Low grade Ductal Carcinoma in situ (DCIS): how best to describe it?

BACKGROUND: In the absence of definitive data about the natural history of DCIS the appropriateness of describing DCIS as cancer is controversial. METHODS: We conducted a survey amongst British Breast Group (BBG) members, to determine which descriptions of DCIS were deemed most accurate and appropriate. RESULTS: 54/73 (74%) attendees completed the survey: A majority (34/54; 63%) said they would be comfortable using the description that explained DCIS as abnormal cells in the milk ducts that had not spread into other breast tissue and which did not need urgent treatment as if it was breast cancer and this description was overall the most preferred (24/54; 44%). CONCLUSIONS: Little consensus exists regarding how best to explain low grade DCIS to patients

Clinical progress and pharmacology of small molecule bromodomain inhibitors

Bromodomains have emerged as an exciting target class for drug discovery over the past decade. Research has primarily focused on the bromodomain and extra terminal (BET) family of bromodomains, which has led to the development of multiple small molecule inhibitors and an increasing number of clinical assets. The excitement centred on the clinical potential of BET inhibition has stimulated intense interest in the broader family and the growing number of non-BET bromodomain chemical probes has facilitated phenotypic investigations, implicating these targets in a variety of disease pathways including cancer, inflammation, embryonic development and neurological disorders

The shifting nature of women’s experiences and perceptions of ductal carcinoma in situ

Aim: This paper is a report of a descriptive qualitative study of the evolution of women’s perceptions and experiences of ductal carcinoma in situ from the period near to diagnosis to one year later. Background: Ductal carcinoma in situ is a non-invasive breast condition where cancer cells are detected but confined to the ducts of the breast. With treatment, the condition has a positive prognosis but ironically patients undergo treatment similar to that for invasive breast cancer. There is a lack of longitudinal qualitative research studying women’s experiences of ductal carcinoma in situ, especially amongst newly diagnosed patients and how experiences change over time. Methods: Forty-five women took part in an initial interview following a diagnosis of ductal carcinoma in situ and twenty-seven took part in a follow-up interview 9-13 months later. Data were collected between January 2007 and October 2008. Transcripts were analysed using a hybrid approach to thematic analysis. Findings: Women’s early perceptions of ductal carcinoma in situ merged and sometimes conflicted with their lay beliefs of breast cancer. Perceptions and experiences of the condition shifted over time. These overriding aspects were evident within four themes identified across the interviews: 1) perceptions of DCIS versus breast cancer, 2) from paradox to acceptance, 3) personal impact, and 4) support and interactions with others. Conclusion: This study represents one of the few longitudinal qualitative studies with newly diagnosed patients, capturing women’s initial and shifting experiences and perceptions of the condition. The issues identified need to be recognised in clinical practice and supported appropriately

Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells

Epigenetic modifiers are an emerging class of anti-tumor drugs, potent in multiple cancer contexts. Their effect on spontaneously developing autoimmune diseases has been little explored. We report that a short treatment with I-BET151, a small-molecule inhibitor of a family of bromodomain-containing transcriptional regulators, irreversibly suppressed development of type-1 diabetes in NOD mice. The inhibitor could prevent or clear insulitis, but had minimal influence on the transcriptomes of infiltrating and circulating T cells. Rather, it induced pancreatic macrophages to adopt an anti-inflammatory phenotype, impacting the NF-κB pathway in particular. I-BET151 also elicited regeneration of islet β-cells, inducing proliferation and expression of genes encoding transcription factors key to β-cell differentiation/function. The effect on β cells did not require T cell infiltration of the islets. Thus, treatment with I-BET151 achieves a ‘combination therapy’ currently advocated by many diabetes investigators, operating by a novel mechanism that coincidentally dampens islet inflammation and enhances β-cell regeneration. DOI: http://dx.doi.org/10.7554/eLife.04631.00

Drug-induced loss of imprinting revealed using bioluminescent reporters of Cdkn1c.

Genomic imprinting is an epigenetically mediated mechanism that regulates allelic expression of genes based upon parent-of-origin and provides a paradigm for studying epigenetic silencing and release. Here, bioluminescent reporters for the maternally-expressed imprinted gene Cdkn1c are used to examine the capacity of chromatin-modifying drugs to reverse paternal Cdkn1c silencing. Exposure of reporter mouse embryonic stem cells (mESCs) to 5-Azacytidine, HDAC inhibitors, BET inhibitors or GSK-J4 (KDM6A/B inhibitor) relieved repression of paternal Cdkn1c, either selectively or by inducing biallelic effects. Treatment of reporter fibroblasts with HDAC inhibitors or GSK-J4 resulted in similar paternal Cdkn1c activation, whereas BET inhibitor-induced loss of imprinting was specific to mESCs. Changes in allelic expression were generally not sustained in dividing cultures upon drug removal, indicating that the underlying epigenetic memory of silencing was maintained. In contrast, Cdkn1c de-repression by GSK-J4 was retained in both mESCs and fibroblasts following inhibitor removal, although this impact may be linked to cellular stress and DNA damage. Taken together, these data introduce bioluminescent reporter cells as tools for studying epigenetic silencing and disruption, and demonstrate that Cdkn1c imprinting requires distinct and cell-type specific chromatin features and modifying enzymes to enact and propagate a memory of silencing

Brd2/4 and Myc regulate alternative cell lineage programmes during early osteoclast differentiation in vitro

Osteoclast (OC) development in response to nuclear factor kappa-Β ligand (RANKL) is critical for bone homeostasis in health and in disease. The early and direct chromatin regulatory changes imparted by the BET chromatin readers Brd2-4 and OC-affiliated transcription factors (TFs) during osteoclastogenesis are not known. Here, we demonstrate that in response to RANKL, early OC development entails regulation of two alternative cell fate transcriptional programmes, OC vs macrophage, with repression of the latter following activation of the former. Both programmes are regulated in a non-redundant manner by increased chromatin binding of Brd2 at promoters and of Brd4 at enhancers/super-enhancers. Myc, the top RANKL-induced TF, regulates OC development in co-operation with Brd2/4 and Max and by establishing negative and positive regulatory loops with other lineage-affiliated TFs. These insights into the transcriptional regulation of osteoclastogenesis suggest the clinical potential of selective targeting of Brd2/4 to abrogate pathological OC activation

Qualitative insights into the feelings, knowledge, and impact of SUDEP: A narrative synthesis

People with epilepsy (PWE) have a two- to threefold increased chance of premature death due to the condition. Interested in exploring the first-person perspective on this topic, we conducted a narrative synthesis to present the qualitative insight of PWE, their family, friends, and healthcare providers (HCPs) in relation to epilepsy-related death. A comprehensive electronic search of all peer-reviewed qualitative studies was conducted through databases using relevant keywords and Medical Subject Headings (MeSH) terms. Handsearching and exploration of pertinent gray literature was conducted thereafter. After a comprehensive literature search, the decisions of inclusion of literature were discussed and confirmed between the two authors. A total of 20 peer-reviewed papers were included. Within this, 17 were qualitative or mixed methods studies, and three were gray literature and guidelines/recommendations in discussing sudden unexpected death in epilepsy (SUDEP) with PWE and their families. The resultant main categories were the following: a) understanding of SUDEP and b) discussion of SUDEP. Findings show that there is an overall lack of understanding of unexpected epilepsy-related death for PWE and their relations. The literature focused on the education of PWE and their family in relation to SUDEP, and therefore, there is a lack of discussion on the general topic of epilepsy-related death. Findings show the conflicting perceptions, feelings, and thought processes that occur in learning about and deciding to discuss SUDEP as a HCP, PWE, or family/friend of a PWE. The literature suggests that it would be appropriate and necessary to discuss the topic of SUDEP with patients and their family members upon diagnosis

Characteristics associated with quality of life among people with drug-resistant epilepsy

Quality of Life (QoL) is the preferred outcome in non-pharmacological trials, but there is little UK population evidence of QoL in epilepsy. In advance of evaluating an epilepsy self-management course we aimed to describe, among UK participants, what clinical and psycho-social characteristics are associated with QoL. We recruited 404 adults attending specialist clinics, with at least two seizures in the prior year and measured their self-reported seizure frequency, co-morbidity, psychological distress, social characteristics, including self-mastery and stigma, and epilepsy-specific QoL (QOLIE-31-P). Mean age was 42 years, 54% were female, and 75% white. Median time since diagnosis was 18 years, and 69% experienced ≥10 seizures in the prior year. Nearly half (46%) reported additional medical or psychiatric conditions, 54% reported current anxiety and 28% reported current depression symptoms at borderline or case level, with 63% reporting felt stigma. While a maximum QOLIE-31-P score is 100, participants’ mean score was 66, with a wide range (25–99). In order of large to small magnitude: depression, low self-mastery, anxiety, felt stigma, a history of medical and psychiatric comorbidity, low self-reported medication adherence, and greater seizure frequency were associated with low QOLIE-31-P scores. Despite specialist care, UK people with epilepsy and persistent seizures experience low QoL. If QoL is the main outcome in epilepsy trials, developing and evaluating ways to reduce psychological and social disadvantage are likely to be of primary importance. Educational courses may not change QoL, but be one component supporting self-management for people with long-term conditions, like epilepsy