Research utilisation and knowledge mobilisation in the commissioning and joint planning of public health interventions to reduce alcohol-related harms: a qualitative case design using a cocreation approach

Background: Considerable resources are spent on research to establish what works to improve the nation’s health. If the findings from this research are used, better health outcomes can follow, but we know that these findings are not always used. In public health, evidence of what works may not ‘fit’ everywhere, making it difficult to know what to do locally. Research suggests that evidence use is a social and dynamic process, not a simple application of research findings. It is unclear whether it is easier to get evidence used via a legal contracting process or within unified organisational arrangements with shared responsibilities. Objective: To work in cocreation with research participants to investigate how research is utilised and knowledge mobilised in the commissioning and planning of public health services to reduce alcohol-related harms. Design, setting and participants: Two in-depth, largely qualitative, cross-comparison case studies were undertaken to compare real-time research utilisation in commissioning across a purchaser–provider split (England) and in joint planning under unified organisational arrangements (Scotland) to reduce alcohol-related harms. Using an overarching realist approach and working in cocreation, case study partners (stakeholders in the process) picked the topic and helped to interpret the findings. In Scotland, the topic picked was licensing; in England, it was reducing maternal alcohol consumption. Methods: Sixty-nine interviews, two focus groups, 14 observations of decision-making meetings, two local feedback workshops (n = 23 and n = 15) and one national workshop (n = 10) were undertaken. A questionnaire (n = 73) using a Behaviourally Anchored Rating Scale was issued to test the transferability of the 10 main findings. Given the small numbers, care must be taken in interpreting the findings. Findings: Not all practitioners have the time, skills or interest to work in cocreation, but when there was collaboration, much was learned. Evidence included professional and tacit knowledge, and anecdotes, as well as findings from rigorous research designs. It was difficult to identify evidence in use and decisions were sometimes progressed in informal ways and in places we did not get to see. There are few formal evidence entry points. Evidence (prevalence and trends in public health issues) enters the process and is embedded in strategic documents to set priorities, but local data were collected in both sites to provide actionable messages (sometimes replicating the evidence base). Conclusions: Two mid-range theories explain the findings. If evidence has saliency (relates to ‘here and now’ as opposed to ‘there and then’) and immediacy (short, presented verbally or visually and with emotional appeal) it is more likely to be used in both settings. A second mid-range theory explains how differing tensions pull and compete as feasible and acceptable local solutions are pursued across stakeholders. Answering what works depends on answering for whom and where simultaneously to find workable (if temporary) ‘blends’. Gaining this agreement across stakeholders appeared more difficult across the purchaser–provider split, because opportunities to interact were curtailed; however, more research is needed. Funding: This study was funded by the Health Services and Delivery Research programme of the National Institute for Health Research

STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa