Empirical Bayes accomodation of batch-effects in microarray data using identical replicate reference samples: application to RNA expression profiling of blood from Duchenne muscular dystrophy patients

<p>Abstract</p> <p>Background</p> <p>Non-biological experimental error routinely occurs in microarray data collected in different batches. It is often impossible to compare groups of samples from independent experiments because batch effects confound true gene expression differences. Existing methods can correct for batch effects only when samples from all biological groups are represented in every batch.</p> <p>Results</p> <p>In this report we describe a generalized empirical Bayes approach to correct for cross-experimental batch effects, allowing direct comparisons of gene expression between biological groups from independent experiments. The proposed experimental design uses identical reference samples in each batch in every experiment. These reference samples are from the same tissue as the experimental samples. This design with tissue matched reference samples allows a gene-by-gene correction to be performed using fewer arrays than currently available methods. We examine the effects of non-biological variation within a single experiment and between experiments.</p> <p>Conclusion</p> <p>Batch correction has a significant impact on which genes are identified as differentially regulated. Using this method, gene expression in the blood of patients with Duchenne Muscular Dystrophy is shown to differ for hundreds of genes when compared to controls. The numbers of specific genes differ depending upon whether between experiment and/or between batch corrections are performed.</p

Using appreciative inquiry to develop, implement and evaluate a multi-organisation ‘Cultivating Compassion’ programme for health professionals and support staff

The ‘Cultivating Compassion’ project was developed in response to a research and innovation call relating to compassion training for National Health Service staff in the South East of England. The project aims included the following: the use of Appreciative Inquiry to develop, implement and evaluate a sustainable and evidence-based programme of compassion awareness training through engaging with a diverse group of health professionals and support staff; an evaluation of a ‘train the trainers’ approach; and an evaluation of ‘compassion lead’ roles and a multi-modal compassion toolkit. The project team included academics from two universities and one medical school, NHS staff from three separate organisations and service users. The participants recruited to the study included doctors, nurses, receptionists, chaplains and others working in close contact with service users from within four NHS organisations in the South East of England. The main findings from the project using thematic analysis from participant focus groups and interviews identified project enablers and inhibitors, the value of project resources, and shifts in perspectives. Project conclusions highlighted the importance of effective senior-level support and organisational leadership in cultivating compassion within a healthcare organisation and the importance of the integration of compassion-promoting resources within existing staff development initiatives

Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions.

We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies

Self-Assembly of Linear Arrays of Semiconductor Nanoparticles on Carbon Single-Walled Nanotubes †

Ligand-stabilized nanocrystals (NCs) were strongly bound to the nanotube surfaces by simple van der Waals forces. Linear arrays of CdSe and InP quantum dots were formed by self-assembly using the grooves in bundles of carbon single-walled nanotubes (SWNTs) as a one-dimensional template. A simple geometrical model explains the ordering in terms of the anisotropic properties of the nanotube surface. CdSe quantum rods were also observed to self-organize onto SWNTs with their long axis parallel to the nanotube axis. This approach offers a route to the formation of ordered NC/SWNT architectures that avoids problems associated with surface derivatization. Both semiconductor quantum dots (QDs) 1 and carbon singlewalled nanotubes (SWNTs) 2 possess interesting and potentially useful optical and electronic properties due to their nanoscale structures. In the case of QDs, quantum confinement in three dimensions produces a size-dependent modification of the electronic band structure, resulting in the formation of discrete electronic states. QDs exhibit unique behaviors such as efficient photoluminescence and photon up-conversion, slowed relaxation and cooling of hot carriers, enhanced lasing, and carrier multiplication via impact ionization. 3 SWNTs, however, consist of sp 2 -hybridized carbon atoms that form the walls of nanometer-wide, seamless cylinders. Past efforts to attach semiconductor nanocrystals (NCs) to nanotubes have focused on forming chemical attachments between the two different nanostructures. In this approach, defects in the nanotube lattice, i.e., any site where the sp 2 -bonded carbon network is broken, are used as sites for chemical bond formation. Such defects are typically present after acid-based purification methods or may be specifically introduced by chemical derivatization. In this paper, we report the formation of organized, onedimensional (1-D) arrays of semiconductor QDs by van der Waals (vdW) adsorption onto SWNTs. Two representative II-VI and the III-V semiconductor NCs, CdSe and InP, respectively, demonstrated linear ordering when adsorbed from nonaqueous colloidal solutions onto high-purity, low-defectdensity SWNTs. The tendency to form linear arrays was greatest when tube-tube alignment was relatively good within bundles and when the QDs were relatively large. The edge-to-edge (ee) separation distance between QDs in the 1-D arrays was ∼18 Å for both the InP and the CdSe QDs, indicating that QD-QD separation is governed by the thickness of the ligand shells, as is the case in two-and three-dimensional QD arrays

Blood pressure self-monitoring in pregnancy: examining feasibility in a prospective cohort study

Background: Raised blood pressure (BP) affects approximately 10% of pregnancies worldwide, and a high proportion of affected women develop pre-eclampsia. This study aimed to evaluate the feasibility of self-monitoring of BP in pregnancy in women at higher risk of pre-eclampsia. Methods: This prospective cohort study of self-monitoring BP in pregnancy was carried out in two hospital trusts in Birmingham and Oxford and thirteen primary care practices in Oxfordshire. Eligible women were those defined by the UK National Institute for Health and Care Excellence (NICE) guidelines as at higher risk of pre-eclampsia. A total of 201 participants were recruited between 12 and 16 weeks of pregnancy and were asked to take two BP readings twice daily three times a week through their pregnancy. Primary outcomes were recruitment, retention and persistence of self-monitoring. Study recruitment and retention were analysed with descriptive statistics. Survival analysis was used to evaluate the persistence of self-monitoring and the performance of self-monitoring in the early detection of gestational hypertension, compared to clinic BP monitoring. Secondary outcomes were the mean clinic and self-monitored BP readings and the performance of self-monitoring in the detection of gestational hypertension and pre-eclampsia compared to clinic BP. Results: Of 201 women recruited, 161 (80%) remained in the study at 36 weeks or to the end of their pregnancy, 162 (81%) provided any home readings suitable for analysis, 148 (74%) continued to self-monitor at 20 weeks and 107 (66%) at 36 weeks. Self-monitored readings were similar in value to contemporaneous matched clinic readings for both systolic and diastolic BP. Of the 23 who developed gestational hypertension or pre-eclampsia and self-monitored, 9(39%) had a raised home BP prior to a raised clinic BP. Conclusions: Self-monitoring of BP in pregnancy is feasible and has potential to be useful in the early detection of gestational hypertensive disorders but maintaining self-monitoring throughout pregnancy requires support and probably enhanced training

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment