Reporter cell lines to screen for inhibitors or regulators of the KRAS-RAF-MEK1/2-ERK1/2 pathway.

The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is activated in cancer due to mutations in RAS proteins (especially KRAS), BRAF, CRAF, MEK1 and MEK2. Whilst inhibitors of KRASG12C (lung adenocarcinoma) and BRAF and MEK1/2 (melanoma and colorectal cancer) are clinically approved, acquired resistance remains a problem. Consequently, the search for new inhibitors (especially of RAS proteins), new inhibitor modalities and regulators of this pathway, which may be new drug targets, continues and increasingly involves cell-based screens with small molecules or genetic screens such as RNAi, CRISPR or protein interference. Here we describe cell lines that exhibit doxycycline-dependent expression KRASG12V or BRAFV600E and harbour a stably integrated EGR1:EmGFP reporter gene that can be detected by flow cytometry, high-content microscopy or immunoblotting. KRASG12V or BRAFV600E-driven EmGFP expression is inhibited by MEK1/2 or ERK1/2 inhibitors (MEKi and ERKi). BRAFi inhibit BRAFV600E-driven EmGFP expression but enhance the response to KRASG12V, recapitulating paradoxical activation of wild type RAF proteins. In addition to small molecules, expression of iDab6, encoding a RAS-specific antibody fragment inhibited KRASG12V- but not BRAFV600E-driven EmGFP expression. Finally, substitution of EmGFP for a bacterial nitroreductase gene allowed KRASG12V or BRAFV600E to drive cell death in the presence of a pro-drug, which may allow selection of pathway inhibitors that promote survival. These cell lines should prove useful for cell-based screens to identify new regulators of KRAS- or BRAF-dependent ERK1/2 signalling (drug target discovery) as well as screening or triaging 'hits' from drug discovery screens.

Paradoxical activation of the protein kinase-transcription factor ERK5 by ERK5 kinase inhibitors.

The dual protein kinase-transcription factor, ERK5, is an emerging drug target in cancer and inflammation, and small-molecule ERK5 kinase inhibitors have been developed. However, selective ERK5 kinase inhibitors fail to recapitulate ERK5 genetic ablation phenotypes, suggesting kinase-independent functions for ERK5. Here we show that ERK5 kinase inhibitors cause paradoxical activation of ERK5 transcriptional activity mediated through its unique C-terminal transcriptional activation domain (TAD). Using the ERK5 kinase inhibitor, Compound 26 (ERK5-IN-1), as a paradigm, we have developed kinase-active, drug-resistant mutants of ERK5. With these mutants, we show that induction of ERK5 transcriptional activity requires direct binding of the inhibitor to the kinase domain. This in turn promotes conformational changes in the kinase domain that result in nuclear translocation of ERK5 and stimulation of gene transcription. This shows that both the ERK5 kinase and TAD must be considered when assessing the role of ERK5 and the effectiveness of anti-ERK5 therapeutics.

How would patients with psychosis like to be in contact with a volunteer: Face-to-face or digitally?

INTRODUCTION: Volunteer befriending can be used to address social isolation in patients with psychosis. Traditionally this involves face-to-face encounters between a volunteer and a patient, but modern digital technology also makes it possible to have these interactions remotely. This study aimed to explore the views and interests of patients with psychosis about different formats of volunteering, face-to-face or digitally. METHODS: A survey was conducted with patients with psychotic disorders in community mental health teams in London. Questions covered socio-demographic characteristics, quality of life, loneliness, views on the different formats of volunteering and types of volunteers, and their interest in getting volunteering support, face-to-face or digitally. Binary logistic regressions were used to investigate potential predictors of interest in getting volunteering support face-to-face or digitally. RESULTS: A total of 151 patients with psychotic disorders were included in this study. More than half of the patients (n = 87, 57.6%) had not heard about these volunteering programs. Many were interested in getting face-to-face (n = 87, 57.6%) and digital (n = 56, 37.1%) volunteering. For the face-to-face encounters, most preferred them to be weekly (n = 36, 41.4%), for one-hour (n = 32, 36.8%), and with an open-ended relationship (n = 45, 51.7%). For the digital contacts, most preferred them to be weekly (n = 17, 30.9%) and through text messages (n = 26, 46.4%). A minority of patients (n = 20, 13.2%) did not use digital technology. Patients with lower quality of life were significantly more likely to prefer face-to-face volunteering (p < .05). Younger patients and with fewer years of diagnosis were significantly more likely to prefer digital volunteering (p < .05). CONCLUSIONS: The variability in patients' interests suggests that different formats of volunteer support should be offered. Digital volunteering may become more important in the future, since many younger patients are interested in it.

Motivations and experiences of volunteers and patients in mental health befriending: a thematic analysis.

BACKGROUND: Volunteers frequently participate in befriending schemes with people with mental illness. This study aimed to explore the motivations and experiences of volunteer befrienders engaging in these schemes in addition to the experiences of befriending recipients. METHODS: Semi-structured interviews were conducted with 38 volunteers and 23 befriending recipients, across 12 mental health befriending schemes in the UK, and analysed using Thematic Analysis. Volunteers highlighted their motivations for wanting to befriend. Individuals discussed their experiences, including the benefits and any challenges. RESULTS: Analysis of interviews revealed the motivations for individuals to volunteer in mental health care, the experiences of both volunteers and recipients of befriending, as well as how complex the role of befriender is. The three overarching themes were (1) Personal growth & altruism as motivations for volunteering, (2) Impact of "doing things" versus "being there" and (3) Negotiating between professional role and friendship. CONCLUSIONS: A number of personal and altruistic factors motivate individuals to volunteer in mental health care. The experiences of both volunteers and befriendees convey important factors affecting these relationships. In particular, the nuance of the befriending role and the ways in which it can impact the lives of recipients. Indeed, such factors need to be considered when formulating these befriending schemes.

Characteristics, motivations and experiences of volunteer befrienders for people with mental illness: a systematic review and narrative synthesis.

BACKGROUND: The literature suggests that many people in the general population tend to distance themselves from those with mental illness. However, there are volunteers that behave differently, spending their free time with people with mental illness and providing direct input in the form of befriending. Whilst there are a range of befriending programmes, little is known about who these volunteer befrienders are, and a previous review of different forms of volunteering in mental health care found data on only 63 befrienders. METHODS: We conducted a systematic electronic search of databases (BNI, CNIL, EMBASE, MEDLINE, PsycINFO, Cochrane Registers, Web of Science) to detect all papers reporting characteristics of befriending volunteers in mental health care published between 2011 and April 2018. The articles retrieved were combined with previous papers identified in an earlier review and with relevant papers identified by experts in the field. The articles that met the inclusion criteria were extracted and narratively synthesised. RESULTS: Nine studies met the inclusion criteria for this review, reporting characteristics of a total of 577 volunteer befrienders. The most often reported characteristics were age and gender, motivations to volunteer and experience of the role. Whilst characteristics vary greatly, most volunteers are female, and the average age is 50 years. Motivations generally fit into the categories of "giving" and "getting" and experiences are mixed. CONCLUSION: Published research on volunteer befrienders has increased in the last eight years, but is still limited. The range of characteristics suggests that there is a potential for encouraging a variety of people to volunteer as befrienders for people with mental illness. Understanding the characteristics and motivations of volunteers may help refine programmes and improve the experience of the volunteer befrienders.

Social networks of patients with chronic depression: A systematic review.

INTRODUCTION AND AIM: The social networks of patients are an important factor for the prognosis of mental disorders and can be potentially targeted through psycho-social interventions. We aimed to explore these networks in patients with chronic depression, by conducting a systematic review on the characteristics of social networks in this patient group. METHODS: Six databases, three key journals and grey literature were searched. Two reviewers screened the articles, assessed the risk of bias and extracted the information needed. Findings were descriptively synthesised. RESULTS: Nineteen articles met the inclusion criteria reporting the findings of a total of 873 patients with chronic depression. Four papers presented results without a comparison group (six in comparison to a healthy population, eight to patients with non-chronic major depression and three to patients with other mental disorders). Social networks of patients with chronic depression appeared to be smaller than those of healthy individuals, patients with non-chronic major depression and other disorders. LIMITATIONS: Studies used different concepts of chronic depression and inconsistent methodologies for assessing social networks. Only three studies adopted objective measures. CONCLUSIONS: Whilst the evidence on social networks of patients with chronic depression is limited, the networks appear smaller than in most comparison groups, including patients with non-chronic depression.

Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1/2 modulating ERK1/2 inhibitors.

Preferences for befriending schemes: a survey of patients with severe mental illness.

BACKGROUND: Befriending has become a widely used method for tackling social isolation in individuals with severe mental illness (SMI), and evidence exists to support its effectiveness. However, patient preferences for befriending remain unclear. We aimed to determine whether patients with SMI want a volunteer befriender and, if so, the volunteer characteristics and character of the relationship they would prefer. METHODS: A survey of outpatients was conducted across London-based community mental health teams, for individuals diagnosed with affective or psychotic disorders. Questions consisted of measures of demographic characteristics, befriending preferences and social context, including measures of time spent in activities, number of social contacts, loneliness and subjective quality of life (SQOL). Binary logistic regressions were used to investigate potential predictors of willingness to participate in befriending. RESULTS: The sample comprised of 201 participants with a mean age of 43 years. The majority (58%) of the sample indicated willingness to participate in befriending. In univariable analyses this was associated with less time spent in activities in the previous week, higher level of loneliness and lower SQOL. When all three variables were tested as predictors in a multivariable analysis, only lower SQOL remained significantly associated with willingness to take part in befriending. Relative to other options presented, large proportions of participants indicated preference for weekly (44%), 1-hour (39%) meetings with a befriender, with no limits on the relationship duration (53%). Otherwise, patient preferences exhibited great variability in relation to other characteristics of befriending schemes. CONCLUSIONS: A substantial number of patients with SMI appear willing to take part in a befriending scheme. Patients with lower SQOL are more likely to accept befriending, so that befriending schemes may be a realistic option to help patients with particularly low SQOL. The large variability in preferences for different types of befriending suggests that there is no one-size-fits-all formula and that schemes may have to be flexible and accommodate different individual preferences.

