Levelling aeromagnetic survey data without the need for tie-lines

A new methodology that levels airborne magnetic data without orthogonal tie-lines is presented in this study. The technique utilizes the low-wavenumber content of the flight-line data to construct a smooth representation of the regional field at a scale appropriate to the line lengths of the survey. Levelling errors are then calculated between the raw flight-line data and the derived regional field through a least squares approach. Minimizing the magnitude of the error, with a first-degree error function, results in significant improvements to the unlevelled data. The technique is tested and demonstrated using three recent airborne surveys

High-resolution genomic and expression profiling reveals 105 putative amplification target genes in pancreatic cancer

Peer reviewe

A Strategy For Identifying Putative Causes Of Gene Expression Variation In Human Cancer

There is often a need to predict the impact of alterations in one variable on another variable. This is especially the case in cancer research, where much effort has been made to carry out large-scale gene expression screening by microarray techniques. However, the causes of this variability from one cancer to another and from one gene to another often remain unknown. In this study we present a systematic procedure for finding genes whose expression is altered by an intrinsic or extrinsic explanatory phenomenon. The procedure has three stages: preprocessing, data integration and statistical analysis. We tested and verified the utility of this approach in a study, where expression and copy number of 13,824 genes were determined in 14 breast cancer samples. The expression of 270 genes could be explained by the variability of gene copy number. These genes may represent an important set of primary, genetically "damaged" genes that drive cancer progression

Alternative splicing discriminates molecular subtypes and has prognostic impact in diffuse large B-cell lymphoma

Effect of alternative splicing (AS) on diffuse large B-cell lymphoma (DLBCL) pathogenesis and survival has not been systematically addressed. Here, we compared differentially expressed genes and exons in association with survival after chemoimmunotherapy, and between germinal center B-cell like (GCB) and activated B-cell like (ABC) DLBCLs. Genome-wide exon array-based screen was performed from samples of 38 clinically high-risk patients who were treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis. The exon expression profile separated the patients according to molecular subgroups and survival better than the gene expression profile. Pathway analyses revealed enrichment of AS genes in inflammation and adhesion-related processes, and in signal transduction, such as phosphatidylinositol signaling system and adenosine triphosphate binding cassette transporters. Altogether, 49% of AS-related exons were protein coding, and domain prediction showed 28% of such exons to include a functional domain, such as transmembrane helix domain or phosphorylation sites. Validation in an independent cohort of 92 DLBCL samples subjected to RNA-sequencing confirmed differential exon usage of selected genes and association of AS with molecular subtypes and survival. The results indicate that AS events are able to discriminate GCB and ABC DLBCLs and have prognostic impact in DLBCL.Peer reviewe

Reproducibility of the computational fluid dynamic analysis of a cerebral aneurysm monitored over a decade

Computational fluid dynamics (CFD) simulations are increasingly utilised to evaluate intracranial aneurysm (IA) haemodynamics to aid in the prediction of morphological changes and rupture risk. However, these models vary and differences in published results warrant the investigation of IA-CFD reproducibility. This study aims to explore sources of intra-team variability and determine its impact on the aneurysm morphology and CFD parameters. A team of four operators were given six sets of magnetic resonance angiography data spanning a decade from one patient with a middle cerebral aneurysm. All operators were given the same protocol and software for model reconstruction and numerical analysis. The morphology and haemodynamics of the operator models were then compared. The segmentation, smoothing factor, inlet and outflow branch lengths were found to cause intra-team variability. There was 80% reproducibility in the time-averaged wall shear stress distribution among operators with the major difference attributed to the level of smoothing. Based on these findings, it was concluded that the clinical applicability of CFD simulations may be feasible if a standardised segmentation protocol is developed. Moreover, when analysing the aneurysm shape change over a decade, it was noted that the co-existence of positive and negative values of the wall shear stress divergence (WSSD) contributed to the growth of a daughter sac

Reply to : Proofreading deficiency in mitochondrial DNA polymerase does not affect total dNTP pools in mouse embryos

Non peer reviewe

High frequency of TTK mutations in microsatellite-unstable colorectal cancer and evaluation of their effect on spindle assembly checkpoint

Frameshift mutations frequently accumulate in microsatellite-unstable colorectal cancers (MSI CRCs) typically leading to downregulation of the target genes due to nonsense-mediated messenger RNA decay. However, frameshift mutations that occur in the 3' end of the coding regions can escape decay, which has largely been ignored in previous works. In this study, we characterized nonsense-mediated decay-escaping frameshift mutations in MSI CRC in an unbiased, genome wide manner. Combining bioinformatic search with expression profiling, we identified genes that were predicted to escape decay after a deletion in a microsatellite repeat. These repeats, located in 258 genes, were initially sequenced in 30 MSI CRC samples. The mitotic checkpoint kinase TTK was found to harbor decay-escaping heterozygous mutations in exon 22 in 59% (105/179) of MSI CRCs, which is notably more than previously reported. Additional novel deletions were found in exon 5, raising the mutation frequency to 66%. The exon 22 of TTK contains an A(9)-G(4)-A(7) locus, in which the most common mutation was a mononucleotide deletion in the A(9) (c.2560delA). When compared with identical non-coding repeats, TTK was found to be mutated significantly more often than expected without selective advantage. Since TTK inhibition is known to induce override of the mitotic spindle assembly checkpoint (SAC), we challenged mutated cancer cells with the microtubule-stabilizing drug paclitaxel. No evidence of checkpoint weakening was observed. As a conclusion, heterozygous TTK mutations occur at a high frequency in MSI CRCs. Unexpectedly, the plausible selective advantage in tumourigenesis does not appear to be related to SAC

Liquorice ingestion attenuates vasodilatation via exogenous nitric oxide donor but not via β2-adrenoceptor stimulation

We examined the effect of liquorice ingestion on haemodynamic responses to exogenous nitric oxide donor (nitroglycerin) and β2-adrenoceptor agonist (salbutamol), and 11β-hydroxysteroid dehydrogenase activity, in 21 volunteers and 21 reference subjects. Haemodynamic data was captured before and after sublingual nitroglycerin (0.25 mg) and inhaled salbutamol (400 μg) during orthostatic challenge utilising radial pulse wave analysis and whole-body impedance cardiography. The recordings were performed at baseline and following two weeks of liquorice intake (290–370 mg/d glycyrrhizin). Urinary cortisone and cortisol metabolites were examined. Liquorice intake elevated aortic systolic and diastolic blood pressure and systemic vascular resistance when compared with the reference group. Following research drug administration the liquorice-induced increase in systemic vascular resistance was observed in the presence of nitroglycerin (pPeer reviewe

Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer

Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite-stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV. Somatic point mutation data from the exome kit-targeted area from 24 exome-sequenced sporadic MSI CRCs and respective normals, and 12 whole-genome-sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs. The MutSigCV ranking identified several well-established MSI CRC driver genes and provided additional evidence for previously proposed CRC candidate genes as well as shortlisted genes that have to our knowledge not been linked to CRC before. Two genes, SMARCB1 and STK38L, were also functionally scrutinized, providing evidence of a tumorigenic role, for SMARCB1 mutations in particular. © 2018 The Authors. Published under the terms of the CC BY 4.0 licensePeer reviewe

DNA methylation signature (SAM40) identifies subgroups of the Luminal A breast cancer samples with distinct survival

Breast cancer patients with Luminal A disease generally have a good prognosis, but among this patient group are patients with good prognosis that are currently overtreated with adjuvant chemotherapy, and also patients that have a bad prognosis and should be given more aggressive treatment. There is no available method for subclassification of this patient group. Here we present a DNA methylation signature (SAM40) that segregates Luminal A patients based on prognosis, and identify one good prognosis group and one bad prognosis group. The prognostic impact of SAM40 was validated in four independent patient cohorts. Being able to subdivide the Luminal A patients may give the two-sided benefit of identifying one subgroup that may benefit from a more aggressive treatment than what is given today, and importantly, identifying a subgroup that may benefit from less treatment.Peer reviewe