Recruiting for Epigenetic Research: Facilitating the Informed Consent Process

Because the effects of epigenetic (gene-environment interaction) changes have been associated with numerous adverse health states, the study of epigenetic measures provides exciting research opportunities for biobehavioral scientists. However, recruitment for studies focusing on any aspect of genetics poses challenges. Multiple factors, including lack of knowledge regarding a research study, have been identified as barriers to recruitment. Strengthening the informed consent process through extended discussion has been found to be effective in recruiting for research studies in general, yet there is a paucity of information that focused on such a recruitment strategy for epigenetic studies. In this paper, we share our experiences with strategies to strengthen the informed consent process as well as provide samples of materials developed to heighten potential participants’ understanding of epigenetics, in 4 epigenetic research studies with women from diverse backgrounds experiencing a range of health issues. The combined enrollment success rate for epigenetic studies using the process was 89% with participants representing a diverse population. We posit that carefully developed recruitment scripts provided a foundation for improving potential participants’ understanding of the research project. Easy to understand illustrations of the epigenetic process provided a basis for active engagement and encouraged individual questions

Epigenetic Alterations and an Increased Frequency of Micronuclei in Women with Fibromyalgia

Fibromyalgia (FM), characterized by chronic widespread pain, fatigue, and cognitive/mood disturbances, leads to reduced workplace productivity and increased healthcare expenses. To determine if acquired epigenetic/genetic changes are associated with FM, we compared the frequency of spontaneously occurring micronuclei (MN) and genome-wide methylation patterns in women with FM () to those seen in comparably aged healthy controls ( (MN); (methylation)). The mean (sd) MN frequency of women with FM (51.4 (21.9)) was significantly higher than that of controls (15.8 (8.5)) (; df = 1; ). Significant differences ( sites) in methylation patterns were observed between cases and controls considering a 5% false discovery rate. The majority of differentially methylated (DM) sites (91%) were attributable to increased values in the women with FM. The DM sites included significant biological clusters involved in neuron differentiation/nervous system development, skeletal/organ system development, and chromatin compaction. Genes associated with DM sites whose function has particular relevance to FM included BDNF, NAT15, HDAC4, PRKCA, RTN1, and PRKG1. Results support the need for future research to further examine the potential role of epigenetic and acquired chromosomal alterations as a possible biological mechanism underlying FM

Validation of the individualised neuromuscular quality of life for the USA with comparison of the impact of muscle disease on those living in USA versus UK

<p>Abstract</p> <p>Background</p> <p>The Individualised Neuromuscular Quality of Life (INQoL) questionnaire is a published muscle disease specific measure of QoL that has been validated using both qualitative and quantitative methods in a United Kingdom population of adults with muscle disease. If INQoL is to be used in other countries it needs to be linguistically and culturally validated for those countries. It may be important to understand any cultural differences in how patients rate their QoL when applying QoL measures in multi-national clinical trials.</p> <p>Methods</p> <p>We conducted a postal survey of QoL issues in US adults with muscle disease using an agreed translation, from UK to US English, of the same questionnaire as was used in the original construction of INQoL. This questionnaire included an opportunity for free text comments on any aspects of QoL that might not have been covered by the questionnaire. We examined the responses using both quantitative and qualitative approaches. The frequency of the responses in US versus UK populations was compared using appropriate correlation tests and Rasch analysis. A phenomenological approach was used to guide the qualitative analysis and facilitate the exploration of patients' perceptions and experiences.</p> <p>Results</p> <p>The US survey received 333 responses which were compared with 251 UK survey responses.</p> <p>We found that INQoL domains covered all the issues raised by US subjects with no additional domains required. The experiences of those with muscle disease were remarkably similar in the US and UK but there were differences related to the impact of muscle disease on relationships and on employment which was greater for those living in the United States. The greater impact on employment was associated with a higher importance rating given to employment in the US. This may reflect the lower level of financial support for those who are unemployed, and the loss of employment related health benefits.</p> <p>Conclusions</p> <p>INQoL is appropriate for use in US population but there may be differences in the importance that US subject attach to certain aspects of QoL that could be the basis for further study.</p> <p>If these differences are confirmed then this may have implications for the interpretation of QoL outcomes in multi-national trials.</p

JQ1 suppresses tumor growth via PTEN/PI3K/AKT pathway in endometrial cancer

Overexpression of c-Myc is associated with worse outcomes in endometrial cancer, indicating that c-Myc may be a promising target for endometrial cancer therapy. A novel small molecule, JQ1, has been shown to block BRD4 resulting in inhibition of c-Myc expression and tumor growth. Thus, we investigated whether JQ1 can inhibit endometrial cancer growth in cell culture and xenograft models. In PTEN-positive endometrial cancer cells, JQ1 significantly suppressed cell proliferation via induction of G1 phase arrest and apoptosis in a dose-dependent manner, accompanied by a sharp decline in cyclin D1 and CDK4 protein expression. However, PTEN-negative endometrial cancer cells exhibited intrinsic resistance to JQ1, despite significant c-Myc inhibition. Moreover, we found that PTEN and its downstream PI3K/AKT signaling targets were modulated by JQ1, as evidenced by microarray analysis. Silencing of PTEN in PTEN-positive endometrial cancer cells resulted in resistance to JQ1, while upregulation of PTEN in PTEN-negative endometrial cancer cells increased sensitivity to JQ1. In xenografts models of PTEN-positive and PTEN-knock-in endometrial cancer, JQ1 significantly upregulated the expression of PTEN, blocked the PI3K/AKT signaling pathway and suppressed tumor growth. These effects were attenuated in PTEN-negative and PTEN-knockdown xenograft models. Thus, JQ1 resistance appears to be highly associated with the status of PTEN expression in endometrial cancer. Our findings suggest that targeting BRD4 using JQ1 might serve as a novel therapeutic strategy in PTEN-positive endometrial cancers

Synthesizing diverse evidence: the use of primary qualitative data analysis methods and logic models in public health reviews

Objectives: The nature of public health evidence presents challenges for conventional systematic review processes, with increasing recognition of the need to include a broader range of work including observational studies and qualitative research, yet with methods to combine diverse sources remaining underdeveloped. The objective of this paper is to report the application of a new approach for review of evidence in the public health sphere. The method enables a diverse range of evidence types to be synthesized in order to examine potential relationships between a public health environment and outcomes. Study design: The study drew on previous work by the National Institute for Health and Clinical Excellence on conceptual frameworks. It applied and further extended this work to the synthesis of evidence relating to one particular public health area: the enhancement of employee mental well-being in the workplace. Methods: The approach utilized thematic analysis techniques from primary research, together with conceptual modelling, to explore potential relationships between factors and outcomes. Results: The method enabled a logic framework to be built from a diverse document set that illustrates how elements and associations between elements may impact on the well-being of employees. Conclusions: Whilst recognizing potential criticisms of the approach, it is suggested that logic models can be a useful way of examining the complexity of relationships between factors and outcomes in public health, and of highlighting potential areas for interventions and further research. The use of techniques from primary qualitative research may also be helpful in synthesizing diverse document types. (C) 2010 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved

Increased interactions and engulfment of dendrites by microglia precede Purkinje cell degeneration in a mouse model of Niemann Pick Type-C.

Niemann Pick Type-C disease (NPC) is an inherited lysosomal storage disease (LSD) caused by pathogenic variants in the Npc1 or Npc2 genes that lead to the accumulation of cholesterol and lipids in lysosomes. NPC1 deficiency causes neurodegeneration, dementia and early death. Cerebellar Purkinje cells (PCs) are particularly hypersensitive to NPC1 deficiency and degenerate earlier than other neurons in the brain. Activation of microglia is an important contributor to PCs degeneration in NPC. However, the mechanisms by which activated microglia promote PCs degeneration in NPC are not completely understood. Here, we are demonstrating that in the Npc1nmf164 mouse cerebellum, microglia in the molecular layer (ML) are activated and contacting dendrites at early stages of NPC, when no loss of PCs is detected. During the progression of PCs degeneration in Npc1nmf164 mice, accumulation of phagosomes and autofluorescent material in microglia at the ML coincided with the degeneration of dendrites and PCs. Feeding Npc1nmf164 mice a western diet (WD) increased microglia activation and corresponded with a more extensive degeneration of dendrites but not PC somata. Together our data suggest that microglia contribute to the degeneration of PCs by interacting, engulfing and phagocytosing their dendrites while the cell somata are still present

A novel nonsense CDK5RAP2 mutation in a Somali child with primary microcephaly and sensorineural hearing loss

Primary microcephaly is a genetically heterogeneous condition characterized by reduced head circumference (-3 SDS or more) and mild-to-moderate learning disability. Here, we describe clinical and molecular investigations of a microcephalic child with sensorineural hearing loss. Although consanguinity was unreported initially, detection of 13.7 Mb of copy neutral loss of heterozygosity (cnLOH) on chromosome 9 implicated the CDK5RAP2 gene. Targeted sequencing identified a homozygous E234X mutation, only the third mutation to be described in CDK5RAP2, the first in an individual of non-Pakistani descent. Sensorineural hearing loss is not generally considered to be consistent with autosomal recessive microcephaly and therefore it seems likely that the deafness in this individual is caused by the co-occurrence of a further gene mutation, independent of CDK5RAP2. Nevertheless, further detailed clinical descriptions of rare CDK5RAP2 patients, including hearing assessments will be needed to resolve fully the phenotypic range associated with mutations in this gene. This study also highlights the utility of SNP-array testing to guide disease gene identification where an autosomal recessive condition is plausible