Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia

FLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL-3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD mutations. PRL-3 expression is upregulated by the FLT3-STAT5 signalling pathway in leukaemia cells, leading an activation of AP-1 transcription factors via ERK and JNK pathways. PRL-3-depleted AML cells showed a significant decrease in cell growth. Clinically, high PRL-3 mRNA expression was associated with FLT3-ITD mutations in four independent AML datasets with 1158 patients. Multivariable Cox-regression analysis on our Cohort 1 with 221 patients identified PRL-3 as a novel prognostic marker independent of other clinical parameters. Kaplan-Meier analysis showed high PRL-3 mRNA expression was significantly associated with poorer survival among 491 patients with normal karyotype. Targeting PRL-3 reversed the oncogenic effects in FLT3-ITD AML models in vitro and in vivo. Herein, we suggest that PRL-3 could serve as a prognostic marker to predict poorer survival and as a promising novel therapeutic target for AML patients.

The effect of socioeconomic deprivation on corneal graft survival in the United Kingdom

Objective: To investigate the effect of socioeconomic deprivation on cornea graft survival in the United Kingdom.

Design: Retrospective cohort study.

Participants: All the recipients (n = 13?644) undergoing their first penetrating keratoplasty (PK) registered on the United Kingdom Transplant Registry between April 1999 and March 2011 were included.

Methods: Data of patients' demographic details, indications, graft size, corneal vascularization, surgical complication, rejection episodes, and postoperative medication were collected at the time of surgery and 1, 2, and 5 years postoperatively. Patients with endophthalmitis were excluded from the study. Patients' home postcodes were used to determine the socioeconomic status using a well-validated deprivation index in the United Kingdom: A Classification of Residential Neighborhoods (ACORN). Kaplan–Meier survival and Cox proportional hazards regression were used to evaluate the influence of ACORN categories on 5-year graft survival, and the Bonferroni method was used to adjust for multiple comparisons.

Main Outcome Measures: Patients' socioeconomic deprivation status and corneal graft failure.

Results: A total of 13?644 patients received their first PK during the study periods. A total of 1685 patients (13.36%) were lost to follow-up, leaving 11?821 patients (86.64%) for analysis. A total of 138 of the 11?821 patients (1.17%) developed endophthalmitis. The risk of graft failure within 5 years for the patients classified as hard-pressed was 1.3 times that of the least deprived (hazard ratio, 1.3; 95% confidence interval, 1.1–1.5; P = 0.003) after adjusting for confounding factors and indications. There were no statistically significant differences between the causes of graft failure and the level of deprivation (P = 0.14).

Conclusions: Patients classified as hard-pressed had an increased risk of graft failure within 5 years compared with the least deprived patients.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article

Large-scale association analysis identifies new risk loci for coronary artery disease

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2)

As William Morris Said - Strand Lamps

Strand lamps selected for inclusion in this exhibition in the Ruthin Crafts Gallery

Julius Caesar by William Shakespeare

Performance by Tyrone Guthrie Society, South Dining Hall, Queen's University, Belfast.

Finding revelation in anthropology: Alexander Winchell, William Robertson Smith and the heretical imperative

Anthropological inquiry has often been considered an agent of intellectual secularization. Not least is this so in the sphere of religion, where anthropological accounts have often been taken to represent the triumph of naturalism. This metanarrative however fails to recognise that naturalistic explanations could sometimes be espoused for religious purposes and in defence of confessional creeds. This essay examines two late nineteenth-century figures – Alexander Winchell in the United States, and William Robertson Smith in Britain – who found in anthropological analysis resources to bolster rather than undermine faith. In both cases these individuals found themselves on the receiving end of ecclesiastical censure and were dismissed from their positions at church-governed institutions. But their motivation was to vindicate divine revelation, in Winchell’s case from the physical anthropology of human origins and in Smith’s from the cultural anthropology of Semitic ritual.

Law's Ethical, Global and Theoretical Contexts: Essays in Honour of William Twining

Law's Ethical, Global and Theoretical Contexts examines William Twining's principal contributions to law and jurisprudence in the context of three issues which will receive significant scholarly attention over the coming decades. Part I explores human rights, including torture, the role of evidence in human rights cases, the emerging discourse on 'traditional values', the relevance of 'Southern voices' to human rights debates, and the relationship between human rights and peace agreements. Part II assesses the impact of globalization through the lenses of sociology and comparative constitutionalism, and features an analysis of the development of pluralistic ideas of law in the context of privatization. Finally, Part III addresses issues of legal theory, including whether global legal pluralism needs a concept of law, the importance of context in legal interpretation, the effect of increasing digitalization on legal theory, and the utility of feminist and postmodern approaches to globalization and legal theory.

Avoiding Negligence and Profusion: The failure of the Joint-Stock form in the Anglo-Indian Tea Trade, 1840-1870

In the 19th century, firms operating in the Anglo-Indian tea trade were organised using a variety ownership forms including the partnership, joint-stock and a combination of the two known as the Managing agency. Faced with both an increasing need for fixed capital and high agency costs caused by the distance between owners and managers, the firms adapted and increasingly adopted the hybrid managing agency model to overcome these problems. Using new data from Calcutta and Bengal Commercial Registers and detailed case studies of the Assam Company and Gillanders, Arbuthnot and Co, this paper demonstrates that British entrepreneurs did not see the choice of ownership as a dichotomy or firm boundaries as fixed, but instead innovatively drew on the strengths of different forms of ownership to compete and grow successfully.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.

METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).

FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.

INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.

FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.