Gene expression and epigenetic discovery screen reveal methylation of SFRP2 in prostate cancer

Aberrant activation of Wnts is common in human cancers, including prostate. Hypermethylation associated transcriptional silencing of Wnt antagonist genes SFRPs (Secreted Frizzled-Related Proteins) is a frequent oncogenic event. The significance of this is not known in prostate cancer. The objectives of our study were to (i) profile Wnt signaling related gene expression and (ii) investigate methylation of Wnt antagonist genes in prostate cancer. Using TaqMan Low Density Arrays, we identified 15 Wnt signaling related genes with significantly altered expression in prostate cancer; the majority of which were upregulated in tumors. Notably, histologically benign tissue from men with prostate cancer appeared more similar to tumor (r = 0.76) than to benign prostatic hyperplasia (BPH; r = 0.57, p < 0.001). Overall, the expression profile was highly similar between tumors of high (≥ 7) and low (≤ 6) Gleason scores. Pharmacological demethylation of PC-3 cells with 5-Aza-CdR reactivated 39 genes (≥ 2-fold); 40% of which inhibit Wnt signaling. Methylation frequencies in prostate cancer were 10% (2/20) (SFRP1), 64.86% (48/74) (SFRP2), 0% (0/20) (SFRP4) and 60% (12/20) (SFRP5). SFRP2 methylation was detected at significantly lower frequencies in high-grade prostatic intraepithelial neoplasia (HGPIN; 30%, (6/20), p = 0.0096), tumor adjacent benign areas (8.82%, (7/69), p < 0.0001) and BPH (11.43% (4/35), p < 0.0001). The quantitative level of SFRP2 methylation (normalized index of methylation) was also significantly higher in tumors (116) than in the other samples (HGPIN = 7.45, HB = 0.47, and BPH = 0.12). We show that SFRP2 hypermethylation is a common event in prostate cancer. SFRP2 methylation in combination with other epigenetic markers may be a useful biomarker of prostate cancer.

The role of secreted frizzled-related protein 2 expression in prostate cancer

AIMS: Improved prostate cancer (PCa)-specific biomarkers are urgently required to distinguish between indolent and aggressive disease, in order to avoid overtreatment. In this study, we investigated the prostatic tissue expression of secreted frizzled-related protein (SFRP)-2.

METHODS AND RESULTS: Following immunohistochemical analysis on PCa tissue microarrays with samples from 216 patients, strong/moderate SFRP-2 expression was observed in epithelial cells of benign prostatic hyperplasia, and negative/weak SFRP-2 expression was observed in the majority of tumour epithelia. However, among Gleason grade 5 carcinomas, 40% showed strong/moderate SFRP-2 expression and 60% showed negative SFRP-2 expression in epithelial cells. Further microscopic evaluation of Gleason grade 5 tumours revealed different morphological patterns, corresponding with differential SFRP-2 expression. The first subgroup (referred to as Type A) appeared to have a morphologically solid growth pattern, whereas the second subgroup (referred to as Type B) appeared to have a more diffuse pattern. Furthermore, 100% (4/4) of Type A patients experienced biochemical recurrence, as compared with 0% (0/6) of Type B patients.

CONCLUSIONS: These results imply: (i) that there is a loss of SFRP-2 expression from benign to malignant prostate glands; and (ii) differential SFRP-2 expression among two possible subgroups of Gleason grade 5 tumours.

The HIF-1alpha C1772T polymorphism may be associated with susceptibility to clinically localised prostate cancer but not with elevated expression of hypoxic biomarkers

We investigated the role of the C1772T polymorphisms in exon 12 of the Hypoxia-inducible factor-1 alpha (HIF-1alpha) gene C1772T genotype in prostate cancer (PCa) and amplification of the hypoxic response. We identified the heterozygous germline CT genotype as an increased risk factor for clinically localised prostate cancer (Odds ratio = 6.2; p < 0.0001). While immunostaining intensity for HIF-1alpha and VEGF was significantly enhanced in 75% of PCa specimens when compared to matched benign specimens (p < 0.0001), the CT genotype did not modulate the kinetics of HIF-1alpha protein expression in hypoxia in vitro, and was not associated with enhanced expression of hypoxic biomarkers. This study provides the first evidence of an increased risk for clinically localised prostate cancer in men carrying the C1772T HIF-1alpha gene polymorphism. Although our results did not suggest an association between expression of hypoxic biomarkers and genotype status, the correlation may merit further investigation.

John Punch, Scotist Holy War, and the Irish Catholic Revolutionary Tradition in the Seventeenth Century

During the 1640s, the Irish Franciscan theologian John Punch taught his theology students in Rome that war against Protestants was made just by their religion alone. Jesuits like Luis de Molina identified the holy war tradition in which Punch stood as a Scotist one, and insisted that the Scotists had confused the natural and supernatural spheres. Among Irishmen, Punch was unusual. The main Irish Catholic revolutionary tradition employed Jesuit and Thomist theory. They argued that the Stuarts had lost the right to rule Ireland for natural reasons, not supernatural ones; because the Stuarts were tyrants, not because they were Protestants.

John Maxwell

Biography of General Sir John Maxwell

Overweight and obesity on the island of Ireland: an estimation of costs

Objectives The increasing prevalence of overweight and obesity worldwide continues to compromise population health and creates a wider societal cost in terms of productivity loss and premature mortality. Despite extensive international literature on the cost of overweight and obesity, findings are inconsistent between Europe and the USA, and particularly within Europe. Studies vary on issues of focus, specific costs and methods. This study aims to estimate the healthcare and productivity costs of overweight and obesity for the island of Ireland in 2009, using both top-down and bottom-up approaches.

Methods Costs were estimated across four categories: healthcare utilisation, drug costs, work absenteeism and premature mortality. Healthcare costs were estimated using Population Attributable Fractions (PAFs). PAFs were applied to national cost data for hospital care and drug prescribing. PAFs were also applied to social welfare and national mortality data to estimate productivity costs due to absenteeism and premature mortality.

Results The healthcare costs of overweight and obesity in 2009 were estimated at €437 million for the Republic of Ireland (ROI) and €127.41 million for NI. Productivity loss due to overweight and obesity was up to €865 million for ROI and €362 million for NI. The main drivers of healthcare costs are cardiovascular disease, type II diabetes, colon cancer, stroke and gallbladder disease. In terms of absenteeism, low back pain is the main driver in both jurisdictions, and for productivity loss due to premature mortality the primary driver of cost is coronary heart disease.

Conclusions The costs are substantial, and urgent public health action is required in Ireland to address the problem of increasing prevalence of overweight and obesity, which if left unchecked will lead to unsustainable cost escalation within the health service and unacceptable societal costs.

Predicting conversion to dementia in a memory clinic: A standard clinical approach compared with an empirically defined clustering method (latent profile analysis) for mild cognitive impairment subtyping

Introduction
Mild cognitive impairment (MCI) has clinical value in its ability to predict later dementia. A better understanding of cognitive profiles can further help delineate who is most at risk of conversion to dementia. We aimed to (1) examine to what extent the usual MCI subtyping using core criteria corresponds to empirically defined clusters of patients (latent profile analysis [LPA] of continuous neuropsychological data) and (2) compare the two methods of subtyping memory clinic participants in their prediction of conversion to dementia.

Methods
Memory clinic participants (MCI, n = 139) and age-matched controls (n = 98) were recruited. Participants had a full cognitive assessment, and results were grouped (1) according to traditional MCI subtypes and (2) using LPA. MCI participants were followed over approximately 2 years after their initial assessment to monitor for conversion to dementia.

Results
Groups were well matched for age and education. Controls performed significantly better than MCI participants on all cognitive measures. With the traditional analysis, most MCI participants were in the amnestic multidomain subgroup (46.8%) and this group was most at risk of conversion to dementia (63%). From the LPA, a three-profile solution fit the data best. Profile 3 was the largest group (40.3%), the most cognitively impaired, and most at risk of conversion to dementia (68% of the group).

Discussion
LPA provides a useful adjunct in delineating MCI participants most at risk of conversion to dementia and adds confidence to standard categories of clinical inference.

