Overexpression of neurone glial-related cell adhesion molecule is an independent predictor of poor prognosis in advanced colorectal cancer

A downstream target of the Wnt pathway, neurone glial-related cell adhesion molecule (Nr-CAM) has recently been implicated in human cancer development. However, its role in colorectal cancer (CRC) pathobiology and clinical relevance remains unknown. In this study, we examined the clinical significance of Nr-CAM protein expression in a retrospective series of 428 CRCs using immunohistochemistry and tissue microarrays. Cox proportional hazards regression was used to calculate hazard ratios (HR) of mortality according to various clinicopathological features and molecular markers. All CRC samples were immunoreactive for Nr-CAM protein expression, compared to 10 / 245 (4%) matched normal tissue (P <0.0001). Of 428 CRC samples, 97 (23%) showed Nr-CAM overexpression, which was significantly associated with nodal (P = 0.012) and distant (P = 0.039) metastasis, but not with extent of local invasion or tumor size. Additionally, Nr-CAM overexpression was associated with vascular invasion (P = 0.0029), p53 expression (P = 0.036), and peritoneal metastasis at diagnosis (P = 0.013). In a multivariate model adjusted for other clinicopathological predictors of survival, Nr-CAM overexpression correlated with a significant increase in disease-specific (HR 1.66; 95% confidence interval 1.11-2.47; P = 0.014) and overall mortality (HR 1.57; 95% confidence interval 1.07-2.30; P = 0.023) in advanced but not early stage disease. Notably, 5-fluorouracil-based chemotherapy conferred significant survival benefit to patients with tumors negative for Nr-CAM overexpression but not to those with Nr-CAM overexpressed tumors. In conclusion, Nr-CAM protein expression is upregulated in CRC tissues. Nr-CAM overexpression is an independent marker of poor prognosis among advanced CRC patients, and is a possible predictive marker for non-beneficence to 5-fluorouracil- based chemotherapy.

Polarisation independent split ring frequency selective surface

A frequency selective surface (FSS) is described which exhibits coincident spectral responses for TE and TM polarisation when the FSS operates at 45 degrees incidence. The structure consists of two closely spaced arrays of ring elements with the conductor split at one or two locations to provide independent control of the resonances for the vertical and horizontal field directions. The FSS is designed to diplex two channels separated by an edge of a band ratio of 1.7:1 and yield a common - 10 dB reflection bandwidth of 10.2%. Measured and numerical results are shown to be in good agreement over the frequency range 9-12 GHz.

Complete nucleotide sequence of pVQS1 containing a quinolone resistance determinant from Salmonella enterica serovar Virchow associated with foreign travel

Nalidixic acid-resistant Salmonella enterica serovars Kentucky (n5) and Virchow (n6) cultured from individuals were investigated for the presence of plasmid-mediated quinolone resistance (PMQR) determinants.

PMQR markers and mutations within the quinolone resistance-determining regions of the target genes were investigated by PCR followed by DNA sequencing. Conjugation, plasmid profiling and targeted PCR were performed to demonstrate the transferability of the qnrS1 gene. Subsequently, a plasmid was identified that carried a quinolone resistance marker and this was completely sequenced.

A Salmonella Virchow isolate carried a qnrS1 gene associated with an IncN incompatibility group conjugative plasmid of 40995 bp, which was designated pVQS1. The latter conferred resistance to ampicillin and nalidixic acid and showed sequence similarity in its core region to plasmid R46, whilst the resistance-encoding region was similar to pAH0376 from Shigella flexneri and pINF5 from Salmonella Infantis and contained an IS26 remnant, a complete Tn3 structure, a truncated IS2 element and a qnrS1 marker, followed by IS26. In contrast to pINF5, IS26 was identified immediately downstream of the qnrS1 gene.

This is the first known report of a qnrS1 gene in Salmonella spp. in Switzerland. Analysis of the complete nucleotide sequence of the qnrS1-containing plasmid showed a novel arrangement of this antibiotic resistance-encoding region.

Apoptosis induction by oxidized glycated LDL in human retinal capillary pericytes is independent of activation of MAPK signaling pathways

Pericyte loss is a cardinal feature of early diabetic retinopathy. We previously reported that highly oxidized-glycated low density lipoprotein (HOG-LDL) induces pericyte apoptosis in vitro. In this study, we investigated the role of the mitogen-activated protein kinase (MAPK) signaling pathways in HOG-LDL-induced apoptosis in human pericytes.

Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes

From our linkage study of Irish families with a high density of schizophrenia, we have previously reported evidence for susceptibility genes in regions 5q21-31, 6p24-21, 8p22-21, and 10p15-p11. In this report, we describe the cumulative results from independent genome scans of three a priori random subsets of 90 families each, and from multipoint analysis of all 270 families in ten regions. Of these ten regions, three (13q32, 18p11-q11, and 18q22-23) did not generate scores above the empirical baseline pairwise scan results, and one (6q13-26) generated a weak signal. Six other regions produced more positive pairwise and multipoint results. They showed the following maximum multipoint H-LOD (heterogeneity LOD) and NPL scores: 2p14-13: 0.89 (P = 0.06) and 2.08 (P = 0.02), 4q24-32: 1.84 (P = 0.007) and 1.67 (P = 0.03), 5q21-31: 2.88 (P= 0.0007), and 2.65 (P = 0.002), 6p25-24: 2.13 (P = 0.005) and 3.59 (P = 0.0005), 6p23: 2.42 (P = 0.001) and 3.07 (P = 0.001), 8p22-21: 1.57 (P = 0.01) and 2.56 (P = 0.005), 10p15-11: 2.04 (P = 0.005) and 1.78 (P = 0.03). The degree of 'internal replication' across subsets differed, with 5q, 6p, and 8p being most consistent and 2p and 10p being least consistent. On 6p, the data suggested the presence of two susceptibility genes, in 6p25-24 and 6p23-22. Very few families were positive on more than one region, and little correlation between regions was evident, suggesting substantial locus heterogeneity. The levels of statistical significance were modest, as expected from loci contributing to complex traits. However, our internal replications, when considered along with the positive results obtained in multiple other samples, suggests that most of these six regions are likely to contain genes that influence liability to schizophrenia.

Botanical travel, climate and David Moore’s moral geographies of Europe

During his forty-year curatorship of the Royal Dublin Society's botanical gardens in Glasnevin (1838–1879), David Moore undertook a number of excursions to continental Europe. These served to deepen the networks of plant exchange between Dublin and other botanical institutions and allowed him to examine the relationships between climate, plant survivability and societal development. This paper focuses on two trips taken in the 1860s to Scandinavia and Iberia and charts how Moore situated his experience of these places within a climatic hermeneutic. Moore's understanding of northern and southern Europe was organized around a set of judgments about their relative backwardness or advancement with respect to his experience of home and was seen through the lens of a moral climatology. Moreover, his Scots Presbyterian background and his commitment to natural theology informed his interpretation of the landscapes he encountered in his excursions across Europe.

PTEN Phosphatase-Independent Maintenance of Glandular Morphology in a Predictive Colorectal Cancer Model System

Organotypic models may provide mechanistic insight into colorectal cancer (CRC) morphology. Three-dimensional (3D) colorectal gland formation is regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN) coupling of cell division cycle 42 (cdc42) to atypical protein kinase C (aPKC). This study investigated PTEN phosphatase-dependent and phosphatase-independent morphogenic functions in 3D models and assessed translational relevance in human studies. Isogenic PTEN-expressing or PTEN-deficient 3D colorectal cultures were used. In translational studies, apical aPKC activity readout was assessed against apical membrane (AM) orientation and gland morphology in 3D models and human CRC. We found that catalytically active or inactive PTEN constructs containing an intact C2 domain enhanced cdc42 activity, whereas mutants of the C2 domain calcium binding region 3 membrane-binding loop (M-CBR3) were ineffective. The isolated PTEN C2 domain (C2) accumulated in membrane fractions, but C2 M-CBR3 remained in cytosol. Transfection of C2 but not C2 M-CBR3 rescued defective AM orientation and 3D morphogenesis of PTEN-deficient Caco-2 cultures. The signal intensity of apical phospho-aPKC correlated with that of Na/H exchanger regulatory factor-1 (NHERF-1) in the 3D model. Apical NHERF-1 intensity thus provided readout of apical aPKC activity and associated with glandular morphology in the model system and human colon. Low apical NHERF-1 intensity in CRC associated with disruption of glandular architecture, high cancer grade, and metastatic dissemination. We conclude that the membrane-binding function of the catalytically inert PTEN C2 domain influences cdc42/aPKC-dependent AM dynamics and gland formation in a highly relevant 3D CRC morphogenesis model system.

A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity

Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of monovalent small biologics, are hypothesized to be "fit for purpose" for developing highly specific and potent antagonists of cancer pathways. Here, we describe a monovalent full MET antagonist, PRS-110, displaying efficacy in both ligand-dependent and ligand-independent cancer models. PRS-110 specifically binds to MET with high affinity and blocks hepatocyte growth factor (HGF) interaction. Phosphorylation assays show that PRS-110 efficiently inhibits HGF-mediated signaling of MET receptor and has no agonistic activity. Confocal microscopy shows that PRS-110 results in the trafficking of MET to late endosomal/lysosomal compartments in the absence of HGF. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in ligand-dependent (U87-MG) and ligand-independent (Caki-1) xenograft models. Analysis of MET protein levels on xenograft biopsy samples show a significant reduction in total MET following therapy with PRS-110 supporting its ligand-independent mechanism of action. Taken together, these data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients.

ARTD1/PARP1 Negatively Regulates Glycolysis by Inhibiting Hexokinase 1 Independent of NAD(+) Depletion

ARTD1 (PARP1) is a key enzyme involved in DNA repair through the synthesis of poly(ADP-ribose) (PAR) in response to strand breaks, and it plays an important role in cell death following excessive DNA damage. ARTD1-induced cell death is associated with NAD(+) depletion and ATP loss; however, the molecular mechanism of ARTD1-mediated energy collapse remains elusive. Using real-time metabolic measurements, we compared the effects of ARTD1 activation and direct NAD(+) depletion. We found that ARTD1-mediated PAR synthesis, but not direct NAD(+) depletion, resulted in a block to glycolysis and ATP loss. We then established a proteomics-based PAR interactome after DNA damage and identified hexokinase 1 (HK1) as a PAR binding protein. HK1 activity is suppressed following nuclear ARTD1 activation and binding by PAR. These findings help explain how prolonged activation of ARTD1 triggers energy collapse and cell death, revealing insight into the importance of nucleus-to-mitochondria communication via ARTD1 activation.

'The End of the Irish Poor Law?: Welfare and Healthcare Reform in Revolutionary and Independent Ireland'

This book explores welfare provision in Ireland from the revolutionary period to the 1940s, This work is a significant addition to the growing historiography of twentieth-century Ireland which moves beyond political history. It demonstrates that concepts of respectability, deservingness, and social class where central dynamics in Irish society and welfare practices. This book provides the first major study of local welfare practices, policies, and attitudes towards poverty and the poor in this era.

This book’s exploration of the poor law during revolutionary and independent Ireland provides fresh and original insights into this critical juncture in Irish history. It charts the transformation of the former workhouse system into a network of local authority welfare and healthcare institutions including county homes, county and hospital hospitals, and mother and baby homes. This book provides historical context to current day debates and controversies relating to the institutionalisation of unwed mothers and child welfare policies.

This book undertakes two cases studies on county Kerry and Cork city; also, Irish experiences are placed against the backdrop of wider transnational trends.

This work has multiple audiences and will appeal to those interested in Irish social, culture, economic and political history. This book will also appeal to historians of welfare, the poor law, and the social history of medicine. It also informs modern-day social affairs.

Polarisation independent resistively loaded frequency selective surface absorber with optimum oblique incidence performance

This study presents the design of a thin electromagnetic absorber which exhibits radar backscatter suppression that is independent of the wave polarisation at large incidence angles. The structure consists of a metal backed printed frequency selective surface (FSS), with resistors placed across narrow gaps inserted in the middle of each of the four sides of the conductor loops. The geometry of the periodic array and the value of the vertical and horizontal resistor pairs are carefully chosen to present a real impedance of 377 Ω at the centre operating frequency for both TE and TM polarised waves. Angular sensitivity and reflectivity bandwidth have been investigated for FSS absorber designs with thicknesses of 1, 2 and 3 mm. Each of the three structures was optimised to work at a centre frequency of 10 GHz and an incident angle of 45°. The design methodology is verified by measuring the radar backscatter suppression from a 3 mm (l / 10) thick screen in the frequency range 8–12 GHz. The absorber construction was simplified by filling the four metal gaps in each unit cell with shielding paint, and selecting the ink thickness to give the two required surface resistance values.