Investigation into survival mechanisms of malignant B cells in the central nervous system

Introduction: Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer. In the early trials of ALL treatment, central nervous system (CNS) relapse was a common occurrence - the introduction of CNS-directed therapy in the 1970s was associated with the largest single improvement in outcome for childhood ALL. Today, despite universal intensive CNS-directed therapy - with significant associated toxicity - the CNS is involved in around 50% of ALL relapses, with approximately 50% of these being isolated CNS (iCNS) relapse. Whilst many factors increase risk of CNS relapse, few are specific for CNS relapse. Discovery of specific risk factors for CNS relapse would allow increased therapy for children at high risk, and potentially less CNS-directed therapy for those at low risk. Relatively little is known about the biological differences between systemic and CNS ALL. In the CNS, leukaemic cells form plaques adherent to the leptomeninges, bathed in low-nutrient, low-oxygen cerebrospinal fluid (CSF). It was hypothesised that leukaemic cells adapt metabolically to this nutritionally poor CNS microenvironment, and these metabolic adaptations may be targets for specific therapy and/or specific biomarkers for CNS relapse. Findings: Transcriptional analysis of ALL cell lines from CNS and spleen in a mouse xenograft model, and of ALL cells retrieved from the CSF at CNS relapse of ALL, have shown the upregulation of cholesterol biosynthesis as a key adaptation to the CNS niche. Analysis of transcriptomic data from the bone marrow or peripheral blood from children with ALL at diagnosis have shown the potential for upregulated cholesterol biosynthesis (and, independently, upregulated IL7R) as a significant risk factor for CNS relapse of ALL. To support this finding, metabolomic analysis found evidence of changes in CSF cholesterol in the presence of CNS leukaemia, and of increased mevalonate (a cholesterol precursor) and cholesterol in ALL cells retrieved from the CNS in a xenograft model. Therapeutic targeting of CNS ALL in vivo with statins resulted in a CNS-specific increase ALL disease burden. Untargeted metabolomic analysis of CSF shows differences between children with ALL (either at diagnosis or on maintenance therapy) and non-ALL controls, and between children with ALL at diagnosis and the same children on maintenance therapy. Creatine abundance was significantly different in children with ALL at diagnosis compared with both other groups (1/3 lower at diagnosis than either on maintenance or non-ALL controls). This change in creatine and persisted on analysis of CSF from mice with and without leukaemia. On analysis of CSF from children at CNS relapse with ALL there is evidence of increased reduced creatine at time of CNS relapse in 3 of 4 patients. Conclusions: There is evidence to confirm the hypothesis that ALL cell adapt metabolically to the CNS niche. Cholesterol biosynthesis was identified as a key pathway upregulated in CNS ALL, and upregulated cholesterol biosynthesis in ALL cells at diagnosis was found to be a key risk factor for CNS relapse of ALL. In addition, clear changes in the CSF metabolome related to both ALL and ALL therapy were shown, and a new potential marker for the presence of CNS ALL identified. Prospective analyses in independent cohorts are required to determine the clinical utility of these novel strategies for prediction of CNS relapse risk

Working conditions, neighbourhood deprivation and quality of life among people with diabetes: a cross-sectional study

Diabetes is a chronic metabolic disorder that requires constant management to maintain good health and quality of life. Poorly managed diabetes could lead to serious complications and early death. With the ageing demographic profile, there is growing recognition that older people, including those with diabetes, are increasingly becoming a significant proportion of the labour force leading to changes in pension and retirement-related policies. For people with diabetes, understanding how working conditions influence their health and wellbeing is an important step to addressing issues that could compromise their prolonged participation in the labour force. This study examined impact of job-strain on health-related quality of life among people with diabetes. A hundred and twenty-three eligible individuals with diabetes who attended two acute trusts, participated in the study. Diabetes specific quality of life, job characteristics and personal/disease characteristics were measured using questionnaires. Univariate and multivariate statistical analyses were undertaken using SPSS version-22. Over a sixth (17.4%) of participants reported poor quality of life. Marital/co-habitation status, type of diabetes and presence of other long-term conditions were associated with quality of life. High deprivation levels was associated with poor quality of life but there was no association between deprivation levels and participants’ perception of the impact of diabetes on their quality of life. High psychological job-demands and physical job-demands were each associated with poor quality of life. High physical and psychological job-demands are potentially detrimental to quality of life in people with diabetes. Adjustments in working conditions could prove crucial in improving quality of life of employees with diabetes

IL7R is associated with CNS infiltration and relapse in pediatric B-cell precursor acute lymphoblastic leukemia

No abstract available

Targeted memory reactivation of newly learned words during sleep triggers REM-mediated integration of new memories and existing knowledge

Recent memories are spontaneously reactivated during sleep, leading to their gradual strengthening. Whether reactivation also mediates the integration of new memories with existing knowledge is unknown. We used targeted memory reactivation (TMR) during slow-wave sleep (SWS) to selectively cue reactivation of newly learned spoken words. While integration of new words into their phonological neighbourhood was observed in both cued and uncued words after sleep, TMR-triggered integration was predicted by the time spent in rapid eye movement (REM) sleep. These data support complementary roles for SWS and REM in memory consolidation

Memory consolidation is linked to spindle-mediated information processing during sleep

How are brief encounters transformed into lasting memories? Previous research has established the role of non-rapid eye movement (NREM) sleep, along with its electrophysiological signatures of slow oscillations (SOs) and spindles, for memory consolidation [1–4]. In related work, experimental manipulations have demonstrated that NREM sleep provides a window of opportunity to selectively strengthen particular memory traces via the delivery of auditory cues [5–10], a procedure known as targeted memory reactivation (TMR). It has remained unclear, however, whether TMR triggers the brain's endogenous consolidation mechanisms (linked to SOs and/or spindles) and whether those mechanisms in turn mediate effective processing of mnemonic information. We devised a novel paradigm in which associative memories (adjective-object and adjective-scene pairs) were selectively cued during a post-learning nap, successfully stabilizing next-day retention relative to non-cued memories. First, we found that, compared to novel control adjectives, memory cues evoked an increase in fast spindles. Critically, during the time window of cue-induced spindle activity, the memory category linked to the verbal cue (object or scene) could be reliably decoded, with the fidelity of this decoding predicting the behavioral consolidation benefits of TMR. These results provide correlative evidence for an information processing role of sleep spindles in service of memory consolidation. Sleep spindles play a crucial role in memory consolidation, but the underlying mechanisms are not well understood. Using an auditory memory-cueing technique and EEG analysis in humans, Cairney et al. show that sleep spindles mediate the informational content of reactivated memory traces in service of offline mnemonic processing

Use of quantitative polymerase chain reaction (qPCR) for the diagnosis and monitoring of CNS leukaemia

No abstract available

Metabolic adaptation of acute lymphoblastic leukemia to the central nervous system microenvironment depends on Stearoyl CoA desaturase

Metabolic reprogramming is a key hallmark of cancer, but less is known about metabolic plasticity of the same tumor at different sites. Here, we investigated the metabolic adaptation of leukemia in two different microenvironments, the bone marrow and the central nervous system (CNS). We identified a metabolic signature of fatty acid synthesis in CNS leukemia, highlighting stearoyl-CoA desaturase (SCD) as a key player. In vivo SCD overexpression increases CNS disease, whereas genetic or pharmacological inhibition of SCD decreases CNS load. Overall, we demonstrated that leukemic cells dynamically rewire metabolic pathways to suit local conditions and that targeting these adaptations can be exploited therapeutically

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI