The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase

Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis,independent of RANK ligand, which disrupts normal bone homeostasisleading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications

Potential climatic transitions with profound impact on Europe

We discuss potential transitions of six climatic subsystems with large-scale impact on Europe, sometimes denoted as tipping elements. These are the ice sheets on Greenland and West Antarctica, the Atlantic thermohaline circulation, Arctic sea ice, Alpine glaciers and northern hemisphere stratospheric ozone. Each system is represented by co-authors actively publishing in the corresponding field. For each subsystem we summarize the mechanism of a potential transition in a warmer climate along with its impact on Europe and assess the likelihood for such a transition based on published scientific literature. As a summary, the ‘tipping’ potential for each system is provided as a function of global mean temperature increase which required some subjective interpretation of scientific facts by the authors and should be considered as a snapshot of our current understanding. <br/

Changes in Present and Future Circulation Types Frequency in Northwest Iberian Peninsula

The aim of the work described herein was to study projection scenarios in order to find changes in the synoptic variability of the northwest Iberian Peninsula in the 21st century. To this end, we investigated the changes in the frequency of the different circulation types computed for the study area using three different models used in the IPCC 4th assessment report. The circulation types were computed using the procedure known as Lamb circulation types. The control simulation for the late 20th century was evaluated objectively from the results obtained using data from the NCEP/NCAR reanalysis, as to evaluate the ability of the model to reproduce the present climate. We have compared not only seasonal mean sea level pressure fields but also the mean seasonal frequency of circulation types. The results for the end of the 21st century show a decrease in the frequency of cyclonic, W, and SW circulation types in the spring and summer months. This trend also appears in the autumn, with a concomitant increase in the anticyclonic types

Minimal Holocene retreat of large tidewater glaciers in Køge Bugt, southeast Greenland

Abstract Køge Bugt, in southeast Greenland, hosts three of the largest glaciers of the Greenland Ice Sheet; these have been major contributors to ice loss in the last two decades. Despite its importance, the Holocene history of this area has not been investigated. We present a 9100 year sediment core record of glaciological and oceanographic changes from analysis of foraminiferal assemblages, the abundance of ice-rafted debris, and sortable silt grain size data. Results show that ice-rafted debris accumulated constantly throughout the core; this demonstrates that glaciers in Køge Bugt remained in tidewater settings throughout the last 9100 years. This observation constrains maximum Holocene glacier retreat here to less than 6 km from present-day positions. Retreat was minimal despite oceanic and climatic conditions during the early-Holocene that were at least as warm as the present-day. The limited Holocene retreat of glaciers in Køge Bugt was controlled by the subglacial topography of the area; the steeply sloping bed allowed glaciers here to stabilise during retreat. These findings underscore the need to account for individual glacier geometry when predicting future behaviour. We anticipate that glaciers in Køge Bugt will remain in stable configurations in the near-future, despite the predicted continuation of atmospheric and oceanic warming

Recent Advances in Our Understanding of the Role of Meltwater in the Greenland Ice Sheet System

Nienow, Sole and Cowton’s Greenland research has been supported by a number of UK NERC research grants (NER/O/S/2003/00620; NE/F021399/1; NE/H024964/1; NE/K015249/1; NE/K014609/1) and Slater has been supported by a NERC PhD studentshipPurpose of the review:  This review discusses the role that meltwater plays within the Greenland ice sheet system. The ice sheet’s hydrology is important because it affects mass balance through its impact on meltwater runoff processes and ice dynamics. The review considers recent advances in our understanding of the storage and routing of water through the supraglacial, englacial, and subglacial components of the system and their implications for the ice sheet Recent findings:   There have been dramatic increases in surface meltwater generation and runoff since the early 1990s, both due to increased air temperatures and decreasing surface albedo. Processes in the subglacial drainage system have similarities to valley glaciers and in a warming climate, the efficiency of meltwater routing to the ice sheet margin is likely to increase. The behaviour of the subglacial drainage system appears to limit the impact of increased surface melt on annual rates of ice motion, in sections of the ice sheet that terminate on land, while the large volumes of meltwater routed subglacially deliver significant volumes of sediment and nutrients to downstream ecosystems. Summary:  Considerable advances have been made recently in our understanding of Greenland ice sheet hydrology and its wider influences. Nevertheless, critical gaps persist both in our understanding of hydrology-dynamics coupling, notably at tidewater glaciers, and in runoff processes which ensure that projecting Greenland’s future mass balance remains challenging.Publisher PDFPeer reviewe

Cost Studies of Buildings [6th edition]

This practical guide to cost studies of buildings has been updated and revised throughout for the 6th edition. New developments in RICS New Rules of Measurement (NRM) are incorporated throughout the book, in addition to new material on e-business, the internet, social media, building information modelling, sustainability, building resilience and carbon estimating. This trusted and easy to use guide to the cost management role: Focuses on the importance of costs of constructing projects during the different phases of the construction process Features learning outcomes and self-assessment questions for each chapter Addresses the requirements of international readers From introductory data on the construction industry and the history of construction economics, to recommended methods for cost analysis and post-contract cost control, Cost Studies of Buildings is an ideal companion for anyone learning about cost management