Identification of Galanin and Its Receptor GalR1 as Novel Determinants of Resistance to Chemotherapy and Potential Biomarkers in Colorectal Cancer

Purpose: A major factor limiting the effective clinical management of colorectal cancer (CRC) is resistance to chemotherapy. Therefore, the identification of novel, therapeutically targetable mediators of resistance is vital.Experimental design: We used a CRC disease-focused microarray platform to transcriptionally profile chemotherapy-responsive and nonresponsive pretreatment metastatic CRC liver biopsies and in vitro samples, both sensitive and resistant to clinically relevant chemotherapeutic drugs (5-FU and oxaliplatin). Pathway and gene set enrichment analyses identified candidate genes within key pathways mediating drug resistance. Functional RNAi screening identified regulators of drug resistance.

Results: Mitogen-activated protein kinase signaling, focal adhesion, cell cycle, insulin signaling, and apoptosis were identified as key pathways involved in mediating drug resistance. The G-protein-coupled receptor galanin receptor 1 (GalR1) was identified as a novel regulator of drug resistance. Notably, silencing either GalR1 or its ligand galanin induced apoptosis in drug-sensitive and resistant cell lines and synergistically enhanced the effects of chemotherapy. Mechanistically, GalR1/galanin silencing resulted in downregulation of the endogenous caspase-8 inhibitor FLIP(L), resulting in induction of caspase-8-dependent apoptosis. Galanin mRNA was found to be overexpressed in colorectal tumors, and importantly, high galanin expression correlated with poor disease-free survival of patients with early-stage CRC.

Conclusion: This study shows the power of systems biology approaches to identify key pathways and genes that are functionally involved in mediating chemotherapy resistance. Moreover, we have identified a novel role for the GalR1/galanin receptor-ligand axis in chemoresistance, providing evidence to support its further evaluation as a potential therapeutic target and biomarker in CRC. Clin Cancer Res; 18(19); 5412–26. © 2012 AACR.

Premiere of "Spaced Images with Noise and Lines" Performance at the Joinery, Dublin, at at Spatial Music Collective concert. Authors: Lyon, E. Keywords: (Spatial Audio, Electroacoustic Music, Computer Music, Algorithmic Music) Publication date: 07 Oct 2011

Performance at the Joinery, Dublin, at at Spatial Music Collective concert

Docosahexaenoic acid induces an anti-inflammatory profile in lipopolysaccharide-stimulated human THP-1 macrophages more effectively than eicosapentaenoic acid

A number of studies have investigated the effects of fish oil on the production of pro-inflammatory cytokines using peripheral blood mononuclear cell models. The majority of these studies have employed heterogeneous blends of long-chain n-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which preclude examination of the individual effects of LC n-3 PUFA. This study investigated the differential effects of pure EPA and DHA on cytokine expression and nuclear factor kappaB (NF-kappaB) activation in human THP-1 monocyte-derived macrophages. Pretreatment with 100 microM EPA and DHA significantly decreased lipopolysaccharide (LPS)-stimulated THP-1 macrophage tumor necrosis factor (TNF) alpha, interleukin (IL) 1beta and IL-6 production (P

Detection of magnetic dipole lines of Fe XII in the ultraviolet spectrum of the dwarf star ε Eri

We report observations of the dwarf star e Eri (K2V) made with the Space Telescope Imaging Spectrograph (STIS) on the Hubble Space Telescope. The high sensitivity of the STIS instrument has allowed us to detect the magnetic dipole transitions of Fe XII at 1242.00 and 1349 38 Å for the first time in a star other than the Sun. The width of the stronger line at 1242.00 Å has also been measured; such measurements are not possible for the permitted lines of Fe XII in the extreme-ultraviolet. To within the accuracy of the measurements the N v and the Fe XII lines occur at their rest wavelengths. Electron densities and linewidths have been measured from other transition region lines. Together, these can be used to investigate the non-thermal energy flux in the lower and upper transition regions, which is useful in constraining possible heating processes. The Fe XII lines are also present in archival STIS spectra of other G/K-type dwarfs.

Modelling the H Lyman lines in evolved late-type stars

The importance of partial redistribution (PRD) in the modelling of the Lyman a and Lyman ß emission lines of hydrogen in stellar atmospheres is examined using simple atmospheric models of a range of late-type stars. These models represent the subgiant Procyon (F5 IV-V), and the two giants ß Gem (K0 III) and a Tau (K5 III). These stars are selected to span a wide range of surface gravities: 1.25 <log g <4.00. The calculations are performed using the computer code MULTI with the modifications made by Hubeny & Lites. It is found that PRD effects are highly significant, both in the direct prediction of the Lyman line profiles and in the application of hydrostatic equilibrium to calculate the atmospheric electron density in static atmospheric models.

Nebular emission-line profiles of Type Ib/c supernovae - Probing the ejecta asphericity

In order to assess qualitatively the ejecta geometry of stripped-envelope core-collapse supernovae (SNe), we investigate 98 late-time spectra of 39 objects, many of them previously unpublished. We perform a Gauss-fitting of the [O ] ??6300, 6364 feature in all spectra, with the position, full width at half maximum and intensity of the ?6300 Gaussian as free parameters, and the ?6364 Gaussian added appropriately to account for the doublet nature of the [O ] feature. On the basis of the best-fitting parameters, the objects are organized into morphological classes, and we conclude that at least half of all Type Ib/c SNe must be aspherical. Bipolar jet models do not seem to be universally applicable, as we find too few symmetric double-peaked [O ] profiles. In some objects, the [O ] line exhibits a variety of shifted secondary peaks or shoulders, interpreted as blobs of matter ejected at high velocity and possibly accompanied by neutron-star kicks to assure momentum conservation. At phases earlier than ~200 d, a systematic blueshift of the [O ] ??6300, 6364 line centroids can be discerned. Residual opacity provides the most convincing explanation of this phenomenon, photons emitted on the rear side of the SN being scattered or absorbed on their way through the ejecta. Once modified to account for the doublet nature of the oxygen feature, the profile of Mg i] ?4571 at sufficiently late phases generally resembles that of [O ] ??6300, 6364, suggesting negligible contamination from other lines and confirming that O and Mg are similarly distributed within the ejecta. © 2009 RAS.

Distinctive Profile of IsomiR Expression and Novel MicroRNAs in Rat Heart Left Ventricle

MicroRNAs (miRNAs) are single-stranded non-coding RNAs that negatively regulate target gene expression through mRNA cleavage or translational repression. There is mounting evidence that they play critical roles in heart disease. The expression of known miRNAs in the heart has been studied at length by microarray and quantitative PCR but it is becoming evident that microRNA isoforms (isomiRs) are potentially physiologically important. It is well known that left ventricular (patho)physiology is influenced by transmural heterogeneity of cardiomyocyte phenotype, and this likely reflects underlying heterogeneity of gene expression. Given the significant role of miRNAs in regulating gene expression, knowledge of how the miRNA profile varies across the ventricular wall will be crucial to better understand the mechanisms governing transmural physiological heterogeneity. To determinine miRNA/isomiR expression profiles in the rat heart we investigated tissue from different locations across the left ventricular wall using deep sequencing. We detected significant quantities of 145 known rat miRNAs and 68 potential novel orthologs of known miRNAs, in mature, mature* and isomiR formation. Many isomiRs were detected at a higher frequency than their canonical sequence in miRBase and have different predicted targets. The most common miR-133a isomiR was more effective at targeting a construct containing a sequence from the gelsolin gene than was canonical miR-133a, as determined by dual-fluorescence assay. We identified a novel rat miR-1 homolog from a second miR-1 gene; and a novel rat miRNA similar to miR-676. We also cloned and sequenced the rat miR-486 gene which is not in miRBase (v18). Signalling pathways predicted to be targeted by the most highly detected miRNAs include Ubiquitin-mediated Proteolysis, Mitogen-Activated Protein Kinase, Regulation of Actin Cytoskeleton, Wnt signalling, Calcium Signalling, Gap junctions and Arrhythmogenic Right Ventricular Cardiomyopathy. Most miRNAs are not expressed in a gradient across the ventricular wall, with exceptions including miR-10b, miR-21, miR-99b and miR-486.

Distributed passive intermodulation generation in coplanar waveguide transmission lines

A phenomenology of distributed passive intermodulation generation in coplanar waveguide transmission line is presented. The theoretical analysis is based upon the generalised nonlinear transmission line model, which accounts for the coupling of two propagating modes. The case of weak substrate nonlinearity is considered and the model is given qualitative verification through the mapping of passive intermodulation products generated in coplanar waveguide fabricated on a commercial laminate. Implications for future research are discussed. © 2012 IEEE.