrangian, except that it should be finite. Together with locality, we also impose manifest Poincare invariance, parity invariance and analyticity of the deformations in the coupling constants.Comment: LaTeX file. 29 pages, no figures. Minor corrections. Accepted for publication in JHE

Spin Glass Ordering in Diluted Magnetic Semiconductors: a Monte Carlo Study

We study the temperature-dilution phase diagram of a site-diluted Heisenberg antiferromagnet on a fcc lattice, with and without the Dzyaloshinskii-Moriya anisotropic term, fixed to realistic microscopic parameters for $IIB_{1-x} Mn_x Te$ (IIB=Cd, Hg, Zn). We show that the dipolar Dzyaloshinskii-Moriya anisotropy induces a finite-temperature phase transition to a spin glass phase, at dilutions larger than 80%. The resulting probability distribution of the order parameter P(q) is similar to the one found in the cubic lattice Edwards-Anderson Ising model. The critical exponents undergo large finite size corrections, but tend to values similar to the ones of the Edwards-Anderson-Ising model.Comment: 4 pages plus 3 postscript figure

Diethyl 2-[(2-benzyl-1-phenyl­sulfonyl-1H-indol-3-yl)methyl­ene]malonate

In the title compound, C29H27NO6S, the sulfonyl-bound phenyl ring is almost perpendicular to the indole ring system [dihedral angle = 87.96 (6)°], while the benzyl­phenyl ring is oriented at an angle of 76.8 (7)°. An intra­molecular C—H⋯O hydrogen bond is observed. In the crystal structure, mol­ecules are linked into a zigzag C(10) chain along the b axis by inter­molecular C—H⋯O hydrogen bonds

Fast-TIPL Occurs for Salient Images without a Memorization Requirement in Men but Not in Women

Recent research of task-irrelevant perceptual learning (TIPL) demonstrates that stimuli that are consistently presented at relevant point in times (e.g. with task-targets or rewards) are learned, even in the absence of attention to these stimuli. However, different research paradigms have observed different results for how salient stimuli are learned; with some studies showing no learning, some studies showing positive learning and others showing negative learning effects. In this paper we focused on how the level of processing of stimuli impacts fast-TIPL. We conducted three different experiments in which the level of processing of the information paired with a target was manipulated. Our results indicated that fast-TIPL occurs when participants have to memorize the information presented with the target, but also when they just have to process this information for a secondary task without an explicit memorization of those stimuli. However, fast-TIPL does not occur when participants have to ignore the target-paired information. This observation is consistent with recent models of TIPL that suggest that attentional signals can either enhance or suppress learning depending on whether those stimuli are distracting or not to the subjects' objectives. Our results also revealed a robust gender effect in fast-TIPL, where male subjects consistently show fast-TIPL, whereas the observation of fast-TIPL is inconsistent in female subjects

Equivalent widths of Lyman α\alpha emitters in MUSE-Wide and MUSE-Deep

The aim of this study is to better understand the connection between the Lyman $\alpha$ rest-frame equivalent width (EW$_0$) and spectral properties as well as ultraviolet (UV) continuum morphology by obtaining reliable EW$_0$ histograms for a statistical sample of galaxies and by assessing the fraction of objects with large equivalent widths. We used integral field spectroscopy from MUSE combined with broad-band data from the Hubble Space Telescope (HST) to measure EW$_0$. We analysed the emission lines of $1920$ Lyman $\alpha$ emitters (LAEs) detected in the full MUSE-Wide (one hour exposure time) and MUSE-Deep (ten hour exposure time) surveys and found UV continuum counterparts in archival HST data. We fitted the UV continuum photometric images using the Galfit software to gain morphological information on the rest-UV emission and fitted the spectra obtained from MUSE to determine the double peak fraction, asymmetry, full-width at half maximum, and flux of the Lyman $\alpha$ line. The two surveys show different histograms of Lyman $\alpha$ EW$_0$. In MUSE-Wide, $20\%$ of objects have EW$_0 > 240$ \r{A}, while this fraction is only $11\%$ in MUSE-Deep and $\approx 16\%$ for the full sample. This includes objects without HST continuum counterparts (one-third of our sample), for which we give lower limits for EW$_0$. The object with the highest securely measured EW$_0$ has EW$_0=589 \pm 193$ \r{A} (the highest lower limit being EW$_0=4464$ \r{A}). We investigate the connection between EW$_0$ and Lyman $\alpha$ spectral or UV continuum morphological properties. The survey depth has to be taken into account when studying EW$_0$ distributions. We find that in general, high EW$_0$ objects can have a wide range of spectral and UV morphological properties, which might reflect that the underlying causes for high EW$_0$ values are equally varied. (abridged)Comment: 28 pages, 21 + 1 figures, 7 + 1 tables, accepted for publication in A&