Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study

BACKGROUND: Understanding the heterogeneous genotypes and phenotypes of prostate cancer is fundamental to improving the way we treat this disease. As yet, there are no validated descriptions of prostate cancer subgroups derived from integrated genomics linked with clinical outcome.

METHODS: In a study of 482 tumour, benign and germline samples from 259 men with primary prostate cancer, we used integrative analysis of copy number alterations (CNA) and array transcriptomics to identify genomic loci that affect expression levels of mRNA in an expression quantitative trait loci (eQTL) approach, to stratify patients into subgroups that we then associated with future clinical behaviour, and compared with either CNA or transcriptomics alone.

FINDINGS: We identified five separate patient subgroups with distinct genomic alterations and expression profiles based on 100 discriminating genes in our separate discovery and validation sets of 125 and 103 men. These subgroups were able to consistently predict biochemical relapse (p = 0.0017 and p = 0.016 respectively) and were further validated in a third cohort with long-term follow-up (p = 0.027). We show the relative contributions of gene expression and copy number data on phenotype, and demonstrate the improved power gained from integrative analyses. We confirm alterations in six genes previously associated with prostate cancer (MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), and also identify 94 genes not previously linked to prostate cancer progression that would not have been detected using either transcript or copy number data alone. We confirm a number of previously published molecular changes associated with high risk disease, including MYC amplification, and NKX3-1, RB1 and PTEN deletions, as well as over-expression of PCA3 and AMACR, and loss of MSMB in tumour tissue. A subset of the 100 genes outperforms established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures (p = 0.0001). We further show how our molecular profiles can be used for the early detection of aggressive cases in a clinical setting, and inform treatment decisions.

INTERPRETATION: For the first time in prostate cancer this study demonstrates the importance of integrated genomic analyses incorporating both benign and tumour tissue data in identifying molecular alterations leading to the generation of robust gene sets that are predictive of clinical outcome in independent patient cohorts.

Impact of long-term storage at ambient temperatures on the total quality and stability of high-pressure processed tomato juice

High-pressure processing (HPP) can produce tomato juice of high quality and safety with a short shelf life under refrigeration temperatures. Long-term higher temperature storage studies are rare and temperature tolerant products are challenging to develop. The effect of high-pressure processing (HPP) on the total quality (colour, microbial counts, phytochemical levels, antioxidant and enzymatic activities) and stability (retention over time) of tomato juice during long-term storage was investigated. Thermal processing (TP) was used as a control treatment, and overall, two different ambient conditions (20 °C and 28 °C) were tested. Immediately after processing, HPP products proved superior to TP ones (enhanced redness, total carotenoids and lycopene, stable total phenols and inactivation of pectin methyl esterase). During initial storage (30 d) most quality attributes of HPP juice remained stable. Prolonged storage, however, led to losses of most quality attributes, although HPP (20 °C) showed lower quality degradation rate constants comparison to TP and HPP (28 °C). Industrial Relevance: There is a demand for ambient stable tomato products, especially in some parts of the world, and current industrial practices (canning, pasteurisation) either compromise in product quality or require refrigeration conditions. High-pressure processing has been investigated as milder technology, with a potential to deliver superior quality. The drawback is that is also requires chill storage. The results of this study show how quality parameters behave in a high-pressured tomato product and pave the way for further development that could optimise this technology. This could be of economic importance for the tomato juice industry to develop new products stable in ambient temperatures and perhaps beneficial for cutting down the refrigeration costs under specific conditions.

Meta-analysis of Positive and Negative Symptoms Reveals Schizophrenia Modifier Genes

BACKGROUND: Evidence suggests that genetic factors may influence both schizophrenia (Scz) and its clinical presentation. In recent years, genome-wide association studies (GWAS) have demonstrated considerable success in identifying risk loci. Detection of "modifier loci" has the potential to further elucidate underlying disease processes.

METHODS: We performed GWAS of empirically derived positive and negative symptom scales in Irish cases from multiply affected pedigrees and a larger, independent case-control sample, subsequently combining these into a large Irish meta-analysis. In addition to single-SNP associations, we considered gene-based and pathway analyses to better capture convergent genetic effects, and to facilitate biological interpretation of these findings. Replication and testing of aggregate genetic effects was conducted using an independent European-American sample.

RESULTS: Though no single marker met the genome-wide significance threshold, genes and ontologies/pathways were significantly associated with negative and positive symptoms; notably, NKAIN2 and NRG1, respectively. We observed limited overlap in ontologies/pathways associated with different symptom profiles, with immune-related categories over-represented for negative symptoms, and addiction-related categories for positive symptoms. Replication analyses suggested that genes associated with clinical presentation are generalizable to non-Irish samples.

