Integrative DNA methylome analysis of pan-cancer biomarkers in cancer discordant monozygotic twin-pairs

BACKGROUND: A key focus in cancer research is the discovery of biomarkers that accurately diagnose early lesions in non-invasive tissues. Several studies have identified malignancy-associated DNA methylation changes in blood, yet no general cancer biomarker has been identified to date. Here, we explore the potential of blood DNA methylation as a biomarker of pan-cancer (cancer of multiple different origins) in 41 female cancer discordant monozygotic (MZ) twin-pairs sampled before or after diagnosis using the Illumina HumanMethylation450 BeadChip. RESULTS: We analysed epigenome-wide DNA methylation profiles in 41 cancer discordant MZ twin-pairs with affected individuals diagnosed with tumours at different single primary sites: the breast, cervix, colon, endometrium, thyroid gland, skin (melanoma), ovary, and pancreas. No significant global differences in whole blood DNA methylation profiles were observed. Epigenome-wide analyses identified one novel pan-cancer differentially methylated position at false discovery rate (FDR) threshold of 10 % (cg02444695, P = 1.8 × 10(-7)) in an intergenic region 70 kb upstream of the SASH1 tumour suppressor gene, and three suggestive signals in COL11A2, AXL, and LINC00340. Replication of the four top-ranked signals in an independent sample of nine cancer-discordant MZ twin-pairs showed a similar direction of association at COL11A2, AXL, and LINC00340, and significantly greater methylation discordance at AXL compared to 480 healthy concordant MZ twin-pairs. The effects at cg02444695 (near SASH1), COL11A2, and LINC00340 were the most promising in biomarker potential because the DNA methylation differences were found to pre-exist in samples obtained prior to diagnosis and were limited to a 5-year period before diagnosis. Gene expression follow-up at the top-ranked signals in 283 healthy individuals showed correlation between blood methylation and gene expression in lymphoblastoid cell lines at PRL, and in the skin tissue at AXL. A significant enrichment of differential DNA methylation was observed in enhancer regions (P = 0.03). CONCLUSIONS: We identified DNA methylation signatures in blood associated with pan-cancer, at or near SASH1, COL11A2, AXL, and LINC00340. Three of these signals were present up to 5 years prior to cancer diagnosis, highlighting the potential clinical utility of whole blood DNA methylation analysis in cancer surveillance

A Mindfulness Program Manual for People With Dementia

This article describes a 10-session group-based Mindfulness Program for people with mild to moderate dementia. It aims to equip people with dementia with skills to manage psychological distress, with support from carers. The Mindfulness Program was developed through reviews of existing literature, consultation with experts, and a focus group with people with dementia. In a randomized controlled feasibility and pilot trial with people with mild to moderate dementia in care homes, it was found to significantly increase quality of life. The manual presented here is designed to be administered flexibly to promote participants' personhood. The protocol is designed for use by therapists with experience in practicing mindfulness meditation

ImpRess: an Implementation Readiness checklist developed using a systematic review of randomised controlled trials assessing cognitive stimulation for dementia

Background Research reporting results of clinical trials, psychosocial or technological interventions frequently omit critical details needed to inform implementation in practice. The aim of this article is to develop an Implementation Readiness (ImpRess) checklist, that includes criteria deemed useful in measuring readiness for implementation and apply it to trials of cognitive stimulation in dementia, providing a systematic review of their readiness for widespread implementation. Methods Five electronic databases were searched. After initial screening of papers, two reviewers assessed quality and scored the included studies based on the ImpRess checklist specifically developed for this review. Results Twenty studies met the inclusion criteria. As determined by the ImpRess checklist, scores ranged from 11 to 29 out of 52. According to the checklist the most comprehensive and ready to implement version of cognitive stimulation was Cognitive Stimulation Therapy. Conclusions Reports of interventions rarely include consideration of implementation in practice. Contrary to the growing number of reporting guidelines, crucial items within the ImpRess checklist have been frequently overlooked. This study was able to show that the ImpRess checklist was feasible in practice and reliable. The checklist may be useful in evaluating readiness for implementation for other manualised interventions

CFRP Dimensional Stability Investigations for Use on the LISA Mission Telescope

The Laser Interferometer Space Antenna (LISA) is a mission designed to detect low frequency gravitational-waves. In order for LISA to succeed in its goal of direct measurement of gravitational waves, many subsystems must work together to measure the distance between proof masses on adjacent spacecraft. One such subsystem, the telescope, plays a critical role as it is the laser transmission and reception link between spacecraft. Not only must the material that makes up the telescope support structure be strong, stiff and light, but it must have a dimensional stability of better than 1 pm Hz(exp -1/2) at 3 mHz and the distance between the primary and the secondary mirrors must change by less than 2.5 micron over the mission lifetime. CFRP is the current baseline materiaL however, it has not been tested to the pico-meter level as required by the LISA mission. In this paper we present dimensional stability results, outgassing effects occurring in the cavity and discuss its feasibility for use as the telescope spacer for the LISA spacecraft

