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Background The prevalence of psychological morbidity among asylum seekers and refugees is high, but these groups encounter extensive barriers to accessing health and social care. The aim of the PROSPER study was to assess the feasibility of conducting a randomised controlled trial in the UK of Problem Management Plus (PM+), an evidence-based psychosocial intervention delivered by lay therapists for distressed and functionally impaired asylum seekers and refugees. Design We undertook a feasibility study of PM+, which included a pilot study of the design features of a future definitive randomised controlled trial and economic evaluation. The feasibility study involved the adaptation of PM+ based on evidence drawn from literature synthesis and local stakeholder engagement, and a two-stage training procedure for lay therapists. These were followed by a pilot trial designed to assess the feasibility of conducting a three-arm randomised controlled trial of five 90-minute sessions of PM+, delivered individually or in groups, with 105 participants randomised 1 : 1 : 1 to individual PM+, group PM+ or a control intervention. Primary health outcomes were anxiety and depressive symptoms at 3 months; other outcomes included post-traumatic stress disorder symptoms, quality of life, progress with identified goals and service use. Findings We demonstrated that the form and content of PM+ could be adapted to meet the needs of asylum seekers and refugees. Twelve people with lived experience of the asylum process were successfully trained as lay therapists to deliver this targeted, low-intensity psychosocial intervention in local asylum seeker and refugee communities. The pilot trial was affected by governance issues. It began in December 2019 and was cut short by the COVID-19 pandemic. We were not able to complete recruitment and follow-up as planned; 11 out of 105 (10%) participants were recruited to the pilot trial (individual PM+, n = 4; group PM+, n = 3; control, n = 4); 8 out of 11 participants were followed up at 13 weeks and 7 out of 11 participants were followed up at 26 weeks. (Preliminary data were gathered on recruitment and retention, intervention fidelity and acceptability of study measures, including service use measures.) Limitations Protracted delays due to governance issues, followed by the COVID-19 pandemic, meant that we were unable to complete the pilot trial or to provide evidence regarding the feasibility of group PM+. The complexities of working with multiple languages and cultural groups were noted. There were mixed views on how successful PM+ might prove, and we had insufficient evidence to provide clear conclusions. Future work Future research could explore how technology can be used to improve the acceptability, feasibility, efficacy and potential cost-effectiveness of scalable mental health interventions and well-being support for distressed asylum seekers and refugees. The use of mobile phone and/or app-based forms of support may help to increase asylum seekers’ and refugees’ willingness to engage in research of this type. Conclusions Although it was not possible to specify the parameters for a full randomised controlled trial of PM+ for asylum seekers and refugees in the UK, our findings offer guidance on strategies that may be of value in future studies of this nature. Trial registration This trial is registered as ISRCTN15214107. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 10, No. 10. See the NIHR Journals Library website for further project information.

Background Asylum seekers and refugees (AS&Rs) experience impaired mental health and wellbeing, related to stresses in their country of origin, experiences in transit and reception on arrival, including significant barriers to accessing mainstream services. Their contact with health care is often crisis-driven and mediated through non-governmental organisations (NGOs). Problem Management Plus (PM+) is a psychosocial intervention recommended by the World Health Organisation to address distress experienced by adults affected by humanitarian crises. We are investigating its application for the first time in a high-income country. Methods In a pilot randomised controlled trial (RCT), PM+ will be delivered to AS&Rs in contact with NGOs in Liverpool City Region, UK by lay therapists who have lived experience of forced migration. Following systematic review and stakeholder engagement, PM+ has been adapted to the local context, and lay therapists have been trained in its delivery. We will assess the feasibility of conducting a three-arm RCT of five 90-min sessions of PM+, delivered individually or in groups by lay therapists to AS&Rs experiencing emotional distress and functional impairment, compared with each other and with usual support offered by local NGOs. Distress and impairment at baseline will be measured by the Hospital Anxiety and Depression Scale (HADS) and the WHO Disability Assessment Schedule (WHO-DAS). We aim to recruit 105 participants, 35 per arm. Primary health outcomes are anxiety and depressive symptoms at 3 months, measured by HADS. Secondary outcomes include subjective wellbeing, functional status, progress on identified problems, presence of post-traumatic stress disorder and depressive disorder and service usage. Longer-term impact will be assessed at 6 months post baseline, on the same parameters. We will assess the feasibility of conducting a full RCT in relation to the following elements: recruitment and retention of lay therapists and study participants; fidelity of delivery of PM+; and suitability of the study measures, including any linguistic or cultural barriers. Discussion We will use these findings to specify the parameters for a full RCT to test the effectiveness and cost-effectiveness of PM+ in reducing emotional distress and health inequalities, and improving functional ability and wellbeing, amongst asylum seekers and refugees. Trial registration ISRCTN, ID: ISRCTN15214107. Registered on 10 September 2019.

