Development of a Single Vector System that Enhances Trans-Splicing of SMN2 Transcripts

RNA modalities are developing as a powerful means to re-direct pathogenic pre-mRNA splicing events. Improving the efficiency of these molecules in vivo is critical as they move towards clinical applications. Spinal muscular atrophy (SMA) is caused by loss of SMN1. A nearly identical copy gene called SMN2 produces low levels of functional protein due to alternative splicing. We previously reported a trans-splicing RNA (tsRNA) that re-directed SMN2 splicing. Now we show that reducing the competition between endogenous splices sites enhanced the efficiency of trans-splicing. A single vector system was developed that expressed the SMN tsRNA and a splice-site blocking antisense (ASO-tsRNA). The ASO-tsRNA vector significantly elevated SMN levels in primary SMA patient fibroblasts, within the central nervous system of SMA mice and increased SMN-dependent in vitro snRNP assembly. These results demonstrate that the ASO-tsRNA strategy provides insight into the trans-splicing mechanism and a means of significantly enhancing trans-splicing activity in vivo

Supporting the role of universities in leading individual and societal transformation through education for sustainable development

There is growing recognition of the value of Education for Sustainable Development (ESD) for all learners, and of the unique role that universities play in the transformation of individuals, institutions and societies towards more sustainable futures. Universities engage and even lead in several areas: education, research and community engagement, all of which are essential in this transformation. Further, given their focus and influence, universities are pivotal to action needed to realise the UN Sustainable Development Goals (SDGs) but, to date, UK university integration of ESD and engagement with the SDGs is relatively limited. In recognition that a more urgent and meaningful response is needed to deliver the 2030 targeted socio-economic transformation outlined by the SDGs, the UK ESD Guidance has been comprehensively revised to support universities to deliver education which enables students to acquire sustainability competencies, equipping them to play leadership roles in an increasingly uncertain world. In this case study, we critically analyse the role of universities and explore why ESD needs to be more urgently integrated in teaching and learning. We review the barriers to achieving ESD in UK universities at political and institutional levels. Finally, we explore the policy-practice interface and outline how the new UK ESD Guidance can support universities in leading individual and societal transformation through ESD and act as a stimulus for embedding ESD in university curricula in both UK and international contexts. We conclude that universities have as yet unfulfilled potential to explore and facilitate ESD for sustainability leadership

Randomized controlled trial of live lactobacillus acidophilus plus bifidobacterium bifidum in prophylaxis of diarrhea during radiotherapy in cervical cancer patients

<p>Abstract</p> <p>Background</p> <p>Radiation-induced diarrhea is frequently observed during pelvic radiotherapy. This study was performed to determine the ability of a probiotic containing live lactobacillus acidophilus plus bifidobacterium bifidum to reduce the incidence of radiation-induced diarrhea in locally advanced cervical cancer patients.</p> <p>Methods</p> <p>Patients who were undergoing pelvic radiotherapy concurrent with weekly cisplatin were randomly assigned to a study drug or placebo, in a double-blind study. Diarrhea was graded weekly according the Common Toxicity Criteria (CTC) system. Stool consistency and white and red blood cell count in stool were also assessed. The primary endpoint was to reduce the incidence of diarrhea, defined by a CTC grade 2 or more, and the need for anti-diarrheal medication.</p> <p>Results</p> <p>A total of 63 patients were enrolled. Grade 2 -3 diarrhea was observed in 45% of the placebo group (n = 31) and 9% of the study drug group (n = 32) (p = 0.002). Anti-diarrheal medication use was significantly reduced in the placebo group (p = 0.03). The patients in the study drug group had a significantly improved stool consistency (p < 0.001).</p> <p>Conclusions</p> <p>Live lactobacillus acidophilus plus bifidobacterium bifidum reduced the incidence of radiation-induced diarrhea and the need for anti-diarrheal medication and had a significant benefits on stool consistency.</p

The National Awareness and Early Diagnosis Initiative in England: assembling the evidence

A National Awareness and Early Diagnosis Initiative (NAEDI) has been established in England as part of the Government's strategy to improve cancer outcomes. One of the early priorities for this initiative has been to assemble the diverse evidence linking late diagnosis with poor survival and avoidable deaths. This supplement brings together new perspectives on existing research in this area together with findings from recently commissioned research. This paper describes a provisional model, the ‘NAEDI pathway', for testing hypotheses relating to late diagnosis and its impact. Key findings from other papers in this supplement are also highlighted

Estimating the potential survival gains by eliminating socioeconomic and sex inequalities in stage at diagnosis of melanoma.

BACKGROUND: Although inequalities in cancer survival are thought to reflect inequalities in stage at diagnosis, little evidence exists about the size of potential survival gains from eliminating inequalities in stage at diagnosis. METHODS: We used data on patients diagnosed with malignant melanoma in the East of England (2006-2010) to estimate the number of deaths that could be postponed by completely eliminating socioeconomic and sex differences in stage at diagnosis after fitting a flexible parametric excess mortality model. RESULTS: Stage was a strong predictor of survival. There were pronounced socioeconomic and sex inequalities in the proportion of patients diagnosed at stages III-IV (12 and 8% for least deprived men and women and 25 and 18% for most deprived men and women, respectively). For an annual cohort of 1025 incident cases in the East of England, eliminating sex and deprivation differences in stage at diagnosis would postpone approximately 24 deaths to beyond 5 years from diagnosis. Using appropriate weighting, the equivalent estimate for England would be around 215 deaths, representing 11% of all deaths observed within 5 years from diagnosis in this population. CONCLUSIONS: Reducing socioeconomic and sex inequalities in stage at diagnosis would result in substantial reductions in deaths within 5 years of a melanoma diagnosis.This article is an independent research supported by different funding bodies, beyond the authors’ own employing organisations. MJR was partially funded by a Cancer Research UK Postdoctoral Fellowship (CRUK_A13275). GL is supported by a Postdoctoral Fellowship award by the National Institute for Health Research (NIHR PDF-2011-04-047) to end of 2014 and a Cancer Research UK Clinician Scientist Fellowship award (A18180) from January 2015. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service (NHS), the National Institute for Health Research, the Department of Health, Cancer Research UK, or any other organisation. We thank all staff at the National Cancer Registration Service, Public Health England, Eastern Office, who helped collect and code data used in this study. We particularly acknowledge the help of Dr Clement H Brown and Dr Brian A Rous who were responsible for staging.This is the final published version. It first appeared at http://www.nature.com/bjc/journal/v112/n1s/full/bjc201550a.html

Primary staging and follow-up in melanoma patients – monocenter evaluation of methods, costs and patient survival

In a German cohort of 661 melanoma patients the performance, costs and survival benefits of staging methods (history and physical examination; chest X-ray; ultrasonography of the abdomen; high resolution sonography of the peripheral lymph nodes) were assessed at initial staging and during follow-up of stage I/II+III disease. At initial staging, 74% (23 out of 31) of synchronous metastases were first detected by physical examination followed by sonography of the lymph nodes revealing 16% (5 out of 31). Other imaging methods were less efficient (Chest X-ray: one out of 31; sonography of abdomen: two out of 31). Nearly 24% of all 127 first recurrences and 18% of 73 second recurrences developed in patients not participating in the follow-up programme. In follow-up patients detection of first or second recurrence were attributed to history and physical examination on a routine visit in 47 and 52% recurrences, respectively, and to routine imaging procedures in 21 and 17% of cases, respectively. Lymph node sonography was the most successful technical staging procedure indicating 13% of first relapses, but comprised 24% of total costs of follow-up in stage I/II. Routine imaging comprised nearly 50% of total costs for follow-up in stage I/II and in stage III. The mode of detecting a relapse (‘patient vs. doctor-diagnosed’ or ‘symptomatic vs asymptomatic’) did not significantly influence patients overall survival. Taken together, imaging procedures for routine follow-up in stage I/II and stage III melanoma patients were inefficient and not cost-efficient

Detection of Melanoma Nodal Metastases; Differences in Detection Between Elderly and Younger Patients Do Not Affect Survival

Background. Melanoma lymph nodes metastases may be detected by patients or by physicians. Understanding the outcomes of self-detection or physician detection is essential for the design of follow-up studies. We evaluated the role of the method of detection in nodal disease in the prognosis of melanoma patients who underwent therapeutic lymph node dissection (TLND). Materials and Methods. All melanoma patients with palpable lymph nodes were included in a prospective database (n = 98), and the method of detection was recorded. Detection of lymph node metastases compared with pathological findings in the TLND was assessed by multivariate logistic regression. Disease-free survival (DFS) and disease-specific survival (DSS) were assessed by univariate and multivariate Cox proportional hazard analysis. Results. Nodal metastases were detected by physicians in 45% and by patients in 55% (P <0.001). Age was significantly associated with method of detection. Patients 60 years (odds ratio [OR] 0.3; P = 0.007). However, this was not associated with prognostic findings in TLND, number of positive nodes, tumor size, or extranodal spread. Method of detection or age at the time of nodal metastases was not significantly associated with 2-year DFS or DSS. Conclusions. 45% of all lymph node metastases in stage I-II melanoma patients are physician detected. Younger patients detect their own lymph node metastases significantly more often than elderly patients. However, neither the method of detection nor age correlates with DSS. More frequent follow-up would not alter DFS and DSS significantly

Modelling of the effect of ELMs on fuel retention at the bulk W divertor of JET

Effect of ELMs on fuel retention at the bulk W target of JET ITER-Like Wall was studied with multi-scale calculations. Plasma input parameters were taken from ELMy H-mode plasma experiment. The energetic intra-ELM fuel particles get implanted and create near-surface defects up to depths of few tens of nm, which act as the main fuel trapping sites during ELMs. Clustering of implantation-induced vacancies were found to take place. The incoming flux of inter-ELM plasma particles increases the different filling levels of trapped fuel in defects. The temperature increase of the W target during the pulse increases the fuel detrapping rate. The inter-ELM fuel particle flux refills the partially emptied trapping sites and fills new sites. This leads to a competing effect on the retention and release rates of the implanted particles. At high temperatures the main retention appeared in larger vacancy clusters due to increased clustering rate

Modelling of tungsten erosion and deposition in the divertor of JET-ILW in comparison to experimental findings

The erosion, transport and deposition of tungsten in the outer divertor of JET-ILW has been studied for an HMode discharge with low frequency ELMs. For this specific case with an inter-ELM electron temperature at the strike point of about 20 eV, tungsten sputtering between ELMs is almost exclusively due to beryllium impurity and self-sputtering. However, during ELMs tungsten sputtering due to deuterium becomes important and even dominates. The amount of simulated local deposition of tungsten relative to the amount of sputtered tungsten in between ELMs is very high and reaches values of 99% for an electron density of 5E13 cm$^{-3}$ at the strike point and electron temperatures between 10 and 30 eV. Smaller deposition values are simulated with reduced electron density. The direction of the B-field significantly influences the local deposition and leads to a reduction if the E×B drift directs towards the scrape-off-layer. Also, the thermal force can reduce the tungsten deposition, however, an ion temperature gradient of about 0.1 eV/mm or larger is needed for a significant effect. The tungsten deposition simulated during ELMs reaches values of about 98% assuming ELM parameters according to free-streaming model. The measured WI emission profiles in between and within ELMs have been reproduced by the simulation. The contribution to the overall net tungsten erosion during ELMs is about 5 times larger than the one in between ELMs for the studied case. However, this is due to the rather low electron temperature in between ELMs, which leads to deuterium impact energies below the sputtering threshold for tungsten