CONCLUSIONS: These findings strongly support the hypothesis that modifier loci contribute to the etiology of distinct Scz symptom profiles. The finding that previously implicated "risk loci" actually influence particular symptom dimensions has the potential to better delineate the roles of these genes in Scz etiology. Furthermore, the over-representation of distinct gene ontologies/pathways across symptom profiles suggests that the clinical heterogeneity of Scz is due in part to complex and diverse genetic factors.

Fast Rule Mining over Multi-dimensional Windows

Association rule mining is an indispensable tool for discovering
insights from large databases and data warehouses.
The data in a warehouse being multi-dimensional, it is often
useful to mine rules over subsets of data defined by selections
over the dimensions. Such interactive rule mining
over multi-dimensional query windows is difficult since rule
mining is computationally expensive. Current methods using
pre-computation of frequent itemsets require counting
of some itemsets by revisiting the transaction database at
query time, which is very expensive. We develop a method
(RMW) that identifies the minimal set of itemsets to compute
and store for each cell, so that rule mining over any
query window may be performed without going back to the
transaction database. We give formal proofs that the set of
itemsets chosen by RMW is sufficient to answer any query
and also prove that it is the optimal set to be computed
for 1 dimensional queries. We demonstrate through an extensive
empirical evaluation that RMW achieves extremely
fast query response time compared to existing methods, with
only moderate overhead in pre-computation and storage

Executing bag of distributed tasks on the cloud: Investigating the trade-offs between performance and cost

Bag of Distributed Tasks (BoDT) can benefit from decentralised execution on the Cloud. However, there is a trade-off between the performance that can be achieved by employing a large number of Cloud VMs for the tasks and the monetary constraints that are often placed by a user. The research reported in this paper is motivated towards investigating this trade-off so that an optimal plan for deploying BoDT applications on the cloud can be generated. A heuristic algorithm, which considers the user's preference of performance and cost is proposed and implemented. The feasibility of the algorithm is demonstrated by generating execution plans for a sample application. The key result is that the algorithm generates optimal execution plans for the application over 91% of the time.

Time-lapse Monitoring of the Slopes of a Heritage Earthwork by Means of Near-surface Seismic Techniques

A significant portion of UK’s infrastructures earthworks was built more than 100 years ago, without modern construction standards: poor maintenance and the change of precipitations pattern experienced in the past decades are currently compromising their stability, leading to an increasing number of failures. To address the need for a reliable and time-efficient monitoring of earthworks at risk of failure we propose here the use of two established seismic techniques for the characterization of the near surface, MASW and P-wave refraction. We have regularly collected MASW and P-wave refraction data, from March 2014 to February 2015, along 4 reduced-scale seismic lines located on the flanks of a heritage railway embankment located in Broadway, SW of England. We have observed a definite temporal variability in terms of phase velocities of SW dispersion curves and of P-wave travel times. The accurate choice of ad-hoc inversion strategies has allowed to reconstruct reliable VP and VS models through which it is potentially possible to track the temporal variations of geo-mechanical properties of the embankment slopes. The variability over time of seismic data and seismic velocities seems to correlate well with rainfall data recorded in the days immediately preceding the date of acquisition.

Development of a Novel Assay for the Detection of Active Neutrophil Elastase in Patients with Chronic Obstructive Pulmonary Disease

Neutrophil elastase (NE), a biomarker of infection and inflammation, correlates with the severity of several respiratory diseases including chronic obstructive pulmonary disease (COPD). However, it’s detection and quantification in biological samples is confounded by a lack of reliable and robust methodologies. Standard assays using chromogenic or fluorogenic substrates are not specific when added to complex clinical samples containing multiple proteolytic and hydrolytic enzymes which have the ability to hydrolyse the substrate, thereby resulting in an over-estimation of the target protease. Furthermore, ELISA systems measure total protease levels which can be a mixture of latent, active and protease-inhibitor complexes. Therefore, we have developed a novel immunoassay (ProteaseTag™ Active NE Immunoassay) which is selective and specific for the capture of active NE in sputum and Bronchoalveolar Lavage (BAL) in patients with COPD. The objective of this study was to clinically validate ProteaseTag™ Active NE Ultra Immunoassay for the detection of NE in sputum from COPD patients. 20 matched sputum sol samples were collected from 10 COPD patients (M=6, F=4; 73 ± 6 years) during stable and exacerbation phases. Samples were assayed for NE activity utilising both ProteaseTag™ Active NE Ultra Immunoassay and a fluorogenic substrate-based kinetic activity assay. Both assays detected elevated levels of NE in the majority of patients (n=7) during an exacerbation (mean=217.2 μg/ml ±296.6) compared to their stable phase (mean=92.37 μg/ml ±259.8). However, statistical analysis did not show this difference to be significant (p=0.07, ProteaseTag™ Active NE Ultra Immunoassay; p=0.06 kinetic assay), most likely due to the low study number. A highly significant correlation was found between the 2 assay types (p≤0.0001, r=0.996). NE as a primary efficacy endpoint in clinical trials or as a marker of inflammation within the clinic has been hampered by the lack of a robust and simple to use assay. ProteaseTag™ Active NE Immunoassay specifically measures only active NE in clinical samples, is quick and easy to use (< 3 hours) and has no dependency on a kinetic readout. ProteaseTag™ technology is currently being transferred to a lateral flow device for use at Point of Care.

Sources of patient knowledge and financing of cataract surgery in rural China: the Sanrao Study of Cataract Outcomes and Up-Take of Services (SCOUTS), report 6.

AIM: To study patient sources of knowledge about cataract surgical services, and strategies for financing surgery in rural China. DESIGN: Cross-sectional case series. METHODS: Patients undergoing cataract surgery by local surgeons in a government, village-level facility in Sanrao, Guangdong between 8 August and 31 December 2005 were examined and had standardised interviews an average of 12 months after surgery. RESULTS: Of 313 eligible patients, 239 (76%) completed the questionnaire. Subjects had a mean (SD) age of 69.9 (10.2) years, 36.4% (87/239) were male, and 87.0% (208/239) had been blind (presenting visual acuity < or = 6/60) before surgery. Word-of-mouth advertising was particularly important: 198 (85.0%) of the subjects knew a person who had undergone cataract surgery, of whom 191 (96.5%) had had cataract surgery at Sanrao itself. Over 70% of subjects (166/239) watched TV daily, whereas 80.0% (188/239) "never" read the newspaper. Nearly two-thirds of suggestions from participants (n = 211, 59.6%) favoured either TV advertisements or word-of-mouth to publicise the programme. While the son or daughter had paid for surgery in over 70% of cases (164/233), the patient's having paid without help was the sole predictor of undergoing second-eye surgery (OR 2.27 (95% CI 1.01 to 5.0, p = 0.04)). DISCUSSION: Strategies to increase uptake of cataract surgery in rural China may benefit from enhancing word-of-mouth advertising (such as with pseudophakic motivators), using television advertising where affordable, and micro-credit or other programmes to enable patients to pay their own fees, thus increasing uptake of second-eye surgery.

Analysis of groundwater-level response to rainfall and recharge estimates in fractured hard rock aquifers, NW Ireland

Despite fractured hard rock aquifers underlying over 65% of Ireland, knowledge of key processes controlling groundwater recharge in these bedrock systems is inadequately constrained. In this study, we examined 19 groundwater-level hydrographs from two Irish hillslope sites underlain by hard rock aquifers. Water-level time-series in clustered monitoring wells completed at the subsoil, soil/bedrock interface, shallow and deep bedrocks were continuously monitored hourly over two hydrological years. Correlation methods were applied to investigate groundwater-level response to rainfall, as well as its seasonal variations. The results reveal that the direct groundwater recharge to the shallow and deep bedrocks on hillslope is very limited. Water-level variations within these geological units are likely dominated by slow flow rock matrix storage. The rapid responses to rainfall (⩽2 h) with little seasonal variations were observed to the monitoring wells installed at the subsoil and soil/bedrock interface, as well as those in the shallow or deep bedrocks at the base of the hillslope. This suggests that the direct recharge takes place within these units. An automated time-series procedure using the water-table fluctuation method was developed to estimate groundwater recharge from the water-level and rainfall data. Results show the annual recharge rates of 42–197 mm/yr in the subsoil and soil/bedrock interface, which represent 4–19% of the annual rainfall. Statistical analysis of the relationship between the rainfall intensity and water-table rise reveal that the low rainfall intensity group (⩽1 mm/h) has greater impact on the groundwater recharge rate than other groups (>1 mm/h). This study shows that the combination of the time-series analysis and the water-table fluctuation method could be an useful approach to investigate groundwater recharge in fractured hard rock aquifers in Ireland.

