Exploiting Parallel R in the Cloud with SPRINT

BACKGROUND: Advances in DNA Microarray devices and next-generation massively parallel DNA sequencing platforms have led to an exponential growth in data availability but the arising opportunities require adequate computing resources. High Performance Computing (HPC) in the Cloud offers an affordable way of meeting this need. OBJECTIVES: Bioconductor, a popular tool for high-throughput genomic data analysis, is distributed as add-on modules for the R statistical programming language but R has no native capabilities for exploiting multi-processor architectures. SPRINT is an R package that enables easy access to HPC for genomics researchers. This paper investigates: setting up and running SPRINT-enabled genomic analyses on Amazon’s Elastic Compute Cloud (EC2), the advantages of submitting applications to EC2 from different parts of the world and, if resource underutilization can improve application performance. METHODS: The SPRINT parallel implementations of correlation, permutation testing, partitioning around medoids and the multi-purpose papply have been benchmarked on data sets of various size on Amazon EC2. Jobs have been submitted from both the UK and Thailand to investigate monetary differences. RESULTS: It is possible to obtain good, scalable performance but the level of improvement is dependent upon the nature of algorithm. Resource underutilization can further improve the time to result. End-user’s location impacts on costs due to factors such as local taxation. Conclusions: Although not designed to satisfy HPC requirements, Amazon EC2 and cloud computing in general provides an interesting alternative and provides new possibilities for smaller organisations with limited funds

Hf–Zr anomalies in clinopyroxene from mantle xenoliths from France and Poland: implications for Lu–Hf dating of spinel peridotite lithospheric mantle

Clinopyroxenes in some fresh anhydrous spinel peridotite mantle xenoliths from the northern Massif Central (France) and Lower Silesia (Poland), analysed for a range of incompatible trace elements by laser ablation inductively coupled plasma mass spectrometry, show unusually strong negative anomalies in Hf and Zr relative to adjacent elements Sm and Nd, on primitive mantle-normalised diagrams. Similar Zr–Hf anomalies have only rarely been reported from clinopyroxene in spinel peridotite mantle xenoliths worldwide, and most are not as strong as the examples reported here. Low Hf contents give rise to a wide range of Lu/Hf ratios, which over geological time would result in highly radiogenic εHf values, decoupling them from εNd ratios. The high 176Lu/177Hf could in theory produce an isochronous relationship with 176Hf/177Hf over time; an errorchron is shown by clinopyroxene from mantle xenoliths from the northern Massif Central. However, in a review of the literature, we show that most mantle spinel peridotites do not show such high Lu/Hf ratios in their constituent clinopyroxenes, because they lack the distinctive Zr–Hf anomaly, and this limits the usefulness of the application of the Lu–Hf system of dating to garnet-free mantle rocks. Nevertheless, some mantle xenoliths from Poland or the Czech Republic may be amenable to Hf-isotope dating in the future

Survival after chemotherapy and/or radiotherapy versus self-expanding metal stent insertion in the setting of inoperable esophageal cancer: a case-control study

<p>Abstract</p> <p>Background</p> <p>Our aim was to compare survival of the various treatment modality groups of chemotherapy and/or radiotherapy in relation to SEMS (self-expanding metal stents) in a retrospective case-control study. We have made the hypothesis that the administration of combined chemoradiotherapy improves survival in inoperable esophageal cancer patients.</p> <p>Methods</p> <p>All patients were confirmed histologically as having surgically non- resectable esophageal carcinoma. Included were patients with squamous cell carcinoma, undifferentiated carcinoma as well as Siewert type I--but not type II - esophagogastric junctional adenocarcinoma. The decision to proceed with palliative treatments was taken within the context of a multidisciplinary team meeting and full expert review based on patient's wish, co-morbid disease, clinical metastases, distant metastases, M1 nodal metastases, T4-tumor airway, aorta, main stem bronchi, cardiac invasion, and peritoneal disease. Patients not fit enough to tolerate a radical course of definitive chemo- and/or radiation therapy were referred for self-expanding metal stent insertion. Our approach to deal with potential confounders was to match subjects according to their clinical characteristics (contraindications for surgery) and tumor stage according to diagnostic work-up in four groups: SEMS group (A), Chemotherapy group (B), Radiotherapy group (C), and Chemoradiotherapy group (D).</p> <p>Results</p> <p>Esophagectomy was contraindicated in 155 (35.5%) out of 437 patients presenting with esophageal cancer to the Department of General and Abdominal Surgery of the University Hospital of Mainz, Germany, between November 1997 and November 2007. There were 133 males and 22 females with a median age of 64.3 (43-88) years. Out of 155 patients, 123 were assigned to four groups: SEMS group (A) n = 26, Chemotherapy group (B) n = 12, Radiotherapy group (C) n = 23 and Chemoradiotherapy group (D) n = 62. Mean patient survival for the 4 groups was as follows: Group A: 6.92 ± 8.4 months; Group B: 7.75 ± 6.6 months; Group C: 8.56 ± 9.5 months, and Group D: 13.53 ± 14.7 months. Significant differences in overall survival were associated with tumor histology (<it>P </it>= 0.027), tumor localization (<it>P </it>= 0.019), and type of therapy (<it>P </it>= 0.005), respectively, in univariate analysis. Treatment modality (<it>P </it>= 0.043) was the only independent predictor of survival in multivariate analysis. The difference in overall survival between Group A and Group D was highly significant (<it>P </it>< 0.01) and in favor of Group D. As concerns Group D versus Group B and Group D versus Group C there was a trend towards a difference in overall survival in favor of Group D (<it>P </it>= 0.069 and <it>P </it>= 0.059, respectively).</p> <p>Conclusions</p> <p>The prognosis of inoperable esophageal cancer seems to be highly dependent on the suitability of the induction of patient-specific therapeutic measures and is significantly better, when chemoradiotherapy is applied.</p

Testing the additional predictive value of high-dimensional molecular data

While high-dimensional molecular data such as microarray gene expression data have been used for disease outcome prediction or diagnosis purposes for about ten years in biomedical research, the question of the additional predictive value of such data given that classical predictors are already available has long been under-considered in the bioinformatics literature. We suggest an intuitive permutation-based testing procedure for assessing the additional predictive value of high-dimensional molecular data. Our method combines two well-known statistical tools: logistic regression and boosting regression. We give clear advice for the choice of the only method parameter (the number of boosting iterations). In simulations, our novel approach is found to have very good power in different settings, e.g. few strong predictors or many weak predictors. For illustrative purpose, it is applied to two publicly available cancer data sets. Our simple and computationally efficient approach can be used to globally assess the additional predictive power of a large number of candidate predictors given that a few clinical covariates or a known prognostic index are already available

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Problems in obtaining precise and accurate Sr isotope analysis from geological materials using laser ablation MC-ICPMS

This paper reviews the problems encountered in eleven studies of Sr isotope analysis using laser ablation multicollector inductively coupled plasma mass spectrometry (LA-MC-ICPMS) in the period 1995–2006. This technique has been shown to have great potential, but the accuracy and precision are limited by: (1) large instrumental mass discrimination, (2) laser-induced isotopic and elemental fractionations and (3) molecular interferences. The most important isobaric interferences are Kr and Rb, whereas Ca dimer/argides and doubly charged rare earth elements (REE) are limited to sample materials which contain substantial amounts of these elements. With modern laser (193 nm) and MC-ICPMS equipment, minerals with >500 ppm Sr content can be analysed with a precision of better than 100 ppm and a spatial resolution (spot size) of approximately 100 μm. The LA MC-ICPMS analysis of 87Sr/86Sr of both carbonate material and plagioclase is successful in all reported studies, although the higher 84Sr/86Sr ratios do suggest in some cases an influence of Ca dimer and/or argides. High Rb/Sr (>0.01) materials have been successfully analysed by carefully measuring the 85Rb/87Rb in standard material and by applying the standard-sample bracketing method for accurate Rb corrections. However, published LA-MC-ICPMS data on clinopyroxene, apatite and sphene records differences when compared with 87Sr/86Sr measured by thermal ionisation mass spectrometry (TIMS) and solution MC-ICPMS. This suggests that further studies are required to ensure that the most optimal correction methods are applied for all isobaric interferences

Spontaneous and radiation-induced chromosomal instability and persistence of chromosome aberrations after radiotherapy in lymphocytes from prostate cancer patients

The aim of the study was to compare the spontaneous and ex vivo radiation-induced chromosomal damage in lymphocytes of untreated prostate cancer patients and age-matched healthy donors, and to evaluate the chromosomal damage, induced by radiotherapy, and its persistence. Blood samples from 102 prostate cancer patients were obtained before radiotherapy to investigate the excess acentric fragments and dicentric chromosomes. In addition, in a subgroup of ten patients, simple exchanges in chromosomes 2 and 4 were evaluated by fluorescent in situ hybridization (FISH), before the onset of therapy, in the middle and at the end of therapy, and 1 year later. Data were compared to blood samples from ten age-matched healthy donors. We found that spontaneous yields of acentric chromosome fragments and simple exchanges were significantly increased in lymphocytes of patients before onset of therapy, indicating chromosomal instability in these patients. Ex vivo radiation-induced aberrations were not significantly increased, indicating proficient repair of radiation-induced DNA double-strand breaks in lymphocytes of these patients. As expected, the yields of dicentric and acentric chromosomes, and the partial yields of simple exchanges, were increased after the onset of therapy. Surprisingly, yields after 1 year were comparable to those directly after radiotherapy, indicating persistence of chromosomal instability over this time. Our results indicate that prostate cancer patients are characterized by increased spontaneous chromosomal instability. This instability seems to result from defects other than a deficient repair of radiation-induced DNA double-strand breaks. Radiotherapy-induced chromosomal damage persists 1 year after treatment

A substrate mimic allows high-throughput assay of the FabA protein and consequently the identification of a novel inhibitor of <i>Pseudomonas aeruginosa</i> FabA

The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 223461, Senior Investigator Award WT100209MA (JHN), Swedish Science Council (GS), Wellcome Trust Strategic grant 100476/Z/12/Z (DWG) and National Institutes of Health R01GM095970 (MB). JHN & ADS are Royal Society Wolfson Merit Award holders.Eukaryotes and prokaryotes possess fatty acid synthase (FAS) biosynthetic pathway(s) that comprise iterative chain elongation, reduction, and dehydration reactions. The bacterial FASII pathway differs significantly from human FAS pathways and is a long-standing target for antibiotic development against Gram-negative bacteria due to differences from the human FAS, and several existing antibacterial agents are known to inhibit FASII enzymes. N-acetylcysteamine (NAC) fatty acid thioesters have been used as mimics of the natural acyl carrier protein (ACP) pathway intermediates to assay FASII enzymes, and we now report an assay of FabV from Pseudomonas aeruginosa using (E)-2-decenoyl-NAC. In addition, we have converted an existing UV absorbance assay for FabA, the bifunctional dehydration/epimerization enzyme and key target in the FAS II pathway, into a high throughput enzyme coupled fluorescence assay that has been employed to screen a library of diverse small molecules. With this approach, N-(4-chlorobenzyl)-3-(2-furyl)-1H-1,2,4-triazol-5-amine (N42FTA) was found to competitively inhibit (pIC50 = 5.7 ± 0.2) the processing of 3-hydroxydecanoyl-NAC by P. aeruginosa FabA. N42FTA was shown to be potent in blocking crosslinking of E. coli ACP and FabA, a direct mimic of the biological process. The co-complex structure of N42FTA with P. aeruginosa FabA protein rationalizes affinity and suggests future design opportunities. Employing NAC fatty acid mimics to developing further high throughput assays for individual enzymes in the FASII pathway should aid in the discovery of new antimicrobials.Publisher PDFPeer reviewe