Background Chk1 inhibitors are currently under clinical evaluation as single agents and in combination with cytotoxic chemotherapy. Understanding determinants of sensitivity and novel combinations is critical for further clinical development. Methods Potentiation of mTOR inhibitor cytotoxicity by the Chk1 inhibitor V158411 was determined in p53 mutant colon cancer cells. DNA damage response, expression levels of repair proteins, cell cycle effects and the contribution of alternative DSB repair pathways were further evaluated by western blotting and high content analysis. Results mTOR inhibitors AZD8055, RAD-001, rapamycin and BEZ235 induced synergistic cytotoxicity with the Chk1 inhibitor V158411 in p53 mutant colon cancer cells. Reduced FANCD2, RAD51 and RPA70, core proteins in homologous recombination repair (HRR) and interstrand crosslink repair (ICLR), following inhibition of mTOR was associated with increased V158411 induced DSBs and caspase 3-independent cell death. Dual mTOR and Chk1 inhibition activated DNA-PKcs. Cells defective in DNA-PKcs exhibited increased resistance to V158411 with Chk1 expression closely correlated to DNA-PKcs expression in various types of cancer. Conclusions Down regulation of proteins involved in HRR or ICLR by mTOR inhibitors is associated with increased sensitivity of human tumours to Chk1 inhibitors such as V158411. High levels of DNA-PKcs may be a potential biomarker to stratify patients to Chk1 inhibitor therapy alone or in combination with mTOR inhibitors.

Background Chk1 inhibitors are currently in clinical trials as putative potentiators of cytotoxic chemotherapy drugs. Chk1 inhibitors may exhibit single agent anti-tumor activity in cancers with underlying DNA repair, DNA damage response or DNA replication defects. Methods Here we describe the cellular effects of the pharmacological inhibition of the checkpoint kinase Chk1 by the novel inhibitor V158411 in triple-negative breast cancer and ovarian cancer. Cytotoxicity, the effect on DNA damage response and cell cycle along with the ability to potentiate gemcitabine and cisplatin cytotoxicity in cultured cells was investigated. Western blotting of proteins involved in DNA repair, checkpoint activation, cell cycle and apoptosis was used to identify potential predictive biomarkers of Chk1 inhibitor sensitivity. Results The Chk1 inhibitors V158411, PF-477736 and AZD7762 potently inhibited the proliferation of triple-negative breast cancer cells as well as ovarian cancer cells, and these cell lines were sensitive compared to ER positive breast and other solid cancer cells lines. Inhibition of Chk1 in these sensitive cell lines induced DNA damage and caspase-3/7 dependent apoptosis. Western blot profiling identified pChk1 (S296) as a predictive biomarker of Chk1 inhibitor sensitivity in ovarian and triple-negative breast cancer and pH2AX (S139) in luminal breast cancer. Conclusions This finding suggests that Chk1 inhibitors either as single agents or in combination chemotherapy represents a viable therapeutic option for the treatment of triple-negative breast cancer. pChk1 (S296) tumor expression levels could serve as a useful biomarker to stratify patients who might benefit from Chk1 inhibitor therapy.

Background Chk1 inhibitors are currently in clinical trials in combination with a range of cytotoxic agents and have the potential to potentiate the clinical activity of a large number of standard of care chemotherapeutic agents. Utilizing pharmacodynamic biomarkers to optimize drug dose and scheduling in these trials could greatly enhance the likelihood of clinical success. Methods In this study, we evaluated the in vitro potentiation of the cytotoxicity of a range of cytotoxic chemotherapeutic drugs by the novel Chk1 inhibitor V158411 in p53 mutant colon cancer cells. Pharmacodynamic biomarkers were evaluated in vitro. Results V158411 potentiated the cytotoxicity of a range of chemotherapeutic agents with distinct mechanisms of action in p53 mutant colon cancer cell lines grown in anchorage dependent or independent culture conditions. Analysis of pharmacodynamic biomarker changes identified dependencies on the chemotherapeutic agent, the concentration of the chemotherapeutic and the duration of time between combination treatment and biomarker analysis. A reduction in total Chk1 and S296/S317/S345 phosphorylation occurred consistently with all cytotoxics in combination with V158411 but did not predict cell line potentiation. Induction of γH2AX levels was chemotherapeutic dependent and correlated closely with potentiation of gemcitabine and camptothecin in p53 mutant colon cancer cells. Conclusions Our results suggest that Chk1 phosphorylation could be a useful biomarker for monitoring inhibition of Chk1 activity in clinical trials involving a range of V158411-chemotherapy combinations and γH2AX induction as a predictor of potentiation in combinations containing gemcitabine or camptothecin.