XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia

XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair1,2. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP3,4,5 and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease

VHE γ\gamma-ray observations of Markarian 501

Markarian 501, a nearby (z=0.033) X-ray selected BL Lacertae object, is a well established source of Very High Energy (VHE, E>=300 GeV) gamma rays. Dramatic variability in its gamma-ray emission on time-scales from years to as short as two hours has been detected. Multiwavelength observations have also revealed evidence that the VHE gamma-ray and hard X-ray fluxes may be correlated. Here we present results of observations made with the Whipple Collaboration's 10 m Atmospheric Cerenkov Imaging Telescope during 1999 and discuss them in the context of observations made on Markarian 501 during the period from 1996-1998

DIgital Alcohol Management ON Demand (DIAMOND) feasibility randomised controlled trial of a web-based intervention to reduce alcohol consumption in people with hazardous and harmful use versus a face-to-face intervention: protocol.

BACKGROUND: "Hazardous and harmful" drinkers make up approximately 23 % of the adult population in England. However, only around 10 % of these people access specialist care, such as face-to-face extended brief treatment in community alcohol services. This may be due to stigma, difficulty accessing services during working hours, a shortage of trained counsellors and limited provision of services in many places. Web-based alcohol treatment programmes may overcome these barriers and may better suit people who are reluctant or unable to attend face-to-face services, but there is a gap in the evidence base for the acceptability, effectiveness and cost-effectiveness of these programmes compared with treatment as usual (TAU) in community alcohol services. This study aims investigate the feasibility of all parts of a randomised controlled trial (RCT) of a psychologically informed web-based alcohol treatment programme called Healthy Living for People who use Alcohol (HeLP-Alcohol) versus TAU in community alcohol services, e.g. recruitment and retention, online data collection methods, and the use and acceptability of the intervention to participants. METHODS: A feasibility RCT delivered in north London community alcohol services, comparing HeLP-Alcohol with TAU. Potential participants are aged ≥18 years referred or self-referred for hazardous and harmful use of alcohol, without co-morbidities or other complex problems. The main purpose of this study is to demonstrate the feasibility of recruiting participants to the study and will test online methods for collecting baseline demographic and outcome questionnaire data, randomising participants and collecting 3-month follow-up data. The acceptability of this intervention will be measured by recruitment and retention rates, automated log-in data collection and an online service satisfaction questionnaire. The feasibility of using tailored text message, email or phone prompt to maintain engagement with the intervention will also be explored. Results of the study will inform a definitive Phase 3 RCT. RESULTS: Recruitment started on 26 September 2014 and will run for 1 year. CONCLUSION: The proposed trial will provide data to inform a fully powered non-inferiority effectiveness and cost-effectiveness RCT comparing HeLP-Alcohol with TAU. TRIAL REGISTRATION: ISRCTN31789096

Glucocorticoid Receptor 1B and 1C mRNA Transcript Alterations in Schizophrenia and Bipolar Disorder, and Their Possible Regulation by GR Gene Variants

Abnormal patterns of HPA axis activation, under basal conditions and in response to stress, are found in individuals with schizophrenia and bipolar disorder. Altered glucocorticoid receptor (GR) mRNA and protein expression in the dorsolateral prefrontal cortex (DLPFC) in psychiatric illness have also been reported, but the cause of these abnormalities is not known. We quantified expression of GR mRNA transcript variants which employ different 5′ promoters, in 35 schizophrenia cases, 31 bipolar disorder cases and 34 controls. We also explored whether sequence variation within the NR3C1 (GR) gene is related to GR mRNA variant expression. Total GR mRNA was decreased in the DLPFC in schizophrenia cases relative to controls (15.1%, p<0.0005) and also relative to bipolar disorder cases (8.9%, p<0.05). GR-1B mRNA was decreased in schizophrenia cases relative to controls (20.2%, p<0.05), while GR-1C mRNA was decreased in both schizophrenia and bipolar disorder cases relative to controls (16.1% and 17.2% respectively, both p<0.005). A dose-dependent effect of rs10052957 genotype on GR-1B mRNA expression was observed, where CC homozygotes displayed 18.4% lower expression than TC heterozygotes (p<0.05), and 31.8% lower expression than TT homozygotes (p<0.005). Similarly, a relationship between rs6190 (R23K) genotype and GR-1C expression was seen, with 24.8% lower expression in GG homozygotes than GA heterozygotes (p<0.01). We also observed an effect of rs41423247 (Bcl1) SNP on expression of 67 kDa GRα isoform, the most abundant GRα isoform in the DLPFC. These findings suggest possible roles for the GR-1B and GR-1C promoter regions in mediating GR gene expression changes in psychotic illness, and highlight the potential importance of sequence variation within the NR3C1 gene in modulating GR mRNA expression in the DLPFC

Vitality and the course of limitations in activities in osteoarthritis of the hip or knee

<p>Abstract</p> <p>Background</p> <p>The objective of the study was to determine whether psychological and social factors predict the course of limitations in activities in elderly patients with osteoarthritis of the hip or knee, in addition to established somatic and cognitive risk factors.</p> <p>Methods</p> <p>A longitudinal cohort study with a follow-up period of three years was conducted. Patients (N = 237) with hip or knee osteoarthritis were recruited from rehabilitation centers and hospitals. Body functions, comorbidity, cognitive functioning, limitations in activities and psychological and social factors (mental health, vitality, pain coping and perceived social support) were assessed. Statistical analyses included univariate and multivariate regression analyses. Psychological and social factors were added to a previously developed model with body functions, comorbidity and cognitive functioning.</p> <p>Results</p> <p>In knee OA, low vitality has a negative impact on the course of self-reported and performance-based limitations in activities, after controlling for somatic and cognitive factors. In hip OA, psychological and social factors had no additional contribution to the model.</p> <p>Conclusion</p> <p>Low vitality predicts deterioration of limitations in activities in elderly patients with osteoarthritis of the knee, in addition to established somatic and cognitive risk factors. However, the contribution of vitality is relatively small. Results of this study are relevant for the group of patients with knee or hip OA, attending hospitals and rehabilitation centers.</p

Inferring Pathway Activity toward Precise Disease Classification

The advent of microarray technology has made it possible to classify disease states based on gene expression profiles of patients. Typically, marker genes are selected by measuring the power of their expression profiles to discriminate among patients of different disease states. However, expression-based classification can be challenging in complex diseases due to factors such as cellular heterogeneity within a tissue sample and genetic heterogeneity across patients. A promising technique for coping with these challenges is to incorporate pathway information into the disease classification procedure in order to classify disease based on the activity of entire signaling pathways or protein complexes rather than on the expression levels of individual genes or proteins. We propose a new classification method based on pathway activities inferred for each patient. For each pathway, an activity level is summarized from the gene expression levels of its condition-responsive genes (CORGs), defined as the subset of genes in the pathway whose combined expression delivers optimal discriminative power for the disease phenotype. We show that classifiers using pathway activity achieve better performance than classifiers based on individual gene expression, for both simple and complex case-control studies including differentiation of perturbed from non-perturbed cells and subtyping of several different kinds of cancer. Moreover, the new method outperforms several previous approaches that use a static (i.e., non-conditional) definition of pathways. Within a pathway, the identified CORGs may facilitate the development of better diagnostic markers and the discovery of core alterations in human disease

Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy

Introduction Some patients with breast cancer develop local recurrence after breast-conservation surgery despite postoperative radiotherapy, whereas others remain free of local recurrence even in the absence of radiotherapy. As clinical parameters are insufficient for identifying these two groups of patients, we investigated whether gene expression profiling would add further information. Methods We performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation. Results Within the estrogen receptor-positive (ER+) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER- subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER+/ER-). Conclusion A highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy