Sphingosine Kinase 1 Promotes Malignant Progression in Colon Cancer and Independently Predicts Survival of Patients With Colon Cancer by Competing Risk Approach in South Asian Population

OBJECTIVES: Sphingosine kinase 1 (SphK1) phosphorylates the membrane sphingolipid, sphingosine, to sphingosine-1-phosphate (S1P), an oncogenic mediator, which drives tumor cell growth and survival. Although SphK1 has gained increasing prominence as an oncogenic determinant in several cancers, its potential as a therapeutic target in colon cancer remains uncertain. We investigated the clinical relevance of SphK1 expression in colon cancer as well as its inhibitory effects in vitro.

METHODS: SphK1 expression in human colon tumor tissues was determined by immunohistochemistry and its clinicopathological significance was ascertained in 303 colon cancer cases. The effects of SphK1 inhibition on colon cancer cell viability and the phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway were investigated using a SphK1-selective inhibitor-compound 5c (5c). The cytotoxicity of a novel combination using SphK1 inhibition with the chemotherapeutic drug, 5-fluorouracil (5-FU), was also determined.

RESULTS: High SphK1 expression correlated with advanced tumor stages (AJCC classification). Using a competing risk analysis model to take into account disease recurrence, we found that SphK1 is a significant independent predictor for mortality in colon cancer patients. In vitro, the inhibition of SphK1 induced cell death in colon cancer cell lines and attenuated the serum-dependent PI3K/Akt signaling. Inhibition of SphK1 also enhanced the sensitivity of colon cancer cells to 5-FU.

CONCLUSION: Our findings highlight the impact of SphK1 in colon cancer progression and patient survival, and provide evidence supportive of further development in combination strategies that incorporate SphK1 inhibition with current chemotherapeutic agents to improve colon cancer outcomes.

Northern Ireland and ‘The Troubles’, outlining an innovative approach to nursing/midwifery student teaching and module evaluation

This discussion paper outlines an approach to developing and evaluating an educative programme primarily delivered by lay `citizen trainers’ in educating student nurses, and student midwives to the impact of and experience of extended and extensive civil unrest within their communities (`the Troubles’ ). This is drawn from experience within the Northern Ireland `Troubles’ and all of the citizen trainers were directly affected physically/psychologically. The programme was intended to both educate but primarily to help facilitate student nurses and student midwives to better understanding to experience and context and to more effective care delivery to those affected by/damaged by `the Troubles’. Evaluation of the teaching and learning by the students was significantly positive.

Evidence-based policymaking and the public interest: lessons in legitimacy

This paper draws upon an analysis of regional spatial planning to highlight the centrality of ethics in praxis. In this context political liberalism is particularly helpful in developing a deeper understanding of the activities of those engaged in planning decision making. At the most basic level it demonstrates the importance of not only using shared liberal values as the foundation for public discourses but also achieving consensus through the development of an inclusive evidence base, derived from both lay and professional knowledge. Specifically, political liberalism provides a practical critique, enabling judgments to be made on problems which pervade operational planning practice and an evaluation to be conducted of the dynamic between and actions of participants.

Fasciola hepatica:the effect of the microfilament inhibitor cytochalasin B on the ultrastructure of the adult fluke

The effect of the microfilament inhibitor cytochalasin B (10 and 100 micrograms/ml) on the ultrastructure of adult Fasciola hepatica was determined in vitro by scanning and transmission electron microscopy (SEM, TEM) using both intact flukes and tissue-slice material. SEM revealed that initial swelling of the tegument led to surface blebbing and limited areas of sloughing after 24 h treatment at 100 micrograms/ml. In the tegumental syncytium, basal accumulations of secretory bodies (especially T2s) were evident in the earlier time periods but declined with longer incubations, until few secretory bodies remained in the syncytium overall. Blebbing of the apical plasma membrane and occasional areas of breakdown and sloughing of the tegument were observed over longer periods of treatment at 100 micrograms/ml. In the tegumental cell bodies, the Golgi complexes gradually decreased in size and activity, and few secretory bodies were produced. In the later time periods, the cells assumed abnormal shapes, the cytoplasm shrinking in towards the nucleus. In the vitelline follicles, a random dispersion of shell protein globules was evident within the intermediate-type cells, rather than their being organized into distinct shell globule clusters. Disruption of this process was more severe at the higher concentration of 100 micrograms/ml and again was more evident in tissue-slice material. In the latter, after prolonged (12 h) exposure to cytochalasin B, the intermediate and mature vitelline cells were filled with loosely packed and expanded shell globule clusters, containing few shell protein globules. The mature vitelline cells continued to lay down "yolk" globules and glycogen deposits. Disruption of the network of processes from the nurse cells was evident at the higher concentration of cytochalasin. Spaces began to appear between the vitelline cells and grew larger with progressively longer incubation periods, and the cells themselves assumed abnormal shapes. A number of binucleate stem cells were observed in tissue-slice material at the longest incubation period (12 h).

Contemporary Politics in the Middle East (Cambridge: Polity, 2011 – third edition)

The third edition of this dynamic book has been fully revised and updated to provide a comprehensive introduction to contemporary politics in the Middle East. Purposefully employing a clear thematic structure and including a wide range of case studies, data, visuals and further reading guidance the book explores and analyses the major issues which define the politics of this region of the globe.
Milton-Edwards begins by introducing and explaining key concepts and debates and goes on to outline the impact of colonialism and its legacy, the rise of Arab nationalism and anti-colonial politics. She then examines major political issues affecting the region, such as American foreign policy, political Islam, war and conflict, political economy, democratization, ethnicity and the role of women. The book concludes by highlighting the politics of the region in the twenty-first century and the future challenges it faces. This is a perfect introduction for undergraduates, covering key political, economic and social debates and providing updates and guidance for further reading.

"The genius of this book is that it integrates together the different themes which run through Middle Eastern politics. The coherence of the approach which the author has adopted is indicated by the manner in which she has updated the work in this second edition. Despite the substantial changes which the East has undergone since 9/11 and the 2003 Gulf War, the original line of analysis retains all its force. It remains a key reference for all those who are seeking to understand the region's politics, whether undergraduates, postgraduates or lay readers."
Tim Niblock, Exeter University
"I welcome the new edition of this comprehensive guide to the politics of such an important region of the world. It combines sensible generalizations with useful case studies of particularly important subjects. It is a must for all those who want to understand the complex politics of the modern Middle East."
Roger Owen, Harvard University
"Beverley Milton-Edwards has produced an excellent book, which is both wide-ranging in its coverage and punchy in its arguments. As such, its functions are dual. It works well as a text book, introducing the general reader to key themes in the contemporary region, from oil politics to ethnicity, to women and nationalism. But it also works as a running commentary on key debates, such as the rile of colonialism and the relationship between Islam and democracy. In short, this is a book with attitude."
Philip Robins, St Antony's College, Oxford

An evaluation of palliative care services for cancer patients in the Southern Health and Social Services Board of Northern Ireland.

An interview study of 55 lay carers of people who died from cancer in the Southern Board of Northern Ireland was undertaken using a combination of closed-format and open-ended questions. The aim of the study was to evaluate palliative care services delivered in the last six months of their lives to cancer patients who died either at home or in hospital. Two-thirds of the deaths (36) occurred in the domestic home, 45 of the deceased were admitted as hospital inpatients, and the great majority were in receipt of community nursing (53) and general practitioner (54) services. Open-ended questions were used to allow respondents to give their views about services in some detail and their views about good and bad aspects of services were sought. While they were generally satisfied with services specific areas of difficulty were identified in each aspect of care addressed by the study. The most favourable assessments were made of community nursing with the greatest number of negative comments being made about inpatient hospital care. Differing interests between some of those who were dying and their lay carers were found in two areas: the receipt of help from nonfamily members and the information that the deceased received about their terminal status.

IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes

Insulin signaling to the glomerular podocyte is important for normal kidney function and is implicated in the pathogenesis of diabetic nephropathy (DN). This study determined the role of the insulin receptor substrate 2 (IRS2) in this system. Conditionally immortalized murine podocytes were generated from wild-type (WT) and insulin receptor substrate 2-deficient mice (Irs2−/−). Insulin signaling, glucose transport, cellular motility and cytoskeleton rearrangement were then analyzed. Within the glomerulus IRS2 is enriched in the podocyte and is preferentially phosphorylated by insulin in comparison to IRS1. Irs2−/− podocytes are significantly insulin resistant in respect to AKT signaling, insulin-stimulated GLUT4-mediated glucose uptake, filamentous actin (F-actin) cytoskeleton remodeling and cell motility. Mechanistically, we discovered that Irs2 deficiency causes insulin resistance through up-regulation of the phosphatase and tensin homolog (PTEN). Importantly, suppressing PTEN in Irs2−/− podocytes rescued insulin sensitivity. In conclusion, this study has identified for the first time IRS2 as a critical molecule for sensitizing the podocyte to insulin actions through its ability to modulate PTEN expression. This finding reveals two potential molecular targets in the podocyte for modulating insulin sensitivity and treating DN.

Debating Darwin at the Cape

This paper focuses attention on the fortunes of Darwin's theory among the English-speaking community in Cape Colony during the latter part of the nineteenth century. The paper begins with a review of early encounters with Darwin dwelling particularly on the response of figures like Roderick Noble - professor and editor of the Cape Monthly Magazine, the geologist John Shaw, and Sir Henry Barkly, governor of the colony. Besides these more theoretical responses, Darwin's ideas were also mobilised in a range of scientific inquiries on such subjects as birds and butterflies. But most conspicuous was the use of evolutionary thought-forms in the work of the eminent philologist Wilhelm Bleek, cousin of Darwin's leading German apologist, Ernst Haeckel. The prevailing sense is of a liberal intelligentsia calmly interacting with a novel theory with all due deference. During the 1870s, an address by Langham Dale at the South African Public Library injected new energy into the Darwin discussion. Dale expressed disquiet over some of the anthropological implications of evolution as well as its apparent reductionism, and this stimulated a range of reactions. Several anonymous commentators responded but the most sustained evaluation of Dale's position emanated from the Queenstown physician and later politician, Sir William Bisset Berry. Then, in 1874, copious extracts from John Tyndall's infamous 'Belfast Address' were printed in the Cape Monthly and this added yet further impetus to the debate. Tyndall's seeming materialism bothered a number of readers, not least Hon William Porter, former attorney-general of Cape Colony. To figures like these the materialist extrapolations of radical Darwinians such as Haeckel were deeply disturbing, not just for religious reasons, but because they seemed to destabilise the moral and pedagogic progressivism that lay at the heart of their civilising credo. While reservations about Darwin's proposals were certainly audible, taken in the round Darwinian conversations among the English-speaking literati at the Cape were conducted with liberal sentiments, not least when evolutionary science approached questions of race. For Darwin's writings were seen to confirm a monogenetic account of the origin and unity of the human race, and could readily be called upon to justify the paternalistic ideology that governed colonial affairs.

Remembering 1916: The Easter Rising, the Somme and the Politics of Memory in Ireland

The year 1916 witnessed two events that would profoundly shape both
politics and commemoration in Ireland over the course of the following
century. Although the Easter Rising and the Battle of the Somme were
important historical events in their own right, their significance also lay
in how they came to be understood as iconic moments in the emergence
of Northern Ireland and the Irish Republic. Adopting an interdisciplinary
approach drawing on history, politics, anthropology and cultural
studies, this volume explores how the memory of these two foundational
events has been constructed, mythologised and revised over the course
of the past century. The aim is not merely to understand how the Rising
and Somme came to exert a central place in how the past is viewed in
Ireland, but to explore wider questions about the relationship between
history, commemoration and memory.

HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population

Histone deacetylases (HDACs) are enzymes involved in transcriptional repression. We aimed to examine the significance of HDAC1 and HDAC2 gene expression in the prediction of recurrence and survival in 156 patients with hepatocellular carcinoma (HCC) among a South East Asian population who underwent curative surgical resection in Singapore. We found that HDAC1 and HDAC2 were upregulated in the majority of HCC tissues. The presence of HDAC1 in tumor tissues was correlated with poor tumor differentiation. Notably, HDAC1 expression in adjacent non-tumor hepatic tissues was correlated with the presence of satellite nodules and multiple lesions, suggesting that HDAC1 upregulation within the field of HCC may contribute to tumor spread. Using competing risk regression analysis, we found that increased cancer-specific mortality was significantly associated with HDAC2 expression. Mortality was also increased with high HDAC1 expression. In the liver cancer cell lines, HEP3B, HEPG2, PLC5, and a colorectal cancer cell line, HCT116, the combined knockdown of HDAC1 and HDAC2 increased cell death and reduced cell proliferation as well as colony formation. In contrast, knockdown of either HDAC1 or HDAC2 alone had minimal effects on cell death and proliferation. Taken together, our study suggests that both HDAC1 and HDAC2 exert pro-survival effects in HCC cells, and the combination of isoform-specific HDAC inhibitors against both HDACs may be effective in targeting HCC to reduce mortality.

Strategies to improve the accuracy of vision measurement by teachers in rural Chinese secondary schoolchildren: Xichang Pediatric Refractive Error Study (X-PRES) report no. 6.

OBJECTIVE: To assess and improve the accuracy of lay screeners compared with vision professionals in detecting visual impairment in secondary schoolchildren in rural China. METHODS: After brief training, 32 teachers and a team of vision professionals independently measured vision in 1892 children in Xichang. The children also underwent vision measurement by health technicians in a concurrent government screening program. RESULTS: Of 32 teachers, 28 (87.5%) believed that teacher screening was worthwhile. Sensitivity (93.5%) and specificity (91.2%) of teachers detecting uncorrected presenting visual acuity of 20/40 or less were better than for presenting visual acuity (sensitivity, 85.2%; specificity, 84.8%). Failure of teachers to identify children owning but not wearing glasses and teacher bias toward better vision in children wearing glasses explain the worse results for initial vision. Wearing glasses was the student factor most strongly predictive of inaccurate teacher screening (P < .001). The sensitivity and specificity of the government screening program detecting low presenting visual acuity were 86.7% and 28.7%, respectively. CONCLUSIONS: Teacher vision screening after brief training can achieve accurate results in this setting, and there is support among teachers for screening. Screening of uncorrected rather than presenting visual acuity is recommended in settings with a high prevalence of corrected and uncorrected refractive error. Low specificity in the government program renders it ineffective.

Bouyid v Belgium: The “minimum level of severity” and Human Dignity's Role in Article 3 ECHR

The Grand Chamber of the European Court of Human Rights recently delivered an important judgment on Article 3 ECHR in the case of Bouyid v Belgium. In Bouyid, the Grand Chamber was called upon to consider whether slaps inflicted on a minor and an adult in police custody were in breach of Article 3 ECHR, which provides that ‘No one shall be subjected to torture or to inhuman or degrading treatment or punishment’. Overruling the Chamber judgment in the case, the Grand Chamber ruled by 14 votes to 3 that there had been a substantive violation of Article 3 in that the applicants had been subjected to degrading treatment by members of the Belgian police; it found that there had been a breach of the investigative duty under Article 3 also. In this comment, I focus on the fundamental basis of disagreement between the majority of the Grand Chamber and those who found themselves in dissent, on the question of whether there had been a substantive breach of Article 3. The crux of the disagreement lay in the understanding and application of the test of ‘minimum level of severity’, which the ECtHR has established as decisive of whether a particular form of ill-treatment crosses the Article 3 threshold, seen also in light of Article 3’s absolute character, which makes it non-displaceable – that is, immune to trade-offs of the type applicable in relation to qualified rights such as privacy and freedom of expression. I consider the way the majority of the Grand Chamber unpacked and applied the concept of dignity – or ‘human dignity’ – towards finding a substantive breach of Article 3, and briefly distil some of the principles underpinning the understanding of human dignity emerging in the Court’s analysis.

The Evolution of Extreme Cooperation via Shared Dysphoric Experiences

Willingness to lay down one’s life for a group of non-kin, well documented in the
historical and ethnographic records, represents an evolutionary puzzle. Here we
present a novel explanation for the willingness to fight and die for a group, combining evolutionary theorizing with empirical evidence from real-world human groups. Building on research in social psychology, we develop a mathematical model showing how conditioning cooperation on previous shared experience can allow extreme (i.e., life-threatening) pro-social behavior to evolve. The model generates a series of predictions that we then test empirically in a range of special sample populations (including military veterans, college fraternity/sorority members, football fans, martial arts practitioners, and twins). Our results show that sharing painful experiences produces “identity fusion” – a visceral sense of oneness – more so even than bonds of kinship, in turn motivating extreme pro-group behavior, including willingness to fight and die for the group. These findings have theoretical and practical relevance. Theoretically, our results speak to the origins of human cooperation, as we offer an explanation of extremely costly actions left unexplained by existing models.
Practically, our account of how shared dysphoric experiences produce identity fusion, which produces a willingness to fight and die for a non-kin group, helps us better understand such pressing social issues as suicide terrorism, holy wars, sectarian violence, gang-related violence, and other forms of intergroup conflict.