Can mindfulness-based interventions benefit people with dementia? Drawing on the evidence from a systematic review in populations with cognitive impairments

Introduction: Non-pharmacological interventions that promote quality of life in people with dementia are urgently needed. To accelerate development, evidence-based psychotherapies used in other populations can be considered. Mindfulness-based interventions with standardised protocols, namely mindfulness-based cognitive therapy (MBCT) and mindfulness-based stress reduction (MBSR), may be effective in people with dementia, although tailoring for cognitive impairment may be needed. Evidence from other cognitive disorders can inform research. / Areas covered: The authors reviewed 12 studies of MBCT or MBSR conducted in people with cognitive impairments, including ten in stroke, traumatic brain injury, and mild cognitive impairment; and two in dementia. Protocol modifications, outcomes, and evidence quality were analysed. Common themes to address cognitive difficulties included: shortened session duration, use of memory aids, increase in repetition, simplified language, and omitted retreat sessions. / Expert opinion: MBCT and MBSR can be applied without drastic modifications in people with cognitive impairment. Their effectiveness in people with dementia remains unknown: empirical studies using/adapting evidence based MBCT/MBSR protocols in this population is seriously lacking. Studies used a diverse range of outcome measures, which made direct comparison difficult. Further research with high methodological quality, sufficient power and longer follow-up are urgently needed. Development of manuals would enhance the replicability of future studies

Effect of Dietary Fats on Oxidative-Antioxidative Status of Blood in Rats

This study was performed to examine the effect of different fat sources, lard, sunflower oil (SO), and fish oil (FO) in high-fat and low-fat diet on reactive oxygen species generation by blood phagocytes, glutathione redox status in erythrocytes, and total plasma antioxidant ability in rats. Whole blood chemiluminescence (CL) did not differ between three low-fat fed groups. However, baseline and phorbol myristate acetate (PMA)-stimulated CL in blood of high-lard fed rats were lower than in low-lard and high-SO fed animals. Phagocyte-stimulated oxidative burst was higher in rats fed high-SO diet than in those fed low-SO and high-FO diets. The highest level of oxidize glutathione (GSSH), the lowest reduce glutathione (GSH)/GSSG ratio in erythrocytes, and the highest plasma activity to reduce ferric ions were observed in rats fed both diets contaning linoleic acid-rich sunflower oil compared to animals fed the corresponding energy from other fats. 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity of plasma was lower in high-lard and high-FO fed rats compared to the corresponding low-fat diets, and the lowest in low-FO fed rats among low-fat fed animals. We presume from our results that linoleic acid may have dual effect, prooxidative in blood cells but maintaining total antioxidant plasma ability

Development of an Evidence-based Extended Programme of Maintenance Cognitive Stimulation Therapy (CST) for People with Dementia

Psychosocial interventions for dementia have often been developed without a sound theoretical, empirical and clinical basis, and most evaluations of these interventions have had serious methodological limitations. This highlights the need to link intervention development with evaluation and design issues during the early stages of phase 1 or development of an intervention. Best practice is to develop interventions systematically, using the best available evidence and appropriate theory. This study focuses on the developmental stage of the Medical Research Council (MRC) guidelines (2008) to develop an evidence-based Maintenance Cognitive Stimulation Therapy (MCST) programme for dementia. The intervention was developed based on a mixed methods approach, using evidence obtained from the Cochrane review of Cognitive Stimulation for dementia followed by a Delphi consultation process with key stake-holders. Four techniques were used: (1) Cochrane review of cognitive stimulation for dementia, (2) a consultation with key stake holders using a Delphi Consensus Process (including an expert consensus conference), (3) focus groups with the target population and (4) a Delphi survey. These techniques were used to complete the theoretical preclinical and phase I modelling of the MRC framework for developing the MCST intervention for dementia. It was feasible and effective to use a systematic development process to produce successive modifications of the draft manual for an evidence based maintenance CST programme for dementia. Close involvement of users and carers ensured that the manual was well targeted on the preferences and abilities of people with dementia. The final Maintenance CST programme and manual is currently being tested as part of a large multicentre, randomised controlled trial

Shape Invariance in the Calogero and Calogero-Sutherland Models

We show that the Calogero and Calogero-Sutherland models possess an N-body generalization of shape invariance. We obtain the operator representation that gives rise to this result, and discuss the implications of this result, including the possibility of solving these models using algebraic methods based on this shape invariance. Our representation gives us a natural way to construct supersymmetric generalizations of these models, which are interesting both in their own right and for the insights they offer in connection with the exact solubility of these models.Comment: Latex file, 23 pages, no picture