Dual abrogation of Mnk and mTOR; a novel therapeutic approach for the treatment of aggressive cancers

Targeting the translational machinery has emerged as a promising therapeutic option for cancer treatment. Cancer cells require elevated protein synthesis for cell growth and exhibit augmented activity to meet the increased metabolic demand. Eukaryotic translation initiation factor 4E (eIF4E) is necessary for mRNA translation, its availability and phosphorylation are regulated by the PI3K/AKT/mTOR and Mnk1/2 pathways, respectively. The phosphorylated form of eIF4E drives the expression of oncogenic proteins including those involved in metastasis. This article will review the role of eIF4E in cancer, its regulation, and discuss the benefit of dual-inhibition of upstream pathways. The discernible interplay between the Mnk1/2 and mTOR signaling pathways provides a novel therapeutic opportunity to target aggressive migratory cancers through the development of hybrid molecules

Auto-extinction of engineered timber

Engineered timber products are becoming increasingly popular in the construction industry due to their attractive aesthetic and sustainability credentials. Cross-laminated timber (CLT) is one such engineered timber product, formed of multiple layers of timber planks glued together with adjacent layers perpendicular to each other. Unlike traditional building materials such as steel and concrete, the timber structural elements can ignite and burn when exposed to fire, and thus this risk must be explicitly addressed during design. Current design guidance focusses on the structural response of engineered timber, with the flammability risk typically addressed by encapsulation of any structural timber elements with the intention of preventing their involvement in a fire. Exposed structural timber elements may act as an additional fuel load, and this risk must be adequately quantified to satisfy the intent of the building regulations in that the structure does not continue burning. This can be achieved through timber’s natural capacity to auto-extinguish when the external heat source is removed or sufficiently reduced. To address these issues, a fundamental understanding of auto-extinction and the conditions necessary to achieve it in real fire scenarios is needed. Bench-scale flammability studies were undertaken in the Fire Propagation Apparatus to explore the conditions under which auto-extinction will occur. Critical conditions were determined experimentally as a mass loss rate of 3.48 ± 0.31 g/m2s, or an incident heat flux of ~30 kW/m2. Mass loss rate was identified as the better criterion, as critical heat flux was shown by comparison with literature data to be heavily dependent on apparatus. Subsequently, full-scale compartment fire experiments with exposed timber surfaces were performed to determine if auto-extinction could be achieved in real fire scenarios. It was demonstrated that auto-extinction could be achieved in a compartment fire scenario, but only if significant delamination of the engineered timber product could be prevented. A full-scale compartment fire experiment with an exposed back wall and ceiling achieved auto-extinction after around 21 minutes, at which point no significant delamination of the first lamella had been observed. Experiments with an exposed back and side wall, and experiments with an exposed back wall, side wall, and ceiling underwent sustained burning due to repeated delamination, and an increased quantity of exposed timber respectively. Firepoint theory was used to predict the mass loss rate as a function of external heat flux and heat losses, and was successfully applied to the bench-scale experiments. This approach was then extended to the full-scale compartment fire experiment which achieved auto-extinction. A simplified approach based on experimentally obtained internal temperature fields was able to predict auto-extinction if delamination had not occurred – predicting an extinction time of 20-21 minutes. This demonstrates that the critical mass loss rate of 3.48 ± 0.31 g/m2s determined from bench-scale experiments was valid for application to full-scale compartment fire experiments. This was further explored through a series of reduced-scale compartment fire experiments, demonstrating that auto-extinction can only reliably be achieved if burnout of the compartment fuel load is achieved before significant delamination of the outer lamella takes place. The quantification of the auto-extinction phenomena and their applicability to full-scale compartment fires explored herein thus allows greater understanding of the effects of exposed timber surfaces on compartment fire dynamics

Point of Care Nucleic Acid Testing for SARS-CoV-2 in Hospitalized Patients: A Clinical Validation Trial and Implementation Study

There is an urgent need for rapid SARS-CoV-2 testing in hospitals to limit nosocomial spread. We report an evaluation of point of care (POC) nucleic acid amplification testing (NAAT) in 149 participants with parallel combined nasal and throat swabbing for POC versus standard lab RT-PCR testing. Median time to result is 2.6 (IQR 2.3–4.8) versus 26.4 h (IQR 21.4–31.4, p < 0.001), with 32 (21.5%) positive and 117 (78.5%) negative. Cohen’s κ correlation between tests is 0.96 (95% CI 0.91–1.00). When comparing nearly 1,000 tests pre- and post-implementation, the median time to definitive bed placement from admission is 23.4 (8.6-41.9) versus 17.1 h (9.0–28.8), p = 0.02. Mean length of stay on COVID-19 “holding” wards is 58.5 versus 29.9 h (p < 0.001). POC testing increases isolation room availability, avoids bed closures, allows discharge to care homes, and expedites access to hospital procedures. POC testing could mitigate the impact of COVID-19 on hospital systems

Cytochrome P450 CYP1B1 activity in renal cell carcinoma

Renal cell carcinoma (RCC) is the most common malignancy of the kidney and has a poor prognosis due to its late presentation and resistance to current anticancer drugs. One mechanism of drug resistance, which is potentially amenable to therapeutic intervention, is based on studies in our laboratory. CYP1B1 is a cytochrome P450 enzyme overexpressed in a variety of malignant tumours. Our studies are now elucidating a functional role for CYP1B1 in drug resistance. Cytochrome P450 reductase (P450R) is required for optimal metabolic activity of CYP1B1. Both CYP1B1 and P450R can catalyse the biotransformation of anticancer drugs at the site of the tumour. In this investigation, we determined the expression of CYP1B1 and P450R in samples of normal kidney and RCC (11 paired normal and tumour and a further 15 tumour samples). The O-deethylation of ethoxyresorufin to resorufin was used to measure CYP1B1 activity in RCC. Cytochrome P450 reductase activity was determined by following the reduction of cytochrome c at 550 nm. The key finding of this study was the presence of active CYP1B1 in 70% of RCC. Coincubation with the CYP1B1 inhibitor alpha-naphthoflavone (10nM) inhibited this activity. No corresponding CYP1B1 activity was detected in any of the normal tissue examined (n = 11). Measurable levels of active P450R were determined in all normal (n = 11) and tumour samples (n = 26). The presence of detectable CYP1B1, which is capable of metabolising anticancer drugs in tumour cells, highlights a novel target for therapeutic intervention

Transition of patients with Gaucher disease type 1 from pediatric to adult care: results from two international surveys of patients and health care professionals

IntroductionGaucher disease (GD) is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency in the enzyme glucocerebrosidase. The most common subtype in Europe and the USA, type 1 (GD1), is characterized by fatigue, cytopenia, splenomegaly, hepatomegaly, bone disease, and rarely pulmonary disease. Increased life expectancy brought about by improved treatments has led to new challenges for adolescents and their transition to adult care. Efficient healthcare transition to adult care is essential to manage the long-term age-related complications of the disease.MethodsThis international study consisted of two online surveys: one survey for patients with GD1 and one survey for healthcare professionals (HCPs) involved in treatment of patients with GD1. The aims of this international, multi-center project were to evaluate the current transition process in various countries and to understand the challenges that both HCPs and patients experience.ResultsA total of 45 patients and 26 HCPs took part in the survey, representing 26 countries. Our data showed that a third (11/33) of patients were aware of transition clinics and most stated that the clinic involved patients with metabolic diseases or with GD. Seven patients attended a transition clinic, where most patients (5/7) received an explanation of the transition process. Approximately half of HCPs (46%; 12/26) had a transition clinic coordinator in their healthcare center, and 10 of HCPs had a transition clinic for patients with metabolic diseases in their healthcare center. HCPs reported that transition clinics were comprised of multi-disciplinary teams, with most patients over the age of 18 years old managed by hematology specialists. The main challenges of the transition process reported by HCPs included limited funding, lack of expertise and difficulty coordinating care amongst different specialties.DiscussionOur study demonstrates the lack of a standardized process, the need to raise awareness of transition clinics amongst patients and the differences between the transition process in different countries. Both patients and HCPs expressed the need for a specialist individual responsible for transition, efficient coordination between pediatricians and adult specialists and for patient visits to the adult center prior to final transition of care

The side effects of service changes: exploring the longitudinal impact of participation in a randomised controlled trial (DOORWAYS) on staff perceptions of barriers to change

Background: Staff and service users have expressed concerns that service improvements in British mental health wards have been slow or transient. It is possible that certain changes are positive for some (e.g. service users), but negative for others (e.g. staff), which may affect implementation success. In this study, we explore whether a programme of change to improve the therapeutic milieu on mental health wards influenced staff perceptions of barriers to change, 12 months after implementation. Method: A cluster randomised controlled trial called DOORWAYS was conducted on eight British, inner-city acute mental health wards. Randomisation was achieved using a list randomly generated by a computer. A psychologist trained ward staff (mainly nurses) to deliver evidence-based groups and supported their initial implementation. The impact of these changes was measured over 12 months (when 4 wards were randomised), according to nurses’ perceptions of barriers to change (VOCALISE), using unstructured multivariate linear regression models. This innovative analysis method allows maximum use of data in randomised controlled trials with reduced sample sizes due to substantial drop out rates. The contextual influences of occupational status (staff) and of workplace setting (ward) were also considered. Results: Staff who participated in the intervention had significantly worse perceptions of barriers to change at follow up. The perceptions of staff in the control group did not change over time. In both groups (N = 120), direct care staff had more negative perceptions of barriers to change, and perceptions varied according to ward. Across time, direct care staff in the intervention group became more negative than those in the control group. Conclusion: Participation in this program of change, worsened staff perceptions of barriers to change. In addition, occupational status (being from the direct care group) had a negative effect on perceptions of barriers to change, an effect that continued across time and was worse in the intervention group. Those providing direct care should be offered extra support when changes are introduced and through the implementation process. More effort should be placed around reducing the perceived burden of innovation for staff in mental health wards

