A randomised, phase II, unblinded trial of an Exercise and Nutrition-based Rehabilitation programme (ENeRgy) versus standard care in patients with cancer: feasibility trial protocol

Acknowledgements - The authors would like to thank Marie Curie and the Chief Scientist Office (UK) for funding this work (MCRGS-07-16-73), as well as acknowledge the support offered from the trial sponsors (ACCORD & NHS Lothian Edinburgh, UK). Also the valued contributions from the Southampton Clinical Trials Unit (UK), the Cicely Saunders Institute of Palliative Care, Policy and Rehabilitation, Kings College London (UK) as well as colleagues from different institutes within Edinburgh University (UK). Thanks to all the St Columba’s staff who helped get the trial set up, or assisted with the administration and the smooth running of the trial. Particular thanks to St Columba’s day therapies team especially Yvonne Whitehouse. Thanks to our dedicated ENeRgy clinic volunteers, Gillian Reid and Tommy Dalgleish for their commitment and helping make our participants feel welcomed and at ease, and for keeping the clinics running smoothly. Thanks to the clinical administration team and both community nurse specialist teams who showed great enthusiasm in identifying potential participants. Thanks to Marie Curie Hospice Edinburgh and the support from Dr. Emma Carduff (Marie Curie Glasgow) for their engagement and assistance with the trial. Thanks also to Abbott Nutrition, for supplying the oral nutritional supplements for the trial (ProSure), also for support from the Abbott team, in particular Dr Anne Voss.Erna Haraldsdottir - ORCID: 0000-0002-6451-1374 https://orcid.org/0000-0002-6451-1374Patients are living longer with incurable cancer [1] such that in many cases, cancer is likened to a chronic disease [2, 3, 4]. This development has wide-ranging implications for both patients and wider society, with increased longevity comes increased morbidity and associated socio-economic burden [5, 6]. Primary cost drivers for patients with advanced cancer are hospitalisation, GP and domiciliary visits [7]. Rehabilitation has been advocated as one such way of optimising the function and quality of life in this group of patients [8]; however, the optimal components of a rehabilitation model for patients with incurable cancer remain to be elucidated...The trial was funded by Marie Curie and the Chief Scientist Office (funding reference MCRGS-07-16-73). The funding bodies specified where changes were required to the design of the trial (including incorporating the impact upon carers and any health-economic impact as outcomes of the trial).4pubpub19

The Endoplasmic Reticulum Chaperone Protein GRP94 Is Required for Maintaining Hematopoietic Stem Cell Interactions with the Adult Bone Marrow Niche

Hematopoietic stem cell (HSC) homeostasis in the adult bone marrow (BM) is regulated by both intrinsic gene expression products and interactions with extrinsic factors in the HSC niche. GRP94, an endoplasmic reticulum chaperone, has been reported to be essential for the expression of specific integrins and to selectively regulate early T and B lymphopoiesis. In GRP94 deficient BM chimeras, multipotent hematopoietic progenitors persisted and even increased, however, the mechanism is not well understood. Here we employed a conditional knockout (KO) strategy to acutely eliminate GRP94 in the hematopoietic system. We observed an increase in HSCs and granulocyte-monocyte progenitors in the Grp94 KO BM, correlating with an increased number of colony forming units. Cell cycle analysis revealed that a loss of quiescence and an increase in proliferation led to an increase in Grp94 KO HSCs. This expansion of the HSC pool can be attributed to the impaired interaction of HSCs with the niche, evidenced by enhanced HSC mobilization and severely compromised homing and lodging ability of primitive hematopoietic cells. Transplanting wild-type (WT) hematopoietic cells into a GRP94 null microenvironment yielded a normal hematology profile and comparable numbers of HSCs as compared to WT control, suggesting that GRP94 in HSCs, but not niche cells, is required for maintaining HSC homeostasis. Investigating this, we further determined that there was a near complete loss of integrin α4 expression on the cell surface of Grp94 KO HSCs, which showed impaired binding with fibronectin, an extracellular matrix molecule known to play a role in mediating HSC-niche interactions. Furthermore, the Grp94 KO mice displayed altered myeloid and lymphoid differentiation. Collectively, our studies establish GRP94 as a novel cell intrinsic factor required to maintain the interaction of HSCs with their niche, and thus regulate their physiology

Trends in temperature and rainfall extremes in the Yellow River source region, China

Spatial and temporal changes in daily temperature and rainfall indices are analyzed for the source region of Yellow River. Three periods are examined: 1960–1990, 1960–2000 and 1960–2006. Significant warming trends have been observed for the whole study region over all the three periods, particularly over the period 1960–2006. This warming is mainly attributed to a significant increase in the minimum temperature, and characterized by pronounced changes in the low temperature events composing a significant increase in the magnitude and a significant decrease in the frequency. In contrast to the temperature indices, no significant changes have been observed in the rainfall indices at the majority of stations. However, the rainfall shows noticeable increasing trends during winter and spring from a basin-wide point of view. Conversely, the frequency and contribution of moderately heavy rainfall events to total rainfall show a significant decreasing trend in summer. To conclude, this study shows that over the past 40–45 years the source region of the Yellow River has become warmer and experienced some seasonally varying changes in rainfall, which also supports an emerging global picture of warming and the prevailing positive trends in winter rainfall extremes over the mid-latitudinal land areas of the Northern Hemisphere.Water ManagementCivil Engineering and Geoscience

The influence of synoptic airflow on UK daily precipitation extremes. Part 1: Observed spatio-temporal relationships

We study the influence of synoptic scale atmospheric circulation on extreme daily precipitation across the United Kingdom, using observed time series from 689 rain gauges. To this end we employ a statistical model, that uses airflow strength, direction and vorticity as predictors for the generalised extreme value distribution of monthly precipitation maxima. The inferred relationships are connected with the dominant westerly flow, the orography, and the moisture supply from surrounding seas. We aggregated the results for individual rain gauges to regional scales to investigate the temporal variability of extreme precipitation. Airflow explains a significant fraction of the variability on subannual to decadal time scales. A large fraction of the especially heavy winter precipitation during the 1980s and 1990s in north Scotland can be attributed to a prevailing positive phase of the North Atlantic Oscillation. Our statistical model can be used for statistical downscaling and to validate regional climate model output