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.

An accelerated method of developing DBT projects using CDIO partner institutions as parallel processors

The cycle of the academic year impacts on efforts to refine and improve major group design-build-test (DBT) projects since the time to run and evaluate projects is generally a full calendar year. By definition these major projects have a high degree of complexity since they act as the vehicle for the application of a range of technical knowledge and skills. There is also often an extensive list of desired learning outcomes which extends to include professional skills and attributes such as communication and team working. It is contended that student project definition and operation, like any other designed product, requires a number of iterations to achieve optimisation. The problem however is that if this cycle takes four or more years then by the time a project’s operational structure is fine tuned it is quite possible that the project theme is no longer relevant. The majority of the students will also inevitably experience a sub-optimal project experience over the 5 year development period. It would be much better if the ratio were flipped so that in 1 year an optimised project definition could be achieved which had sufficient longevity that it could run in the same efficient manner for 4 further years. An increased number of parallel investigators would also enable more varied and adventurous project concepts to be examined than a single institution could undertake alone in the same time frame.
This work-in-progress paper describes a parallel processing methodology for the accelerated definition of new student DBT project concepts. This methodology has been devised and implemented by a number of CDIO partner institutions in the UK & Ireland region. An agreed project theme was operated in parallel in one academic year with the objective of replacing a multi-year iterative cycle. Additionally the close collaboration and peer learning derived from the interaction between the coordinating academics facilitated the development of faculty teaching skills in line with CDIO standard 10.

Dialogicality in university classroom talk

University classroom talk is a collaborative struggle to make meaning. Taking the perspectival nature of interaction as central, this paper presents an investigation of the genre of spoken academic discourse and in particular the types of activities which are orientated to the goal of collaborative ideas or tasks, such as seminars, tutorials, workshops. The purpose of the investigation was to identify examples of dialogicality through an examination of stance-taking. The data used in this study is a spoken corpus of academic English created from recordings of a range of subject discipline classrooms at a UK university. A frequency-based approach to recurrent word sequences (lexical bundles) was used to identify signals of epistemic and attitudinal stance and to initiate an exploration of the features of elaboration. Findings of quantitative and qualitative analyses reveal some similarities and differences between this study and those of US based classroom contexts in relation to the use and frequency of lexical bundles. Findings also highlight the process that elaboration plays in grounding perspectives and negotiating alignment of interactants. Elaboration seems to afford the space for the enactment of student stance in relation to the tutor embodiment of discipline knowledge.

UNITALK: a corpus of university classroom talk

This is a dataset of recordings and transcriptions of spoken English collected from a range of university classrooms. UNITALK is a modest-sized untagged synchronic specialized full-text corpus of spoken academic discourse collected from fifteen university classrooms. UNITALK was designed to study the genre of small group teaching contexts across academic divisions and subject disciplines and specifically designed to study those teaching events whose goal is to work on collaborative ideas or tasks. The corpus is over 100,000 words and can be used to investigate academic language use and small group university teaching and learning contexts.

'You' and 'I' in university seminars and spoken learner discourse

You and I may be little words but they do a great deal. In spoken discourse they reference shared knowledge and mark stance. In pedagogical contexts, they maintain relations in teacher-student discourse. However, language classrooms may rarely explore this array of pragmatic meanings. A lack of awareness of the variety of these functions may be problematic for learners when seeking to construct interpersonal relations and operate successfully in particular spoken contexts. This paper presents a study of you and I in two spoken corpora: a corpus of English language learner task talk and a corpus of university seminar talk. Findings illustrate different patterns of I and you between the two corpora: I and you have a higher rate of occurrence in learner discourse, and pronoun repetition is more frequent in learner discourse, though it does not account for the higher rate of you and I. These findings suggest that language learner task talk displays more features tied to speech production and self-regulation and fewer features associated with attempting to point to the informational space of others, a key feature of university classroom talk. This paper concludes by outlining pedagogical applications to overcome features perceived as disfluent.

What is the learning in games-based learning?

This chapter explores the nature of “learning” in games-based learning and the cognitive and motivational processes that might underpin that learning by drawing on psychological theories and perspectives. Firstly, changing conceptions of learning over the last few decades are reviewed. This is described in relation to the changes in formal learning theories and connections made between learning theory and GBL. Secondly, the chapter reviews empirical research on the learning outcomes that have been identified for GBL, with specific focus on cognitive benefits, school attainment, collaborative working, and the motivational and engaging appeal of games. Finally, an overview of the dominant theoretical perspectives/findings mostly associated with GBL is presented in an attempt to broaden understanding of the potential for GBL in the classroom.

The prognostic significance of the aberrant extremes of p53 immunophenotypes in breast cancer

Aims: The utility of p53 as a prognostic assay has been elusive. The aims of this study were to describe a novel, reproducible scoring system and assess the relationship between differential p53 immunohistochemistry (IHC) expression patterns, TP53 mutation status and patient outcomes in breast cancer.

Methods and Results: Tissue microarrays were used to study p53 IHC expression patterns: expression was defined as extreme positive (EP), extreme negative (EN), and non-extreme (NE; intermediate patterns). Overall survival (OS) was used to define patient outcome. A representative subgroup (n = 30) showing the various p53 immunophenotypes was analysed for TP53 hotspot mutation status (exons 4-9). Extreme expression of any type occurred in 176 of 288 (61%) cases. As compared with NE expression, EP expression was significantly associated (P = 0.039) with poorer OS. In addition, as compared with NE expression, EN expression was associated (P = 0.059) with poorer OS. Combining cases showing either EP or EN expression better predicted OS than either pattern alone (P = 0.028). This combination immunophenotype was significant in univariate but not multivariate analysis. In subgroup analysis, six substitution exon mutations were detected, all corresponding to extreme IHC phenotypes. Five missense mutations corresponded to EP staining, and the nonsense mutation corresponded to EN staining. No mutations were detected in the NE group.

Conclusions: Patients with extreme p53 IHC expression have a worse OS than those with NE expression. Accounting for EN as well as EP expression improves the prognostic impact. Extreme expression positively correlates with nodal stage and histological grade, and negatively with hormone receptor status. Extreme expression may relate to specific mutational status.

Walking Exercise for Chronic Musculoskeletal Pain: Systematic Review and Meta-Analysis

Objective: To systematically review the evidence examining effects of walking interventions on pain and self-reported function in individuals with chronic musculoskeletal pain.
Data Sources: Six electronic databases (Medline, CINAHL, PsychINFO, PEDro, Sport Discus and the Cochrane Central Register of Controlled Trials) were searched from January 1980 up to March 2014.
Study Selection: Randomized and quasi-randomized controlled trials in adults with chronic low back pain, osteoarthritis or fibromyalgia comparing walking interventions to a non-exercise or non-walking exercise control group.
Data Extraction: Data were independently extracted using a standardized form. Methodological quality was assessed using the United States Preventative Services Task Force (USPSTF) system.
Data Synthesis: Twenty-six studies (2384 participants) were included and suitable data from 17 were pooled for meta-analysis with a random effects model used to calculate between group mean differences and 95% confidence intervals. Data were analyzed according to length of follow-up (short-term: ≤8 weeks post randomization; medium-term: >2 months - 12 months; long-term: > 12 months). Interventions were associated with small to moderate improvements in pain at short (mean difference (MD) -5.31, 95% confidence interval (95% CI) -8.06 to -2.56) and medium-term follow-up (MD -7.92, 95% CI -12.37 to -3.48). Improvements in function were observed at short (MD -6.47, 95% CI -12.00 to -0.95), medium (MD -9.31, 95% CI -14.00 to -4.61) and long-term follow-up (MD -5.22, 95% CI 7.21 to -3.23).
Conclusions: Evidence of fair methodological quality suggests that walking is associated with significant improvements in outcome compared to control interventions but longer-term effectiveness is uncertain. Using the USPSTF system, walking can be recommended as an effective form of exercise or activity for individuals with chronic musculoskeletal pain but should be supplemented with strategies aimed at maintaining participation. Further work is also required examining effects on important health related outcomes in this population in robustly designed studies.

Fit for Purpose?:Challenges for Irish Public Administration and Priorities for Public Service Reform

The depth of the current economic and fiscal crisis has raised concerns about the Irish political and administrative system, and prompted calls for fundamental reform of our structures of public governance. Both the state and its financial system are reliant on international support. This crisis requires a coherent response from our public administration. There is recognition that this change cannot simply be a repeat or extension of the public service reform programmes of the past. It will need to be more radical than this. Over the coming years, the numbers employed in the public service will continue to fall and expenditure will need to be restrained, targeted and prioritised. The Public Service Agreement 2010-2014 (the Croke Park Agreement) sets out a framework for change. But there is a need to look beyond the agreement to consider more fundamentally the future role of public administration in the context of the new economic and social dispensation in Ireland. Our public services need to adapt to this new environment if they are to continue to be fit for purpose.

In this paper we set out the main challenges facing public administration and where we see reform as vital. We note what changes have taken place to date, including experience with previous reform efforts, and outline what should happen next. Where appropriate, we draw on national and international practice to provide exemplars of change.

Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression

The oncogenic role of WNT is well characterized. Wntless (WLS) (also known as GPR177, or Evi), a key modulator of WNT protein secretion, was recently found to be highly overexpressed in malignant astrocytomas. We hypothesized that this molecule may be aberrantly expressed in other cancers known to possess aberrant WNT signaling such as ovarian, gastric, and breast cancers. Immunohistochemical analysis using a TMA platform revealed WLS overexpression in a subset of ovarian, gastric, and breast tumors; this overexpression was associated with poorer clinical outcomes in gastric cancer (P=0.025). In addition, a strong correlation was observed between WLS expression and human epidermal growth factor receptor 2 (HER2) overexpression. Indeed, 100% of HER2-positive intestinal gastric carcinomas, 100% of HER2-positive serous ovarian carcinomas, and 64% of HER2-positive breast carcinomas coexpressed WLS protein. Although HER2 protein expression or gene amplification is an established predictive biomarker for trastuzumab response in breast and gastric cancers, a significant proportion of HER2-positive tumors display resistance to trastuzumab, which may be in part explainable by a possible mechanistic link between WLS and HER2.

Automated tumour annotation and analysis for molecular pathology using TissueMark (R)

Objective: Molecular pathology relies on identifying anomalies using PCR or analysis of DNA/RNA. This is important in solid tumours where molecular stratification of patients define targeted treatment. These molecular biomarkers rely on examination of tumour, annotation for possible macro dissection/tumour cell enrichment and the estimation of % tumour. Manually marking up tumour is error prone. Method: We have developed a method for automated tumour mark-up and % cell calculations using image analysis called TissueMark® based on texture analysis for lung, colorectal and breast (cases=245, 100, 100 respectively). Pathologists marked slides for tumour and reviewed the automated analysis. A subset of slides was manually counted for tumour cells to provide a benchmark for automated image analysis. Results: There was a strong concordance between pathological and automated mark-up (100 % acceptance rate for macro-dissection). We also showed a strong concordance between manually/automatic drawn boundaries (median exclusion/inclusion error of 91.70 %/89 %). EGFR mutation analysis was precisely the same for manual and automated annotation-based macrodissection. The annotation accuracy rates in breast and colorectal cancer were 83 and 80 % respectively. Finally, region-based estimations of tumour percentage using image analysis showed significant correlation with actual cell counts. Conclusion: Image analysis can be used for macro-dissection to (i) annotate tissue for tumour and (ii) estimate the % tumour cells and represents an approach to standardising/improving molecular diagnostics.

Docking the value of pigmeat? Prevalence and financial implications of welfare lesions in Irish slaughter pigs.

Expansion of the meat inspection process to incorporate animal-based welfare measurements could contribute towards significant improvements in pig (Sus scrofa domesticus) welfare and farm profitability. This study aimed to determine the prevalence of different welfare-related lesions on the carcase and their relationship with carcase condemnations (CC) and carcase weight (CW). The financial implications of losses associated with CC and CW reductions related to the welfare lesions were also estimated. Data on tail lesions, loin bruising and bursitis, CW and condemnation/trimming outcome (and associated weights) were collected for 3,537slaughter pigs (mean [± SEM] carcase weight: 79.2 [± 8.82] kg). Overall, 72.5% of pigs had detectable tail lesions, whilst 16.0 and 44.0% were affected by severe loin bruising and hind limb bursitis, respectively. There were 2.5% of study carcases condemned and a further 3.3% were trimmed. The primary cause of CC was abscessation. While tail lesion severity did not increase the risk of abscessation, it was significantly associated with CC. Male pigs had a higher risk of tail lesions and of CC. The financial loss to producers associated with CC and trimmings was estimated at €1.10 per study pig. CW was reduced by up to 12 kg in cases of severe tail lesions. However, even mild lesions were associated with a significant reduction in CW of 1.2 kg. The value of the loss in potential CW associated with tail lesions was €0.59 per study pig. Combined with losses attributable to CC and trimmings this represented a loss of 43% of the profit margin per pig, at the time of the study, attributable to tail biting. These findings illustrate the magnitude of the impact of tail biting on pig welfare and on profitability of the pig industry. They also emphasise the potential contribution that the inclusion of welfare parameters at meat inspection could make to pig producers in informing herd health and welfare management plans.

Development of a Polymer-carbon Nanotubes based Economic Solar Collector

A low cost solar collector was developed by using polymeric components as opposed to metal and glass components of traditional solar collectors. In order to utilize polymers for the absorber of the solar collector, Carbon Nanotubes (CNT) has been added as a filler to improve the thermal conductivity and the solar absorptivity of polymers. The solar collector was designed as a multi-layer construction with considering the economic manufacturing. Through the mathematical heat transfer analysis, the performance and characteristics of the designed solar collector have been estimated. Furthermore, the prototypes of the proposed system were built and tested at a state-of-the-art solar simulator facility to evaluate the actual performance of the developed solar collector. The cost-effective polymer-CNT solar collector, which achieved efficiency as much as that of a conventional glazed flat plate solar panel, has been successfully developed.