Prevalence of Posttraumatic Stress Disorder in Prisoners.

People involved with criminal justice frequently are exposed to violence and traumatic experiences. This may lead to posttraumatic stress disorder (PTSD); however, no review, to our knowledge, has synthetized findings in this setting. We conducted a systematic review and meta-analysis to estimate prevalence rates of PTSD in prison populations. Original studies in which prevalence rates of PTSD in unselected samples of incarcerated people were reported were systematically searched between 1980 and June 2017. Data were pooled using random-effects meta-analysis, and sources of heterogeneity for prespecified characteristics were assessed by meta-regression. We identified 56 samples comprising 21,099 imprisoned men and women from 20 countries. Point prevalence of PTSD ranged from 0.1% to 27% for male, and from 12% to 38% for female prisoner populations. The random-effects pooled point prevalence was 6.2% (95% confidence interval: 3.9, 9.0) in male prisoners and 21.1% (95% confidence interval: 16.9, 25.6) in female prisoners. The heterogeneity between the included studies was very high. Higher prevalence was reported in samples of female prisoners, smaller studies (n ≤ 200), and for investigations based in high-income countries. Existing evidence shows high levels of PTSD among imprisoned people, especially women. Psychosocial interventions to prevent violence, especially against children and women, and to mitigate its consequences in marginalized communities must be improved. Trauma-informed approaches for correctional programs and scalable PTSD treatments in prisons require further consideration.

Effectiveness of befriending interventions: a systematic review and meta-analysis.

OBJECTIVE: Befriending is an emotional supportive relationship in which one-to-one companionship is provided on a regular basis by a volunteer. It is commonly and increasingly offered by the voluntary sector for individuals with distressing physical and mental conditions. However, the effectiveness of this intervention on health outcomes is largely unknown. We aim to conduct a systematic review of the benefits of befriending. DESIGN: Systematic review. METHODS: A systematic search of electronic databases was conducted to identify randomised controlled trials and quasi-experimental trials of befriending for a range of physical and mental health indications including depression, anxiety, mental illness, cancer, physical illness and dementia. Main outcomes included patient-relevant and disease-specific outcomes, such as depression, loneliness, quality of life, self-esteem, social support and well-being. RESULTS: A total of 14 trials (2411 participants) were included; 7 were judged at low risk of bias. Most trials showed improvement in symptoms associated with befriending but these associations did not reach statistical significance in all trials. Befriending was significantly associated with better patient-reported outcomes across primary measures (standardised mean difference 0.18 (95% CI, -0.002 to 0.36, I2=26%, seven trials)). However, there was no significant benefit on single outcomes, including depression, quality of life, loneliness ratings, self-esteem measures, social support structures and well-being. CONCLUSIONS: There was moderate quality evidence to support the use of befriending for the treatment of individuals with different physical and mental health conditions. This evidence refers to an overall improvement benefit in patient-reported primary outcomes, although with a rather small effect size. The current evidence base does not allow for firm conclusions on more specific outcomes. Future trials should hypothesise a model for the precise effects of befriending and use specified inclusion and outcome criteria.

The Application of Positive Psychotherapy in Mental Health Care: A Systematic Review.

OBJECTIVE: Positive psychotherapy (PPT) stems from the positive psychology movement and is a multicomponent model promoting therapeutic change by developing engagement, pleasure, and meaning. There is some evidence it is effective for depression. PPT is recommended as a flexible model that can be applied to other patient groups alongside other treatments approaches. However, it remains unclear which of the many components are applied. The study aimed to identify how PPT is applied in mental health care. METHOD: We systematically searched online databases, including Medline, Embase, PsycINFO, British Nursing Index, Cumulative Index of Nursing and Applied Health, and Cochrane registers (CENTRAL), and completed complementary hand and citation searches. Narrative synthesis was used for analysis. RESULTS: A total of 12 papers (from 9 studies) widely applied some PPT components (e.g., blessings journal, character strengths) and scarcely applied others (e.g., satisficing plan or family strengths tree). However, papers poorly described the intervention and rationale for applying components. CONCLUSION: Given the lack of rationale for applying PPT, further research is needed to establish which components are acceptable and feasible for use in different patient groups and settings.