Activating Transcription Factor 3 regulates in part the enhanced tumour cell cytotoxicity of the histone deacetylase inhibitor M344 and cisplatin in combination

<p>Abstract</p> <p>Background</p> <p>Activating Transcription Factor (ATF) 3 is a key regulator of the cellular integrated stress response whose expression has also been correlated with pro-apoptotic activities in tumour cell models. Combination treatments with chemotherapeutic drugs, such as cisplatin, and histone deacetylase (HDAC) inhibitors have been demonstrated to enhance tumour cell cytotoxicity. We recently demonstrated a role for ATF3 in regulating cisplatin-induced apoptosis and others have shown that HDAC inhibition can also induce cellular stress. In this study, we evaluated the role of ATF3 in regulating the co-operative cytotoxicity of cisplatin in combination with an HDAC inhibitor.</p> <p>Results</p> <p>The HDAC inhibitor M344 induced ATF3 expression at the protein and mRNA level in a panel of human derived cancer cell lines as determined by Western blot and quantitative RT-PCR analyses. Combination treatment with M344 and cisplatin lead to increased induction of ATF3 compared with cisplatin alone. Utilizing the MTT cell viability assay, M344 treatments also enhanced the cytotoxic effects of cisplatin in these cancer cell lines. The mechanism of ATF3 induction by M344 was found to be independent of MAPKinase pathways and dependent on ATF4, a known regulator of ATF3 expression. ATF4 heterozygote (+/-) and knock out (-/-) mouse embryonic fibroblast (MEF) as well as chromatin immunoprecipitation (ChIP) assays were utilized in determining the mechanistic induction of ATF3 by M344. We also demonstrated that ATF3 regulates the enhanced cytotoxicity of M344 in combination with cisplatin as evidenced by attenuation of cytotoxicity in shRNAs targeting ATF3 expressing cells.</p> <p>Conclusion</p> <p>This study identifies the pro-apoptotic factor, ATF3 as a novel target of M344, as well as a mediator of the co-operative effects of cisplatin and M344 induced tumour cell cytotoxicity.</p

A ‘random group of misfits’ or being ‘part of something bigger’? Exploring experiences of attending a non-religious congregation.

Purpose Religion is an important part of many people’s lives and there is some evidence that attending church or other religious congregations is positively associated with psychological well-being. However, religious participation is declining in Western Europe and North America. Sunday Assembly is a non-religious gathering that intends to provide a similar communal experience and a sense of spirituality to the church, but without the religious element. In the current study, we aimed to explore the experiences of and motivations for attending a non-religious congregation in relation to well-being. Methods A qualitative approach was taken, gathering data through semi-structured interviews with participants from Sunday Assembly congregations across England. Results Thematic analysis was used and three key themes were found: (1) searching for meaning and community, (2) Sunday Assembly as protective of mental health, and (3) loneliness in a crowd. Conclusions Sunday Assembly can provide a sense of belonging and improvement in mental health through shared experience and spirituality, and it can act as a coping mechanism during difficult times. Further research could explore the benefits of Sunday Assembly upon attendee’s mental health, test the effectiveness of Sunday Assembly as a coping mechanism, and whether continued attendance improves mood over time

Cisplatin Induces Cytotoxicity through the Mitogen-Activated Protein Kinase Pathways ana Activating Transcription Factor 3

AbstractThe mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3) as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogenactivated protein kinase (MAPK) pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellularsignal-regulated kinase, and p38) resulted in decreasedATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-ylF2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/murine embryonic fibroblasts (MEFs) were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin’s cytotoxic effects

Joint modelling of longitudinal processes and time-to-event outcomes in heart failure: systematic review and exemplar examining the relationship between serum digoxin levels and mortality

Background: Joint modelling combines two or more statistical models to reduce bias and increase efficiency. As the use of joint modelling increases it is important to understand how and why it is being applied to heart failure research. Methods: A systematic review of major medical databases of studies which used joint modelling within heart failure alongside an exemplar; joint modelling repeat measurements of serum digoxin with all-cause mortality using data from the Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure (DIG) trial. Results: Overall, 28 studies were included that used joint models, 25 (89%) used data from cohort studies, the remaining 3 (11%) using data from clinical trials. 21 (75%) of the studies used biomarkers and the remaining studies used imaging parameters and functional parameters. The exemplar findings show that a per unit increase of square root serum digoxin is associated with the hazard of all-cause mortality increasing by 1.77 (1.34–2.33) times when adjusting for clinically relevant covariates. Conclusion: Recently, there has been a rise in publications of joint modelling being applied to heart failure. Where appropriate, joint models should be preferred over traditional models allowing for the inclusion of repeated measures while accounting for the biological nature of biomarkers and measurement error

BEIS Call for Evidence - The Future for Small-scale Low-carbon Generation : Response from the UK Energy Research Centre (UKERC)

This submission draws on two streams of work undertaken as part of the UKERC research programme. Firstly, one stream concerns community energy, and our responses on this topic draw primarily on data from the UKERC Financing Community Energy project. Secondly, it draws on a number of recent UKERC publications on electricity systems and networks

The contribution of physician assistants/associates to secondary care : a systematic review

