Loss of expression of ATM is associated with worse prognosis in colorectal cancer and loss of Ku70 expression is associated with CIN

Repair of double strand DNA breaks (DSBs) is pivotal in maintaining normal cell division and disruption of this system has been shown to be a key factor in carcinogenesis. Loss of expression of the DSB repair proteins have previously been shown to be associated with poorer survival in colorectal cancer. We wished to ascertain the relationship of altered expression of the DSB repair proteins γ-H2AX (gamma-H2AX), ATM and Ku70 with biological and clinico-pathological features of colorectal cancer. 908 tumours from the VICTOR clinical trial of stage II/III colorectal cancer were analysed for expression of γ-H2AX, ATM and Ku70 using immunohistochemistry. Expression levels were correlated with CIN and with diseasefree survival, correcting for microsatellite instability, BRAF/KRAS mutation status, Dukes stage, chemo/radiotherapy, age, gender and tumour location. Down-regulated Ku70 expression was associated with chromosomal instability (p=0.029) in colorectal cancer. Reduced ATM expression was an independent marker of poor disease-free survival (HR=1.67, 95% CI 1.11-2.50, p=0.015). For Ku70, further studies are required to investigate the potential relationship of non-homologous end joining with chromosomal instability. Loss of ATM expression might serve as a biomarker of poor prognosis in colorectal cancer

TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres.

Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC

Methodology for evaluating thermal track buckling in dual gauge tracks with continuous welded rail

In the National Spanish railway network, two types of track gauge with continuous welded rails are currently in use: the Iberian wide gauge (1668 mm) and the standard gauge (1435 mm). In order to improve links and freight traffic between different lines and with the rest of Europe, a dual gauge track with three rails was developed. This solution modifies the classical track configuration, so it is necessary to develop new methodologies and studies to understand its behavior. Among other loads applied on a continuous welded rail track, a considerable rise in temperature induces compressive stresses in the three rails that can lead to lateral track buckling. Moreover, on dual gauge tracks, the addition of the third rail increases the axial compression, which may lead to track instability. For this reason, a three-dimensional continuous welded rail model is developed in this study to be used for dual gauge track buckling analysis on straight tracks subjected to temperature load. The continuous welded rail dual gauge track model consists of beam, solid and spring elements, in which a non-linear behaviour of the ballast is considered. The results obtained may be used to predict the buckling capacity of the continuous welded rail on dual gauge tracks with respect to different parameters such as lateral resist-ance, lateral imperfections, sleeper spacing or torsional stiffness.Villalba Sanchis, I.; Insa Franco, R.; Salvador Zuriaga, P.; Martínez Fernández, P. (2017). Methodology for evaluating thermal track buckling in dual gauge tracks with continuous welded rail. Proceedings of the Institution of Mechanical Engineers, Part F: Journal of Rail and Rapid Transit. 231(3):269-279. doi:10.1177/0954409715626957S269279231

Analytical model for predicting the buckling load of continuous welded rail tracks

The use of continuous welded rail (CWR) track has solved many of the problems associated with tread surface discontinuities that occur in jointed tracks. However, due to the longitudinal expansion of the rails in CWR tracks being highly constrained, the generated compressive stresses in the rails can cause track buckling in the horizontal plane. Track buckling is a complex phenomenon, in which many factors are involved and around which there is much uncertainty. The objective of this paper is to present an analytical model that can be used to calculate the buckling load of a CWR track. This model accounts for the contributions of base, crib and shoulder ballast and includes the effect of vertical loading on each of these components. Moreover, a parametric study based on this model is developed, in order to understand how and the extent to which the considered factors affect track stability. The results of the study indicate that the characteristics of the existing misalignments in the track are the critical parameters involved in the phenomenon. In addition, maintenance operations that affect the ballast, such as tamping or surfacing, and the dimensions and material of the track sleepers are also important factors.Navarro Martinez, JI.; Villalba Sanchis, I.; Martínez Fernández, P.; Insa Franco, R. (2015). Analytical model for predicting the buckling load of continuous welded rail tracks. Proceedings of the Institution of Mechanical Engineers, Part F: Journal of Rail and Rapid Transit. 229(5):542-552. doi:10.1177/0954409713518039S5425522295Kerr, A. D. (1978). Analysis of thermal track buckling in the lateral plane. Acta Mechanica, 30(1-2), 17-50. doi:10.1007/bf01177436Grissom, G. T., & Kerr, A. D. (2006). Analysis of lateral track buckling using new frame-type equations. International Journal of Mechanical Sciences, 48(1), 21-32. doi:10.1016/j.ijmecsci.2005.09.006Le Pen, L. M., & Powrie, W. (2011). Contribution of Base, Crib, and Shoulder Ballast to the Lateral Sliding Resistance of Railway Track: A Geotechnical Perspective. Proceedings of the Institution of Mechanical Engineers, Part F: Journal of Rail and Rapid Transit, 225(2), 113-128. doi:10.1177/095440971039709

