The HSP90 Inhibitor NVP-AUY922 Radiosensitizes by Abrogation of Homologous Recombination Resulting in Mitotic Entry with Unresolved DNA Damage

Heat shock protein 90 (HSP90) is a molecular chaperone responsible for the conformational maintenance of a number of client proteins that play key roles in cell cycle arrest, DNA damage repair and apoptosis following radiation. HSP90 inhibitors exhibit antitumor activity by modulating the stabilisation and activation of HSP90 client proteins. We sought to evaluate NVP-AUY922, the most potent HSP90 inhibitor yet reported, in preclinical radiosensitization studies.NVP-AUY922 potently radiosensitized cells in vitro at low nanomolar concentrations with a concurrent depletion of radioresistance-linked client proteins. Radiosensitization by NVP-AUY922 was verified for the first time in vivo in a human head and neck squamous cell carcinoma xenograft model in athymic mice, as measured by delayed tumor growth and increased surrogate end-point survival (p = <0.0001). NVP-AUY922 was shown to ubiquitously inhibit resolution of dsDNA damage repair correlating to delayed Rad51 foci formation in all cell lines tested. Additionally, NVP-AUY922 induced a stalled mitotic phenotype, in a cell line-dependent manner, in HeLa and HN5 cell lines irrespective of radiation exposure. Cell cycle analysis indicated that NVP-AUY922 induced aberrant mitotic entry in all cell lines tested in the presence of radiation-induced DNA damage due to ubiquitous CHK1 depletion, but resultant downstream cell cycle effects were cell line dependent.These results identify NVP-AUY922 as the most potent HSP90-mediated radiosensitizer yet reported in vitro, and for the first time validate it in a clinically relevant in vivo model. Mechanistic analysis at clinically achievable concentrations demonstrated that radiosensitization is mediated by the combinatorial inhibition of cell growth and survival pathways, ubiquitous delay in Rad51-mediated homologous recombination and CHK1-mediated G(2)/M arrest, but that the contribution of cell cycle perturbation to radiosensitization may be cell line specific

Barriers and enablers for participation in healthy lifestyle programs by adolescents who are overweight: a qualitative study of the opinions of adolescents, their parents and community stakeholders

Background: Overweight or obesity during adolescence affects almost 25% of Australian youth, yet limited research exists regarding recruitment and engagement of adolescents in weight-management or healthy lifestyle interventions, or best-practice for encouraging long-term healthy behaviour change. A sound understanding of community perceptions, including views from adolescents, parents and community stakeholders, regarding barriers and enablers to entering and engaging meaningfully in an intervention is critical to improve the design of such programs. Methods: This paper reports findings from focus groups and semi-structured interviews conducted with adolescents (n=44), parents (n=12) and community stakeholders (n=39) in Western Australia. Three major topics were discussed to inform the design of more feasible and effective interventions: recruitment, retention in the program and maintenance of healthy change. Data were analysed using content and thematic analyses.Results: Data were categorised into barriers and enablers across the three main topics. For recruitment, identified barriers included: the stigma associated with overweight, difficulty defining overweight, a lack of current health services and broader social barriers. The enablers for recruitment included: strategic marketing, a positive approach and subsidising program costs. For retention, identified barriers included: location, timing, high level of commitment needed and social barriers. Enablers for retention included: making it fun and enjoyable for adolescents, involving the family, having an on-line component, recruiting good staff and making it easy for parents to attend. For maintenance, identified barriers included: the high degree of difficulty in sustaining change and limited services to support change. Enablers for maintenance included: on-going follow up, focusing on positive change, utilisation of electronic media and transition back to community services. Conclusions: This study highlights significant barriers for adolescents and parents to overcome to engage meaningfully with weight-management or healthy lifestyle programs. A number of enablers were identified to promote ongoing involvement with an intervention. This insight into specific contextual opinions from the local community can be used to inform the delivery of healthy lifestyle programs for overweight adolescents, with a focus on maximising acceptability and feasibility

Behavioural activation by mental health nurses for late-life depression in primary care: a randomized controlled trial

Background: Depressive symptoms are common in older adults. The effectiveness of pharmacological treatments and the availability of psychological treatments in primary care are limited. A behavioural approach to depression treatment might be beneficial to many older adults but such care is still largely unavailable. Behavioural Activation (BA) protocols are less complicated and more easy to train than other psychological therapies, making them very suitable for delivery by less specialised therapists. The recent introduction of the mental health nurse in primary care centres in the Netherlands has created major opportunities for improving the accessibility of psychological treatments for late-life depression in primary care. BA may thus address the needs of older patients while improving treatment outcome and lowering costs.The primary objective of this study is to compare the effectiveness and cost-effectiveness of BA in comparison with treatment as usual (TAU) for late-life depression in Dutch primary care. A secondary goal is to explore several potential mechanisms of change, as well as predictors and moderators of treatment outcome of BA for late-life depression. Methods/design: Cluster-randomised controlled multicentre trial with two parallel groups: a) behavioural activation, and b) treatment as usual, conducted in primary care centres with a follow-up of 52 weeks. The main inclusion criterion is a PHQ-9 score > 9. Patients are excluded from the trial in case of severe mental illness that requires specialized treatment, high suicide risk, drug and/or alcohol abuse, prior psychotherapy, change in dosage or type of prescribed antidepressants in the previous 12 weeks, or moderate to severe cognitive impairment. The intervention consists of 8 weekly 30-min BA sessions delivered by a trained mental health nurse. Discussion: We expect BA to be an effective and cost-effective treatment for late-life depression compared to TAU. BA delivered by mental health nurses could increase the availability and accessibility of non-pharmacological treatments for late-life depression in primary care. Trial registration: This study is retrospectively registered in the Dutch Clinical Trial Register NTR6013on August 25th 2016. © 2017 The Author(s)

Recommendations for active correction of hypernatremia in volume-resuscitated shock or sepsis patients should be taken with a grain of salt: A systematic review

Background: Healthcare-acquired hypernatremia (serum sodium >145 mEq/dL) is common among critically ill and other hospitalized patients and is usually treated with hypotonic fluid and/or diuretics to correct a “free water deficit.� However, many hypernatremic patients are eu- or hypervolemic, and an evolving body of literature emphasizes the importance of rapidly returning critically ill patients to a neutral fluid balance after resuscitation. Objective: We searched for any randomized- or observational-controlled studies evaluating the impact of active interventions intended to correct hypernatremia to eunatremia on any outcome in volume-resuscitated patients with shock and/or sepsis. Data sources: We performed a systematic literature search with studies identified by searching MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, ClinicalTrials.gov, IndexCatalogue of the Library of the Surgeon General’s Office, DARE (Database of Reviews of Effects), and CINAHL and scanning reference lists of relevant articles with abstracts published in English. Data synthesis: We found no randomized- or observational-controlled trials measuring the impact of active correction of hypernatremia on any outcome in resuscitated patients. Conclusion: Recommendations for active correction of hypernatremia in resuscitated patients with sepsis or shock are unsupported by clinical research acceptable by modern evidence standards.ECU Open Access Publishing Support Fun