OBJECTIVE: To appraise and synthesise research on the impact of physician assistants/associates (PA) in secondary care, specifically acute internal medicine, care of the elderly, emergency medicine, trauma and orthopaedics, and mental health. DESIGN: Systematic review. SETTING: Electronic databases (Medline, Embase, ASSIA, CINAHL, SCOPUS, PsycINFO, Social Policy and Practice, EconLit and Cochrane), reference lists and related articles. INCLUDED ARTICLES: Peer-reviewed articles of any study design, published in English, 1995-2017. INTERVENTIONS: Blinded parallel processes were used to screen abstracts and full text, data extractions and quality assessments against published guidelines. A narrative synthesis was undertaken. OUTCOME MEASURES: Impact on: patients' experiences and outcomes, service organisation, working practices, other professional groups and costs. RESULTS: 5472 references were identified and 161 read in full; 16 were included-emergency medicine (7), trauma and orthopaedics (6), acute internal medicine (2), mental health (1) and care of the elderly (0). All studies were observational, with variable methodological quality. In emergency medicine and in trauma and orthopaedics, when PAs are added to teams, reduced waiting and process times, lower charges, equivalent readmission rate and good acceptability to staff and patients are reported. Analgesia prescribing, operative complications and mortality outcomes were variable. In internal medicine outcomes of care provided by PAs and doctors were equivalent. CONCLUSIONS: PAs have been deployed to increase the capacity of a team, enabling gains in waiting time, throughput, continuity and medical cover. When PAs were compared with medical staff, reassuringly there was little or no negative effect on health outcomes or cost. The difficulty of attributing cause and effect in complex systems where work is organised in teams is highlighted. Further rigorous evaluation is required to address the complexity of the PA role, reporting on more than one setting, and including comparison between PAs and roles for which they are substituting. PROSPERO REGISTRATION NUMBER: CRD42016032895

Physician associates working in secondary care teams in England: Interprofessional implications from a national survey

Physician associates (PAs) are a new type of healthcare professional to the United Kingdom; however, they are well established in the United States (where they are known as physician assistants). PAs are viewed as one potential solution to the current medical workforce doctor shortage. This study investigated the deployment of PAs within secondary care teams in England, through the use of a cross-sectional electronic, self-report survey. The findings from 14 questions are presented. Sixty-three PAs working in a range of specialties responded. A variety of work settings were reported, most frequently inpatient wards, with work generally taking place during weekdays. Both direct and non-direct patient care activities were reported, with the type of work undertaken varying at times, depending on the presence or absence of other healthcare professionals. PAs reported working within a variety of secondary care team staffing permutations, with the majority of these being interprofessional. Line management was largely provided by consultants; however day-to-day supervision varied, often relating to different work settings. A wide variation in ongoing supervision was also reported. Further research is required to understand the nature of PAs' contribution to collaborative care within secondary care teams in England

A qualitative study of the impact of plexiform neurofibromas on need fulfilment in adults with neurofibromatosis type 1

Objective: To explore the impact of plexiform neurofibromas on the lives of adults with neurofibromatosis type 1. Background: Neurofibromatosis type 1 is a complex neurogenetic syndrome that affects many aspects of health and functioning. A common manifestation of neurofibromatosis type 1 is plexiform neurofibromas, non-cancerous tumours that can cause disfigurement, pain and neurologic disability. Patient-reported outcome measures used in this condition have addressed symptoms and functional ability but not how the condition affects patients’ lives, particularly, their ability to meet their human needs. Methods: Unstructured qualitative interviews were conducted with adults with neurofibromatosis type 1–associated plexiform neurofibromas in the United Kingdom and United States. Interviewees were encouraged to describe how plexiform neurofibromas affected their ability to meet their needs. Interviews were audio-recorded and transcribed verbatim. The UK and US transcripts were combined and theoretical thematic analysis was conducted. Results: In all, 42 interviews (United Kingdom = 20, United States = 22) were conducted. Transcripts revealed 696 statements on the impact of plexiform neurofibromas on need fulfilment. Five major themes emerged: appearance, relationships, independence, role fulfilment and pleasure. Conclusion: Neurofibromatosis type 1–associated plexiform neurofibromas have a major effect on individuals’ ability to meet their needs. An understanding of need fulfilment will complement information generated from traditional patient-reported outcome measures, particularly in a multi-faceted syndrome such as neurofibromatosis type 1

A repeated measures experiment of school playing environment to increase physical activity and enhance self esteem in UK school children

School playtime provides daily opportunities for children to be active outdoors, but only makes small contributions to physical activity (PA) requirements. Natural environments facilitate unstructured PA and children report a preference for play in nature. Thus, play on the school field might encourage children to be more active during playtime. The primary aim of this study was to examine the impact of the school playing environment on children's PA. Descriptive data and fitness were assessed in 25 children aged 8–9 years from a single primary school. Over two consecutive weeks participants were allocated to either play on the school field or playground during playtime. The order of play in the two areas was randomised and counterbalanced. Moderate to vigorous PA (MVPA) was assessed during playtime on the last two days of each week using accelerometers. There was a significant interaction of environment and sex on MVPA during morning play (F(1,22) = 6.27; P0.05; np2 = 0.060) or all of playtime combined (P>0.05; np2 = 0.140). During morning play boys were significantly more active than girls on the playground (t(23) = 1.32; P0.05; n2 = 0.071). For lunch (F(1,22) = 24,11; P<0.001; np2 = 0.523) and all of playtime combined (F(1,22) = 33.67; P<0.001; np2 = 0.616) there was a significant effect of environment. There was also a significant main effect of sex during lunch (F(1,22) = 11.56; P<0.01; np2 = 0.344) and all of playtime combined (F(1,22) = 12.37; P<0.01; np2 = 0.371). MVPA was higher on the field and boys were more active than girls. Play on the field leads to increases in MVPA, particularly in girls. The promising trend for the effect of the natural environment on MVPA indicates that interventions aimed at increasing MVPA should use the natural environment and that schools should encourage greater use of their natural areas to increase PA