Multivariate meta-analysis of proteomics data from human prostate and colon tumours

<p>Abstract</p> <p>Background</p> <p>There is a vast need to find clinically applicable protein biomarkers as support in cancer diagnosis and tumour classification. In proteomics research, a number of methods can be used to obtain systemic information on protein and pathway level on cells and tissues. One fundamental tool in analysing protein expression has been two-dimensional gel electrophoresis (2DE). Several cancer 2DE studies have reported partially redundant lists of differently expressed proteins. To be able to further extract valuable information from existing 2DE data, the power of a multivariate meta-analysis will be evaluated in this work.</p> <p>Results</p> <p>We here demonstrate a multivariate meta-analysis of 2DE proteomics data from human prostate and colon tumours. We developed a bioinformatic workflow for identifying common patterns over two tumour types. This included dealing with pre-processing of data and handling of missing values followed by the development of a multivariate Partial Least Squares (PLS) model for prediction and variable selection. The variable selection was based on the variables performance in the PLS model in combination with stability in the validation. The PLS model development and variable selection was rigorously evaluated using a double cross-validation scheme. The most stable variables from a bootstrap validation gave a mean prediction success of 93% when predicting left out test sets on models discriminating between normal and tumour tissue, common for the two tumour types. The analysis conducted in this study identified 14 proteins with a common trend between the tumour types prostate and colon, i.e. the same expression profile between normal and tumour samples.</p> <p>Conclusions</p> <p>The workflow for meta-analysis developed in this study enabled the finding of a common protein profile for two malign tumour types, which was not possible to identify when analysing the data sets separately.</p

The unique genomic properties of sex-biased genes: Insights from avian microarray data

In order to develop a framework for the analysis of sex-biased genes, we present a characterization of microarray data comparing male and female gene expression in 18 day chicken embryos for brain, gonad, and heart tissue

Fee Arrangements and Fee Shifting: Lessons From the Experience in Ontario

About one-third of oestrogen receptor alpha-positive breast cancer patients treated with tamoxifen relapse. Here we identify the nuclear receptor retinoic acid receptor alpha as a marker of tamoxifen resistance. Using quantitative mass spectrometry-based proteomics, we show that retinoic acid receptor alpha protein networks and levels differ in a tamoxifen-sensitive (MCF7) and a tamoxifen-resistant (LCC2) cell line. High intratumoural retinoic acid receptor alpha protein levels also correlate with reduced relapse-free survival in oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen solely. A similar retinoic acid receptor alpha expression pattern is seen in a comparable independent patient cohort. An oestrogen receptor alpha and retinoic acid receptor alpha ligand screening reveals that tamoxifen-resistant LCC2 cells have increased sensitivity to retinoic acid receptor alpha ligands and are less sensitive to oestrogen receptor alpha ligands compared with MCF7 cells. Our data indicate that retinoic acid receptor alpha may be a novel therapeutic target and a predictive factor for oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen

Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome

Objectives Clinical presentation of primary Sjögren’s syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints. Methods We performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls. Results We found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10−62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS. Conclusion Two subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups.publishedVersio

Faced with inequality: chicken do not have a general dosage compensation of sex-linked genes

<p>Abstract</p> <p>Background</p> <p>The contrasting dose of sex chromosomes in males and females potentially introduces a large-scale imbalance in levels of gene expression between sexes, and between sex chromosomes and autosomes. In many organisms, dosage compensation has thus evolved to equalize sex-linked gene expression in males and females. In mammals this is achieved by X chromosome inactivation and in flies and worms by up- or down-regulation of X-linked expression, respectively. While otherwise widespread in systems with heteromorphic sex chromosomes, the case of dosage compensation in birds (males ZZ, females ZW) remains an unsolved enigma.</p> <p>Results</p> <p>Here, we use a microarray approach to show that male chicken embryos generally express higher levels of Z-linked genes than female birds, both in soma and in gonads. The distribution of male-to-female fold-change values for Z chromosome genes is wide and has a mean of 1.4–1.6, which is consistent with absence of dosage compensation and sex-specific feedback regulation of gene expression at individual loci. Intriguingly, without global dosage compensation, the female chicken has significantly lower expression levels of Z-linked compared to autosomal genes, which is not the case in male birds.</p> <p>Conclusion</p> <p>The pronounced sex difference in gene expression is likely to contribute to sexual dimorphism among birds, and potentially has implication to avian sex determination. Importantly, this report, together with a recent study of sex-biased expression in somatic tissue of chicken, demonstrates the first example of an organism with a lack of global dosage compensation, providing an unexpected case of a viable system with large-scale imbalance in gene expression between sexes.</p

Faced with inequality: chicken do not have a general dosage compensation of sex-linked genes-0

<p><b>Copyright information:</b></p><p>Taken from "Faced with inequality: chicken do not have a general dosage compensation of sex-linked genes"</p><p>http://www.biomedcentral.com/1741-7007/5/40</p><p>BMC Biology 2007;5():40-40.</p><p>Published online 20 Sep 2007</p><p>PMCID:PMC2099419.</p><p></p> (a) soma and (b) gonads of male and female chicken embryos. The red line corresponds to twofold higher hybridization intensity in males than in females

Faced with inequality: chicken do not have a general dosage compensation of sex-linked genes-3

<p><b>Copyright information:</b></p><p>Taken from "Faced with inequality: chicken do not have a general dosage compensation of sex-linked genes"</p><p>http://www.biomedcentral.com/1741-7007/5/40</p><p>BMC Biology 2007;5():40-40.</p><p>Published online 20 Sep 2007</p><p>PMCID:PMC2099419.</p><p></p>change), in (a) soma and (b) gonads. Male autosomal genes are shown in blue and female genes in red, whereas Z-linked genes in males are shown in yellow and in females in green. Error bars correspond to 95% confidence intervals

Faced with inequality: chicken do not have a general dosage compensation of sex-linked genes-1

<p><b>Copyright information:</b></p><p>Taken from "Faced with inequality: chicken do not have a general dosage compensation of sex-linked genes"</p><p>http://www.biomedcentral.com/1741-7007/5/40</p><p>BMC Biology 2007;5():40-40.</p><p>Published online 20 Sep 2007</p><p>PMCID:PMC2099419.</p><p></p> and (b) gonads. Boxes represent the mid 50% of the data (first and third quartiles) and whiskers extend to the minimum and maximum values that are not outliers (defined as >1.5 units away from first and third quartiles. Data from the Z chromosome is shown in red