Attenuated reovirus displays oncolysis with reduced host toxicity

Background: Although the naturally occurring reovirus causes only mild symptoms in humans, it shows considerable potential as an oncolytic agent because of its innate ability to target cancer cells. In immunocompromised hosts, however, wild-type reovirus can target healthy tissues, including heart, liver, pancreas and neural structures. Methods: We characterized an attenuated form of reovirus (AV) derived from a persistently infected cell line through sequence analysis, as well as western blot and in vitro transcription and translation techniques. To examine its pathogenesis and oncolytic potential, AV reovirus was tested on healthy embryonic stem cells, various non-transformed and transformed cell lines, and in severe combined immunodeficiency (SCID) mice with tumour xenografts. Results: Sequence analysis of AV reovirus revealed a premature STOP codon in its sigma 1 attachment protein. Western blot and in vitro translation confirmed the presence of a truncated ?1. In comparison to wild-type reovirus, AV reovirus did not kill healthy stem cells or induce black tail formation in SCID mice. However, it did retain its ability to target cancer cells and reduce tumour size. Conclusion: Despite containing a truncated attachment protein, AV reovirus still preferentially targets cancer cells, and compared with wild-type reovirus it shows reduced toxicity when administered to immunodeficient hosts, suggesting the potential use of AV reovirus in combination cancer therapy

Exploring the role of external experts in supporting staff to implement psychosocial interventions in care home settings: results from the process evaluation of a randomized controlled trial

Background: Psychosocial interventions offer opportunities to improve care for people with dementia in care homes. However, implementation is often led by staff who are not well prepared for the role. Some interventions use external experts to support staff. However little is known about external expert, care home staff and manager perceptions of such support. This paper addresses this gap. Methods: Multi-methods study within a process evaluation of a cluster randomised controlled trial of Dementia Care MappingTM (DCM). Interviews were conducted with six external experts who also completed questionnaires, 17 care home managers and 25 care home staff responsible for DCM implementation. Data were analysed using descriptive statistics and template analysis. Results: Three themes were identified: the need for expert support, practicalities of support and broader impacts of providing support. Expert support was vital for successful DCM implementation, although the five-days provided was felt to be insufficient. Some homes felt the support was inflexible and did not consider their individual needs. Practical challenges of experts being located at a geographical distance from the care homes, limited when and how support was available. Experts gained knowledge they were able to then apply in delivering DCM training. Experts were not able to accurately predict which homes would be able to implement DCM independently in future cycles. Conclusions: An external expert may form a key component of successful implementation of psychosocial interventions in care home settings. Future research should explore optimal use of the expert role

Mapping anhedonia onto reinforcement learning: A behavioural meta-analysis

BACKGROUND: Depression is characterised partly by blunted reactions to reward. However, tasks probing this deficiency have not distinguished insensitivity to reward from insensitivity to the prediction errors for reward that determine learning and are putatively reported by the phasic activity of dopamine neurons. We attempted to disentangle these factors with respect to anhedonia in the context of stress, Major Depressive Disorder (MDD), Bipolar Disorder (BPD) and a dopaminergic challenge. METHODS: Six behavioural datasets involving 392 experimental sessions were subjected to a model-based, Bayesian meta-analysis. Participants across all six studies performed a probabilistic reward task that used an asymmetric reinforcement schedule to assess reward learning. Healthy controls were tested under baseline conditions, stress or after receiving the dopamine D2 agonist pramipexole. In addition, participants with current or past MDD or BPD were evaluated. Reinforcement learning models isolated the contributions of variation in reward sensitivity and learning rate. RESULTS: MDD and anhedonia reduced reward sensitivity more than they affected the learning rate, while a low dose of the dopamine D2 agonist pramipexole showed the opposite pattern. Stress led to a pattern consistent with a mixed effect on reward sensitivity and learning rate. CONCLUSION: Reward-related learning reflected at least two partially separable contributions. The first related to phasic prediction error signalling, and was preferentially modulated by a low dose of the dopamine agonist pramipexole. The second related directly to reward sensitivity, and was preferentially reduced in MDD and anhedonia. Stress altered both components. Collectively, these findings highlight the contribution of model-based reinforcement learning meta-analysis for dissecting anhedonic behavior