John Thompson: Seeing through China

In 1848, Karl Marx predicted that a flow of cheap commodities would be the heavy artillery which would batter down all Chinese walls and open up the country to the west (Marx, 1978, p. 477). The Scottish photographer John Thomson (1837-1921) was both chronicler of and participant in the early moments of this process. Thomson was a commercial photographer who first arrived in the Far East in 1862. He earned the moniker of 'China' in a decade-long stay during which he photographed what he considered to be the key aspects of its culture and landscape. In this body of work, Illustrations of China and its People (first published in 1874) is perhaps the most comprehensive. It explores, through two hundred photographs and accompanying texts, a series of phenomena from the macro-scale of landscape, infrastructure and industry to the smaller scales of streetscapes, domestic spaces, individual portraits, and other details of everyday life. Despite his own description of the volumes as encyclopedic, Illustrations is geographically quite limited. Thomson's explorations into the hinterland proceed up the country’s principal rivers from those coastal ports which had already been wrested into western hands during the Opium Wars (of the 1840s) and subsequently opened up to trade. This is perhaps one of the reasons why Illustrations has been described as an explicitly colonial text, a guide-book for the prospective settler whose content offered the strategic knowledge of land, culture and natural resources necessary if the territorial advantages of the coastal periphery were to extended to the interior (Jeffrey, 1981, p. 64). It can also be argued, however, that Thomson’s volume offered justification for a potential colonial presence. Faced with a civilization whose history was as sophisticated as the west, it depicts a culture that is static and moribund, its addiction to traditional values an impediment to progress. While this is perhaps most explicit in the texts of Illustrations of China, it can also be seen in the images whose uniform chemical rendering also serves to make an essentially diverse culture seem homogenous. Yet it is these images that distinguish Illustrations from previous attempts to collate China’s culture and landscape. Here, the mechanical precision of his camera captures a reality that often subverts the colonial narrative, confounding stereotypes as Thomson’s mass-produced images allow another China to emerge.

In the Shadows of the Old Town: Thomas Anna and 19th-century Glasgow

In 1858, a volume entitled Midnight Scenes and Social Photographs – being sketches of life in the streets, wynds and dens of the city of Glasgow was published under the pseudonym of ‘Shadow’ by Alexander Brown, a Glaswegian flâneur and reformer. Its frontispiece is an etching which depicts a theatre-like proscenium arch whose curtains have been withdrawn to reveal to the audience all the poverty, destitution and disorder that one was likely to find after dark in the insalubrious quarters of the city. At the extreme left-hand side, partly obscured by the curtain a silhouetted figure stands behind an unwieldy camera perched on a tripod. Distinctly unaffected by the mêlée, an arm is calmly raised and a finger precisely arched in the moment before the shutter is clicked and the scene committed to record. The volume, however, relies exclusively on textual descriptions to evoke the underside of the city and contains no photographs at all. Instead, the use of the word photograph in the title can be understood as a metaphor for detached scientific objectivity, a quality much celebrated by nineteenth-century reformers and investigators of social ills. As it happened, a decade after Shadow disappeared into the labyrinthine back-lands of Old Town Glasgow, he was followed there by a real photographer. In 1868, Thomas Annan was commissioned by the City Improvements Trust to take photographs of the Old Town in its last moments of existence before it was pulled down under a series of legislative acts. But perhaps paradoxically, given Shadow’s faith in the analytical properties of photography, Annan’s work seems to refute much of the material contained in Midnight Scenes and other similar tracts. Instead of the dens, shebeens, labyrinths and rowdy crowds described by Shadow, Annan’s depictions of the Old Town convey a static, calm environment, one which is often sparsely inhabited by a curious but apparently orderly population.

Taking account of the sensational tendencies of many reformists’ texts, this paper investigates the discrepancies between the two representations, focussing in particular on the constraints which operated on Annan during his commission. It argues that Annan’s compositions – which became very influential on other 19th century photographers of everyday life such as John Thomson or Jacob Riis – far from being dispassionate analytical works, emerged as a result of a matrix of factors which included: photographic and artistic precedents; Annan’s own predilections as a photographer; technological limitations; the nature of the commission from the City Improvements Trust and political climate in which it was given; the medieval urban fabric in which he had to operate; and, perhaps, most importantly, the identity of the Old Towns inhabitants themselves.