Retinopathy of prematurity and risk factors: a prospective cohort study

BACKGROUND: Increased survival of extremely low birth infants due to advances in antenatal and neonatal care has resulted in a population of infants at high risk of developing retinopathy of prematurity (ROP). Therapeutic interventions include the use of antenatal and postnatal steroids however, their effects on the severity of ROP is in dispute. In addition, it has not been investigated whether severe ROP is due to therapeutic interventions or due to the severity of illness. The aim of the present study was to assess the association between the incidence of severe retinopathy of prematurity (greater than stage 2 – International classification of ROP) and mechanical ventilation, oxygen therapy, gestational age, antenatal and postnatal steroids in extremely low birth weight infants. METHODS: Neonates admitted to the neonatal intensive care unit in Lansing, Michigan, during 1993–2000 were followed to determine factors influencing the development of severe retinopathy of prematurity. Ophthalmologic examinations were started at 6 weeks and followed until resolution. We used logistic regression to estimate the relative risk (odds ratio) associated with risk factors of ROP. RESULTS: Of the neonates with ≤ 1500 g birth weight, admitted to the neonatal intensive care unit, 85% (616/725) survived. Severe retinopathy of prematurity was detected in 7.8% of 576 neonates who had eye examinations. Neonates of lower gestational age (≤ 25 weeks and 26–28 weeks) had an increased odds ratio of 8.49 and 3.19 for the development of severe retinopathy of prematurity, respectively, compared to those 29 weeks and older. Late postnatal steroid treatment starting after 3 weeks of life showed 2.9-fold increased odds ratio, in particular administration for two weeks and more (OR: 4.09, 95% CI: 1.52–11.03). With increasing antenatal steroids courses the risk of severe retinopathy of prematurity decreased, however, it was not significant. Lower gestational age, dependence on ventilation, and use of postnatal steroids were intertwined. Simultaneous presence of these factors seems to indicate severe disease status. CONCLUSION: Prolonged and late postnatal steroids treatment in very low birth weight infants may pose an increased risk for the development of severe retinopathy of prematurity; however, use of postnatal steroids may also be a marker for severity of illness. Further studies need to focus on biologic markers in the pathogenesis of retinopathy of prematurity and to better understand the influence of therapies

Struggling for acceptance : the New Zealand Human Rights Commission : a history of the first twenty years 1978-1998 : presented in partial fulfilment of the requirements for the degree of Master of Arts in History, Massey University, Palmerston North, New Zealand

In the past twenty years human rights have commanded the growing attention of both the most powerful and powerless people in the world. The global focus on nuclear and biological disarmament and on the implementation of 'development' programmes in 'developing' countries is evidence of a world more aware of basic human rights. The recent vote for independence in East Timor, the resulting atrocities, and the world's swift reaction to these, further demonstrate that human rights violations will not be tolerated. The United Nations has also renewed its emphasis on human rights, first outlined fifty years ago in the 1948 Universal Declaration of Human Rights. They have both implemented several UN Development Programmes in Asia, Africa and South America, and focused on drafting many new human rights covenants such as the Declaration of the Rights of Indigenous People. [From Introduction

The Regional Assistance Mission to Solomon Islands and democratic accountability

Peace operations are notoriously difficult to manage. In pursuit of more easily managed operations, those who lead them often sacrifice accountability to the local population. Without democratic accountability, operations find it difficult to succeed. The Regional Assistance Mission to Solomon Islands (RAMSI, 2003 - present), offers lessons in democratic accountability. In principle and in practice, it is important that peace operations display the hallmarks of the ideologies they seek to impress upon others. Not to be a bastion of democracy while professing its virtues is both hypocritical and self-defeating. Despite overwhelming local support for the mission, the Solomon Star, and reviews of RAMSI all reflect local concern about the mission's accountability. Australia's national security interests greatly influenced the geo-political context of RAMSI. Australian personnel and ways of working heavily dominate the mission. It creates the perception that RAMSI is more accountable to Australia than to Solomon Islanders. RAMSI provides some unique answers to longstanding dilemmas in the accountability of international peace operations - particularly regarding immunity - but there are significant areas for improvement. Those areas include local ownership; cultural appropriateness; complaint and oversight mechanisms; regional engagement; and issues at the nexus of development and security - particularly the root causes of the initial conflict