Aflatoxin Exposure and Associated Human Health Effects, a Review of Epidemiological Studies

flatoxins are fungal toxins that possess acute life threatening toxicity, carcinogenic properties and other potential chronic adverse effects. Dietary exposure to aflatoxins is considered a major public health concern, especially for subsistence farming communities in sub-Saharan Africa and South Asia, where dietary staple food crops such as groundnuts and maize are often highly contaminated with aflatoxin due to hot and humid climates and poor storage, together with low awareness of risk and lack of enforcement of regulatory limits. Biomarkers have been developed and applied in many epidemiological studies assessing aflatoxin exposure and the associated health effects in these high-risk population groups. This review discusses the recent epidemiological evidence for aflatoxin exposure, co-exposure with other mycotoxins and associated health effects in order to provide evidence on risk assessment, and highlight areas where further research is necessary. Aflatoxin exposure can occur at any stage of life and is a major risk factor for hepatocellular carcinoma, especially when hepatitis B infection is present. Recent evidence suggests that aflatoxin may be an underlying determinant of stunted child growth, and may lower cell-mediated immunity, thereby increasing disease susceptibility. However, a causal relationship between aflatoxin exposure and these latter adverse health outcomes has not been established, and the biological mechanisms for these have not been elucidated, prompting further research. Furthermore, there is a dearth of information regarding the health effects of co-exposure to aflatoxin with other mycotoxins. Recent developments of biomarkers provide opportunities for important future research in this area.

Magnetic collimation of petawatt driven fast electron beam for prospective fast ignition studies

Collimated transport of fast electron beam through solid density matter is one of the key issues behind the success of the fast ignition scheme by means of which the required amount of ignition energy can be delivered to the hot spot region of the compressed fuel. Here we report on a hot electron beam collimation scheme in solids by tactfully using the strong magnetic fields generated by an electrical resistivity gradient according to Faraday's law. This was accomplished by appropriately fabricating the targets in such a way that the electron beam is directed to flow in a metal which is embedded in a much lower resistivity and atomic number metal. Experimental results showed guided transport of hot electron beam over hundreds of microns length inside solid density plasma, which were obtained from two experiments examining the scheme for petawatt laser driven hot electron beam while employing various target configurations.

Measuring the shape of degree distributions

Degree distribution is a fundamental property of networks. While mean degree provides a standard measure of scale, there are several commonly used shape measures. Widespread use of a single shape measure would enable comparisons between networks and facilitate investigations about the relationship between degree distribution properties and other network features. This paper describes five candidate measures of heterogeneity and recommends the Gini coefficient. It has theoretical advantages over many of the previously proposed measures, is meaningful for the broad range of distribution shapes seen in different types of networks, and has several accessible interpretations. While this paper focusses on degree, the distribution of other node based network properties could also be described with Gini coefficients.

A comprehensive strategy to detect the fraudulent adulteration of herbs: The oregano approach

Fraud in the global food supply chain is becoming increasingly common due to the huge profits associated with this type of criminal activity. Food commodities and ingredients that are expensive and are part of complex supply chains are particularly vulnerable. Both herbs and spices fit these criteria perfectly and yet strategies to detect fraudulent adulteration are still far from robust. An FT-IR screening method coupled to data analysis using chemometrics and a second method using LC-HRMS were developed, with the latter detecting commonly used adulterants by biomarker identification. The two tier testing strategy was applied to 78 samples obtained from a variety of retail and on-line sources. There was 100% agreement between the two tests that over 24% of all samples tested had some form of adulterants present. The innovative strategy devised could potentially be used for testing the global supply chains for fraud in many different forms of herbs.

An Evaluation of the Dual Diagnosis (substance use and mental health )Strategy in the South Eastern Trust Workers and Service Users Perceptions of Dual Diagnosis Issues

In the UK it is estimated that over 33% of psychiatric patients with enduring mental illness have a substance misuse problem, whilst over 50 % of clients currently accessing drug and alcohol services have a mental health problem. Between 2003 and 2013 in Northern Ireland, there were 741 recorded suicides by patients who were in contact with mental health services. Of this number, 68% (n=501) had a history of either alcohol or drug misuse or both, resulting in an average of 46 patient suicides per year associated with dual diagnosis (University of Manchester 2015).
The current evaluation examined staff attitudes towards working with dual diagnosis (co-existing difficulties) issues, staff confidence in working with clients with dual diagnosis, workers’ perceptions of the South Eastern dual diagnosis strategy and service user perspectives of dual diagnosis service provision.
The purpose of the evaluation was to provide evidence regarding the following in accordance with the current dual diagnosis strategy;
Staff understanding of the concept of dual diagnosis,
Staff attitudes towards working with dual diagnosis,
Staff confidence in working with individuals, who present with dual diagnosis,
Service users’ perspectives of SE Trust provision for dual diagnosis.
Staff views on the South Eastern Trust Dual Diagnosis Strategy.