Eurilia (European Initiative in Library & Information in Aerospace) :

This report is the final deliverable (D7) of the Eurilia (European Initiative in Libraries and Information in Aerospace) project: a three year programme that aims to enhance information access and utilisation of information within the European aerospace sector. The partners involved in this project, which ended in February 1997, were: University of Limerick (UL), Ireland, Cranfield University (CU), UK, Technical University of Delft (TUD), Netherlands, Digital Equipment Corporation (DEC), Netherlands, Sup’ Aero, ENSAE - Ecole National Superieure de Instituto Nacional de Tecnica Aerospacial (INTA), Spain, l’Aeronautique et de l’Espace (SA), France. This project was funded by the EC Action Programme for Libraries. From the outset the project has attempted to focus on user needs within the aerospace sector and the first section of this report summarises the key conclusions of the studies that were conducted at the beginning of the project, all of which focused on the aerospace user. The second section of this report replicated the tests on users which were deployed in the first stage of the project to try to assess what changes had occurred in aerospace information seeking behaviour and attitudes. Section two also presents the results of a lengthy evaluation by users of the Eurilia software and the final section presents the results of the commercial study, which included both an extensive use of software specifically designed to test commercial viability, together with the results of users’ views on the market potential of both the Eurilia software and the content of th

Revisiting Insularity and Expansion: A Theory Note

This is the final version. Available on open access from Cambridge University Press via the DOI in this recordWhat is the relationship between insularity—a state’s separation from other states via large bodies of water—and expansion? The received wisdom, prominent in (though not exclusive to) realist theories, holds that insularity constrains expansion by making conquest difficult. We contend, by contrast, that this received wisdom faces important limits. Focusing on U.S. expansion via means short of conquest, we interrogate the underlying theoretical logics to demonstrate that insular powers enjoy two distinct advantages when it comes to expansion. First, insularity translates into a “freedom to roam”: because insular powers are less threatened at home, they can project more power and influence abroad. Second, insularity “sterilizes” power, which explains why insular powers are seen as attractive security providers and why we do not see more counterbalancing against them. On net, existing scholarship is correct to argue that insularity impedes conquest between great powers. Still, it has missed the ways that insularity abets expansion via spheres of influence abroad. One consequence is an under-appreciation for the role of geography writ large and insularity in particular in shaping contemporary great power behavior

Phase II study to evaluate combining gemcitabine with flutamide in advanced pancreatic cancer patients

A phase II study was undertaken to determine the safety of combining flutamide with gemcitabine, with response rate being the primary end point. Twenty-seven patients with histologically proven, previously untreated, unresectable pancreatic adenocarcinoma received gemcitabine, 1 g m−2 intravenously on days 1, 8 and 15 of a 28 day cycle, and flutamide 250 mg given orally three times daily. Treatment was halted if there was unacceptable toxicity, or evidence of disease progression. Toxicity was documented every cycle. Tumour assessment was undertaken after cycles 2 and 4, and thereafter at least every additional four cycles. One hundred and seventeen cycles of treatment were administered, median four cycles per patient (range 1–18). Gemcitabine combined with flutamide was well tolerated, with most toxicities being recorded as grade 1 or 2 and only nine treatment cycles associated with grade 3 toxicity. The most frequent toxicity was myelosuppression. One case of transient jaundice was recorded. The commonest symptomatic toxicity was nausea and vomiting. The response rate was 15% (four partial responses), median survival 6 months and 22% of patients were alive at 1 year. These results suggest antitumour activity of the combination therapy to be equivalent to single agent gemcitabine

"A different world" exploring and understanding the climate of a recently re-rolled sexual offender prison

Understanding how sexual offenders experience prison and its environment is important because such experiences can impact on rehabilitation outcomes. The purpose of this research investigation was to explore the rehabilitative and therapeutic climate of a recently re-rolled sexual offender prison. The research took a mixed methods approach and consisted of quantitative and qualitative phases. There were differences between prisoners and staff on their perception of the prison climate and for prisoner and staff relationships. The qualitative results helped to explain the quantitative findings and added a more nuanced understanding of the experience of the prison, the nature of prisoner and staff relationships and the opportunities for personal growth within the prison. The study has important implications for prisons that co-locate sexual offenders and want to provide an environment conducive to rehabilitation

Subcellular mRNA Localization Regulates Ribosome Biogenesis in Migrating Cells

Translation of ribosomal protein-coding mRNAs (RP-mRNAs) constitutes a key step in ribosome biogenesis, but the mechanisms that modulate RP-mRNA translation in coordination with other cellular processes are poorly defined. Here, we show that subcellular localization of RP-mRNAs acts as a key regulator of their translation during cell migration. As cells migrate into their surroundings, RP-mRNAs localize to the actin-rich cell protrusions. This localization is mediated by La-related protein 6 (LARP6), an RNA-binding protein that is enriched in protrusions. Protrusions act as hotspots of translation for RP-mRNAs, enhancing RP synthesis, ribosome biogenesis, and the overall protein synthesis in migratory cells. In human breast carcinomas, epithelial-to-mesenchymal transition (EMT) upregulates LARP6 expression to enhance protein synthesis and support invasive growth. Our findings reveal LARP6-mediated mRNA localization as a key regulator of ribosome biogenesis during cell migration and demonstrate a role for this process in cancer progression downstream of EMT

Using Drug Development Methodology to Improve Survivorship and Supportive Care Intervention Trials.

This is the peer reviewed version of the following article: Howells, L., Hulbert-Williams, N. J. & Blagden, S. P. (2019). Using drug development methodology to improve survivorship and supportive care intervention trials (Invited Editorial). Psycho-Oncology, 28(7), which has been published in final form at https://doi.org/10.1002/pon.5100. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-ArchivingN/

A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours

Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m−2) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m−2) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m−2 in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m−2 in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a >50% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug–drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m−2 and 420 mg pertuzumab following a loading dose of 840 mg

The osteoporosis treatment gap in patients at risk of fracture in European primary care : a multi-country cross-sectional observational study

Summary This study in 8 countries across Europe found that about 75% of elderly women seen in primary care who were at high risk of osteoporosis-related fractures were not receiving appropriate medication. Lack of osteoporosis diagnosis appeared to be an important contributing factor. Introduction Treatment rates in osteoporosis are documented to be low. We wished to assess the osteoporosis treatment gap in women ≥ 70 years in routine primary care across Europe. Methods This cross-sectional observational study in 8 European countries collected data from women 70 years or older visiting their general practitioner. The primary outcome was treatment gap: the proportion who were not receiving any osteoporosis medication among those at increased risk of fragility fracture (using history of fracture, 10-year probability of fracture above country-specific Fracture Risk Assessment Tool [FRAX] thresholds, T-score ≤ − 2.5). Results Median 10-year probability of fracture (without bone mineral density [BMD]) for the 3798 enrolled patients was 7.2% (hip) and 16.6% (major osteoporotic). Overall, 2077 women (55%) met one or more definitions for increased risk of fragility fracture: 1200 had a prior fracture, 1814 exceeded the FRAX threshold, and 318 had a T-score ≤ − 2.5 (only 944 received a dual-energy x-ray absorptiometry [DXA] scan). In those at increased fracture risk, the median 10-year probability of hip and major osteoporotic fracture was 11.2% and 22.8%, vs 4.1% and 11.5% in those deemed not at risk. An osteoporosis diagnosis was recorded in 804 patients (21.2%); most (79.7%) of these were at increased fracture risk. The treatment gap was 74.6%, varying from 53% in Ireland to 91% in Germany. Patients with an osteoporosis diagnosis were found to have a lower treatment gap than those without a diagnosis, with an absolute reduction of 63%. Conclusions There is a large treatment gap in women aged ≥ 70 years at increased risk of fragility fracture in routine primary care across Europe. The gap appears to be related to a low rate of osteoporosis diagnosis

The La-related protein 1-specific domain repurposes HEAT-like repeats to directly bind a 5′TOP sequence

La-related protein 1 (LARP1) regulates the stability of many mRNAs. These include 5′TOPs, mTOR-kinase responsive mRNAs with pyrimidine-rich 5′ UTRs, which encode ribosomal proteins and translation factors. We determined that the highly conserved LARP1-specific C-terminal DM15 region of human LARP1 directly binds a 5′TOP sequence. The crystal structure of this DM15 region refined to 1.86 Å resolution has three structurally related and evolutionarily conserved helix-turn-helix modules within each monomer. These motifs resemble HEAT repeats, ubiquitous helical protein-binding structures, but their sequences are inconsistent with consensus sequences of known HEAT modules, suggesting this structure has been repurposed for RNA interactions. A putative mTORC1-recognition sequence sits within a flexible loop C-terminal to these repeats. We also present modelling of pyrimidine-rich single-stranded RNA onto the highly conserved surface of the DM15 region. These studies lay the foundation necessary for proceeding toward a structural mechanism by which LARP1 links mTOR signaling to ribosome biogenesis