TBX2 represses CST6 resulting in uncontrolled legumain activity to sustain breast cancer proliferation: a novel cancer-selective target pathway with therapeutic opportunities.

TBX2 is an oncogenic transcription factor known to drive breast cancer proliferation. We have identified the cysteine protease inhibitor Cystatin 6 (CST6) as a consistently repressed TBX2 target gene, co-repressed through a mechanism involving Early Growth Response 1 (EGR1). Exogenous expression of CST6 in TBX2-expressing breast cancer cells resulted in significant apoptosis whilst non-tumorigenic breast cells remained unaffected. CST6 is an important tumor suppressor in multiple tissues, acting as a dual protease inhibitor of both papain-like cathepsins and asparaginyl endopeptidases (AEPs) such as Legumain (LGMN). Mutation of the CST6 LGMN-inhibitory domain completely abrogated its ability to induce apoptosis in TBX2-expressing breast cancer cells, whilst mutation of the cathepsin-inhibitory domain or treatment with a pan-cathepsin inhibitor had no effect, suggesting that LGMN is the key oncogenic driver enzyme. LGMN activity assays confirmed the observed growth inhibitory effects were consistent with CST6 inhibition of LGMN. Knockdown of LGMN and the only other known AEP enzyme (GPI8) by siRNA confirmed that LGMN was the enzyme responsible for maintaining breast cancer proliferation. CST6 did not require secretion or glycosylation to elicit its cell killing effects, suggesting an intracellular mode of action. Finally, we show that TBX2 and CST6 displayed reciprocal expression in a cohort of primary breast cancers with increased TBX2 expression associating with increased metastases. We have also noted that tumors with altered TBX2/CST6 expression show poor overall survival. This novel TBX2-CST6-LGMN signaling pathway, therefore, represents an exciting opportunity for the development of novel therapies to target TBX2 driven breast cancers.

Significance Driven Computation: A Voltage-Scalable, Variation-Aware, Quality-Tuning Motion Estimator

In this paper we present a design methodology for algorithm/architecture co-design of a voltage-scalable, process variation aware motion estimator based on significance driven computation. The fundamental premise of our approach lies in the fact that all computations are not equally significant in shaping the output response of video systems. We use a statistical technique to intelligently identify these significant/not-so-significant computations at the algorithmic level and subsequently change the underlying architecture such that the significant computations are computed in an error free manner under voltage over-scaling. Furthermore, our design includes an adaptive quality compensation (AQC) block which "tunes" the algorithm and architecture depending on the magnitude of voltage over-scaling and severity of process variations. Simulation results show average power savings of similar to 33% for the proposed architecture when compared to conventional implementation in the 90 nm CMOS technology. The maximum output quality loss in terms of Peak Signal to Noise Ratio (PSNR) was similar to 1 dB without incurring any throughput penalty.

From Francis Hutcheson to James McCosh: Irish Presbyterians and Defining the Scottish Philosophy in the Nineteenth Century

This article examines the disputes amongst Irish Presbyterians about the teaching of moral philosophy by Professor John Ferrie in the college department of the Royal Belfast Academical Institution in the early nineteenth century and the substantive philosophical and theological issues that were raised. These issues have largely been ignored by Irish historians, but a discussion of them is of general relevance to historians of ideas as they illuminate a series of broader questions about the definition and development of Scottish philosophy. These are represented in the move from two philosophers who had strong connections with Irish Presbyterianism—Francis Hutcheson, the early eighteenth-century moral sense philosopher and theological moderate from County Down, and James McCosh, nineteenth-century exponent of modified Common Sense philosophy at Queen's College Belfast and a committed evangelical. In particular, this article addresses three important themes—the definition and character of ‘the Scottish philosophy’, the relationship between evangelicalism and Common Sense philosophy, and the process of development and adaptation that occurred in eighteenth-century Scottish thought during the first half of the nineteenth century.

Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Calvinist Absolutism: Archbishop James Ussher and Royal Power

Archbishop James Ussher's manuscript notebooks allow us to observe the making of a Calvinist absolutist and to orientate the archbishop's beliefs about royal power within European Reformed thought as a whole. By 1643, Ussher was preaching a polished and complete theory of absolute royal power, and it is possible to track the development of this political theory forward from his undergraduate days in the 1590s. Throughout his life Ussher engaged anxiously with Reformed theologians abroad, who generally favored limited rather than absolute monarchy. Nevertheless, Ussher shared with these Reformed colleagues both an antipathy to aspects of Aristotelian politics and a commitment to the divine institution of royal power. Finally, despite Ussher's hostility to Laudian innovations in the Irish Church, his heartfelt political beliefs made him a firm supporter of Stuart absolutism throughout the Three Kingdoms.

Essays on James Clarence Mangan: The Man in the Cloak

This volume explores the extraordinary literary achievement of James Clarence Mangan (1803-1849), increasingly recognised as one of the most important Irish writers of the nineteenth century and a crucial influence on later writers such as W.B. Yeats and James Joyce. It is the first collection of essays to focus on Mangan, and features articles by leading scholars in the field (including Jacques Chuto and David Lloyd) as well as contributions from acclaimed contemporary writers, Paul Muldoon and Ciaran Carson. The collection expands existing fields of debate--translation, the supernatural, intertextuality, nationalism, romanticism-- and introduces new ones: Mangan's afterlife in the English literary canon, cosmopolitanism and Weltliteratur, antiquity and futurity, nineteenth-century spiritualism and magical thinking. 'The man in the cloak', one of Mangan's favourite pseudonyms, is still a a resonant soubriquet for a writer who has eluded sustained critical attention, and this volumes restores him to his proper place in European and British, as well as Irish literary history.

Molecular classification of non-invasive breast lesions for personalised therapy and chemoprevention

Breast cancer screening has led to a dramatic increase in the detection of pre-invasive breast lesions. While mastectomy is almost guaranteed to treat the disease, more conservative approaches could be as effective if patients can be stratified based on risk of co-existing or recurrent invasive disease.Here we use a range of biomarkers to interrogate and classify purely non-invasive lesions (PNL) and those with co-existing invasive breast cancer (CEIN). Apart from Ductal Carcinoma In Situ (DCIS), relative homogeneity is observed. DCIS contained a greater spread of molecular subtypes. Interestingly, high expression of p-mTOR was observed in all PNL with lower expression in DCIS and invasive carcinoma while the opposite expression pattern was observed for TOP2A.Comparing PNL with CEIN, we have identified p53 and Ki67 as predictors of CEIN with a combined PPV and NPV of 90.48% and 43.3% respectively. Furthermore, HER2 expression showed the best concordance between DCIS and its invasive counterpart.We propose that these biomarkers can be used to improve the management of patients with pre-invasive breast lesions following further validation and clinical trials. p53 and Ki67 could be used to stratify patients into low and high-risk groups for co-existing disease. Knowledge of expression of more actionable targets such as HER2 or TOP2A can be used to design chemoprevention or neo-adjuvant strategies. Increased knowledge of the molecular profile of pre-invasive lesions can only serve to enhance our understanding of the disease and, in the era of personalised medicine, bring us closer to improving breast cancer care.

Quantification of HER2 heterogeneity in breast cancer-implications for identification of sub-dominant clones for personalised treatment

Breast cancer is a heterogeneous disease, at both an inter- and intra-tumoural level. Appreciating heterogeneity through the application of biomarkers and molecular signatures adds complexity to tumour taxonomy but is key to personalising diagnosis, treatment and prognosis. The extent to which heterogeneity exists, and its interpretation remains a challenge to pathologists. Using HER2 as an exemplar, we have developed a simple reproducible heterogeneity index. Cell-to-cell HER2 heterogeneity was extensive in a proportion of both reported 'amplified' and 'non-amplified' cases. The highest levels of heterogeneity objectively identified occurred in borderline categories and higher ratio non-amplified cases. A case with particularly striking heterogeneity was analysed further with an array of biomarkers in order to assign a molecular diagnosis. Broad biological complexity was evident. In essence, interpretation, depending on the area of tumour sampled, could have been one of three distinct phenotypes, each of which would infer different therapeutic interventions. Therefore, we recommend that heterogeneity is assessed and taken into account when determining treatment options.