Development of a decision support tool to facilitate primary care management of patients with abnormal liver function tests without clinically apparent liver disease [HTA03/38/02]. Abnormal Liver Function Investigations Evaluation (ALFIE)

Liver function tests (LFTs) are routinely performed in primary care, and are often the gateway to further invasive and/or expensive investigations. Little is known of the consequences in people with an initial abnormal liver function (ALF) test in primary care and with no obvious liver disease. Further investigations may be dangerous for the patient and expensive for Health Services. The aims of this study are to determine the natural history of abnormalities in LFTs before overt liver disease presents in the population and identify those who require minimal further investigations with the potential for reduction in NHS costs

Generation Scotland: Donor DNA Databank; A control DNA resource

<p>Abstract</p> <p>Background</p> <p>Many medical disorders of public health importance are complex diseases caused by multiple genetic, environmental and lifestyle factors. Recent technological advances have made it possible to analyse the genetic variants that predispose to complex diseases. Reliable detection of these variants requires genome-wide association studies in sufficiently large numbers of cases and controls. This approach is often hampered by difficulties in collecting appropriate control samples. The Generation Scotland: Donor DNA Databank (GS:3D) aims to help solve this problem by providing a resource of control DNA and plasma samples accessible for research.</p> <p>Methods</p> <p>GS:3D participants were recruited from volunteer blood donors attending Scottish National Blood Transfusion Service (SNBTS) clinics across Scotland. All participants gave full written consent for GS:3D to take spare blood from their normal donation. Participants also supplied demographic data by completing a short questionnaire.</p> <p>Results</p> <p>Over five thousand complete sets of samples, data and consent forms were collected. DNA and plasma were extracted and stored. The data and samples were unlinked from their original SNBTS identifier number. The plasma, DNA and demographic data are available for research. New data obtained from analysis of the resource will be fed back to GS:3D and will be made available to other researchers as appropriate.</p> <p>Conclusions</p> <p>Recruitment of blood donors is an efficient and cost-effective way of collecting thousands of control samples. Because the collection is large, subsets of controls can be selected, based on age range, gender, and ethnic or geographic origin. The GS:3D resource should reduce time and expense for investigators who would otherwise have had to recruit their own controls.</p

Impact of soil and water conservation measuren on catchment hydrological response: a case in north Ethiopia

Impact studies of catchment management in the developing world rarely include detailed hydrological components. Here, changes in the hydrological response of a 200-ha catchment in north Ethiopia are investigated. The management included various soil and water conservation measures such as the construction of dry masonry stone bunds and check dams, the abandonment of post-harvest grazing, and the establishment of woody vegetation. Measurements at the catchment outlet indicated a runoff depth of 5 mm or a runoff coefficient (RC) of 1·6% in the rainy season of 2006. Combined with runoff measurements at plot scale, this allowed calculating the runoff curve number (CN) for various land uses and land management techniques. The pre-implementation runoff depth was then predicted using the CN values and a ponding adjustment factor, representing the abstraction of runoff induced by the 242 check dams in gullies. Using the 2006 rainfall depths, the runoff depth for the 2000 land management situation was predicted to be 26·5mm(RCD 8%), in line with current RCs of nearby catchments. Monitoring of the ground water level indicated a rise after catchment management. The yearly rise in water table after the onset of the rains (ΔT) relative to the water surplus (WS) over the same period increased between 2002-2003 (ΔT/WS D 3·4) and 2006 (ΔT/WS >11·1). Emerging wells and irrigation are other indicators for improved water supply in the managed catchment. Cropped fields in the gullies indicate that farmers are less frightened for the destructive effects of flash floods. Due to increased soil water content, the crop growing period is prolonged. It can be concluded that this catchment management has resulted in a higher infiltration rate and a reduction of direct runoff volume by 81% which has had a positive influence on the catchment water balance. © 2010 John Wiley & Sons, Ltd

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders