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Background: Improving Access to Psychological Therapies (IAPT) constitutes a key element of England's national mental health strategy. Accessing IAPT usually requires patients to self-refer on the advice of their GP. Little is known about how GPs perceive and communicate IAPT services with patients from low-income communities, nor how the notion of self-referral is understood and responded to by such patients. Aims: This paper examines how IAPT referrals are made by GPs and how these referrals are perceived and acted on by patients from low-income backgrounds Method: Findings are drawn from in-depth interviews with low-income patients experiencing mental distress (n = 80); interviews with GPs (n = 10); secondary analysis of video-recorded GP-patient consultations for mental health (n = 26). Results: GPs generally supported self-referral, perceiving it an important initial step towards patient recovery. Most patients however, perceived self-referral as an obstacle to accessing IAPT, and felt their mental health needs were being undermined. The way that IAPT was discussed and the pathway for referral appears to affect uptake of these services. Conclusions: A number of factors deter low-income patients from self-referring for IAPT. Understanding these issues is necessary in enabling the development of more effective referral and support mechanisms within primary care. [ABSTRACT FROM AUTHOR]

High cellular heterogeneity within neuroblastomas (NBs) may account for the non-uniform response to treatment. c-KIT+ cells are frequently detected in NB, but how they influence NB behavior still remains elusive. Here, we used NB tumor-initiating cells to reconstitute NB development and demonstrated that c-KIT+ cells are de novo generated and dynamically maintained within the tumors to sustain tumor progression. c-KIT+ NB cells express higher levels of neural crest and stem cell markers (SLUG, SOX2 and NANOG) and are endowed with high clonogenic capacity, differentiation plasticity and are refractory to drugs. With serial transplantation assays, we found that c-KIT expression is not required for tumor formation, but c-KIT+ cells are more aggressive and can induce tumors ninefold more efficiently than c-KIT−/low cells. Intriguingly, c-KIT+ cells exhibited a long-term in vivo self-renewal capacity to sustain the formation of secondary and tertiary tumors in mice. In addition, we showed that Prokineticin signaling and mitogen-activated protein kinase pathways are crucial for the maintenance of c-KIT+ cells in tumor to promote NB progression. Our results highlight the importance of this de novo population of NB cells in sustainable growth of NB and reveal specific signaling pathways that may provide targets leading to more effective NB therapies. [ABSTRACT FROM AUTHOR]

This commentary draws on our experience organising a targeted networking event at the 10th International Conference on Health and Hepatitis in Substance Users, in Glasgow, Scotland in October 2022. The event, held the day before the conference, brought together people with lived and living experiences of drug use and early- and mid-career researchers on an equitable basis. We offer reflections, focussing on how the event promoted community-academic engagement from members of the respective groups. We provide recommendations for how conferences can organise to engage with people who use drugs-both those with lived and living experience and foster greater inclusion for all attendees., (© 2024 The Author(s). Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Background: The South West Peninsula (Cornwall, Devon, Somerset) has the highest proportion of over 65s (24.2%) and is the only English rural population with greater economic deprivation than in urban areas. Coastal populations have the worst health outcomes in England. Despite innovation among communities to support those with health and care needs in later life, recruitment to palliative care research in the region is low and there has been no evaluation of public health palliative care interventions., Objectives: A new South West Peninsula Palliative Care Research Partnership was funded for 15 months, bringing together four universities, the voluntary and community sector (including hospices) and local National Institute for Health and Care Research networks. The aim was to establish a sustainable multisectoral partnership that would identify community-based support needs for underserved rural and coastal populations by: • conducting a literature scoping review on interventions to enable community members to support the dying; • delivering a research capacity-building programme; • co-creating public and patient involvement capacity; • determining the resources and needs for communities to support dying well; • integrating findings to develop a framework of community-based support and identify future research questions; • establishing a sustainable research network infrastructure for the long-term design and delivery of palliative care research., Design: We convened partners to identify research needs and co-designed activities to meet our objectives. These included a scoping review; a capacity-building programme of training, seminars and a journal club; forming a patient and public involvement group; a multistranded community engagement programme using different creative approaches; four focus groups with members of the public and one with community workers; and producing three 'storytelling' audio recordings. Findings were presented to the partnership at a regional workshop., Results: The scoping review showed that community-engaged palliative care interventions can improve outcomes for individuals but provided little evidence about which approaches work for different communities. Five online seminars and a quarterly journal club to develop research capacity were regularly attended by 15 to 25 participants from across the partnership. While evaluating our engagement methods was beyond the partnership's scope, levels of participation suggested that creative methods of engagement show potential to help researchers and practitioners better understand the needs and priorities of underserved populations. Data showed that rural, coastal and low-income communities face challenges in accessing end-of-life care and support due to issues such as transport to and distance from services, erosion of neighbourhood networks, isolation from family and friends, 'patchiness' of palliative care services and a lack of care providers. Community organisations are well-placed to co-produce and facilitate methodologies for involving communities in palliative care research., Limitations: Although activities took place in diverse areas, it was not possible within the available resources to cover the entire large geographical region, particularly the most isolated rural areas., Conclusions: Partnerships bringing together voluntary and community sector organisations, palliative care providers, health and social care providers, individuals with experience and academics have potential to design future research and public health interventions that better understand local context, involving and supporting communities to address their needs at end of life., Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme as award number NIHR135312.

Background: England's South-west Peninsula is largely rural, has a high proportion of over 65s, and has areas of rural and coastal deprivation. Rural and low-income populations face inequities at end of life and little is known about the support needs of rural, coastal and low-income communities., Objectives: To understand how to foster community support for dying and grieving well, a regional, multi-sectoral research partnership developed a community engagement programme to explore experiences of seeking support, issues important to people and the community support they valued. This article shares what people told us about the role that communities can play at end of life, and reflects on learning from our process of engaging communities in conversations about dying., Design and Methods: A programme of varied community engagement which included: the use of the 'Departure Lounge' installation and four focus groups with interested individuals in a range of community settings; the co-creation of a 'Community Conversation' toolkit to facilitate conversations with individuals with experience of end-of-life care and their carers with Community Builders; a focus group with Community Builders and a storytelling project with three bereaved individuals., Results: People valued community support at the end of life or in bereavement that offered connection with others, peer support without judgement, responded to their individual needs and helped them to access services. Creative methods of engagement show potential to help researchers and practitioners better understand the needs and priorities of underserved populations. Collaboration with existing community groups was key to engagement, and contextual factors influenced levels of engagement., Conclusion: Local community organizations are well placed to support people at end of life. This work highlighted the potential for partnership with palliative care and bereavement organizations, who could offer opportunities to develop people's knowledge and skills, and together generate sustainable solutions to meet local need., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

There is a need to understand how to improve palliative care provision for people impacted by social inequity. Social inequity, such as that related to socioeconomic circumstances, has profound impacts on experiences of death and dying, posing personal and professional challenges for frontline professionals tasked to ensure that everyone receives the best standard of care at the end of their lives. Recent research has highlighted an urgent need to find ways of supporting healthcare professionals to acknowledge and unpack some of the challenges experienced when trying to deliver equitable palliative care. For example, those involved in patient or person-centred activities within health settings often feel comfortable focusing on individual choice and responsibility. This can become ethically problematic when considering that inequities experienced towards the end of life are produced and constrained by socio-structural forces beyond one individual's control. Ideas and theories originating outside palliative care, including work on structural injustice, cultural safety and capabilities approach, offer an alternative lens through which to consider roles and responsibilities for attending to inequities experienced at the end of life. This paper draws upon these ideas to offer a new way of framing individual responsibility, agency and collective action that may help palliative care professionals to support patients nearing their end of life, and their families, in the context of socioeconomic disadvantage. In this paper, we argue that, ultimately, for action on inequity in palliative care to be effective, it must be coherent with how people understand the production of, and responsibility for, those inequities, something that there is limited understanding of within palliative care., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Background: Public health palliative care views communities as an integral part of care delivery at the end of life. This community-provider partnership approach has the potential to improve end-of-life care for people who are dying and their carers., Objective: To identify and appraise the current literature related to public health interventions that enable communities to support people who are dying and their carers., Methods: A scoping review was conducted, applying Arksey and O'Malley's methods. Data was extracted and synthesized using narrative techniques, and results are reported using PRISMA guidelines., Results: The search yielded 2,902 results. Eighteen met inclusion criteria and were included in the analysis. Interventions were categorized according to their target population: people with life-limiting illness (ex. facilitated social interaction, helplines and guided discussions about death and dying); carers (ex. social support mapping, psychoeducation, and community resource identification and facilitation); or dyads (ex. reminiscence activities, practical and emotional support from volunteers, online modules to bolster coping mechanisms). Public health palliative care approaches were delivered by key community stakeholders such as community health workers, volunteers, peer mentors, and pre-established support groups. Despite reported challenges in identifying appropriate tools to measure effectiveness, studies report improvement in quality of life, loneliness, social support, stress and self-efficacy., Conclusion: We found that community-engaged palliative care interventions can lead to appreciable changes in various outcomes, though it was difficult to determine in which contexts this approach works best because of the dearth of contextual information reported. Based on the varied design and implementation strategies, it is clear that no one method for enhancing end of life care will benefit all communities and it is crucial to engage community members at all stages of the design and implementation process. Future research should be grounded in appropriate theory, describe contextual differences in these communities, and should specifically examine how demographics, resource availability, and social capital might impact the design, implementation, and results of public health palliative care interventions., Competing Interests: LS was employed by St Christopher's Hospice. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Peeler, Doran, Winter-Dean, Ijaz, Brittain, Hansford, Wyatt, Sallnow and Harding.)

Background: The Incredible Years ® (IY) Teacher Classroom Management (TCM) programme may reduce disruptive behaviour in the classroom and improve child and teacher mental health; however, few studies have considered how acceptable TCM is to teachers or what facilitators and barriers there are to its implementation., Aims: In this paper we examine the acceptability of the full 6-day TCM programme and teachers' perceived barriers and facilitators to implementation in the English (UK) primary school context., Sample: Forty-four English (UK) primary school teachers who attended the TCM programme as part of the STARS trial., Methods: We completed focus groups and telephone interviews with participating teachers 2 months after they completed the TCM programme. Thematic analysis was used to examine the data, and a framework approach was applied to organize and summarize themes., Results: Teachers liked the structure of the course, the peer group learning environment, delivery methods, and the opportunity to reflect outside the classroom on their practice. They reported that the video clips used lacked cultural relevance and highlighted the importance of group leadership style. Perceived facilitators to implementation included an understanding of the theory underpinning TCM and adaptability of the TCM strategies. Barriers included perceived gaps in the course content in relation to challenging behaviour, applying strategies with older children and the school context within which teachers were working., Conclusion: Our findings suggest high levels of acceptability to TCM overall, but also highlight the need for a whole school approach to combat potential barriers to implementation., (© 2022 The Authors. British Journal of Educational Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Background: Access to affordable, appropriate housing is one of the key social determinants of health, affecting well-being across the lifecourse. However, beyond a recognition that housing quality is linked to place of death, little is known about the ways in which housing status impacts social, emotional, and practical aspects of dying and bereavement., Method: The Checking Out project is a qualitative study aiming to explore the ways in which socio-economic status impacts people's experiences of, and attitudes towards, death, dying, and bereavement in the United Kingdom. Qualitative interviews were carried out with 14 bereaved individuals with experience of poverty at end of life or in bereavement, and 15 professionals supporting individuals in low-income communities. Interviews were conducted via phone/video call, and data include experiences of end of life and bereavement both before and during the pandemic. Transcripts were examined using thematic analysis., Results: Housing emerged as an important factor affecting people's experiences, with 7 of the 14 bereaved individuals and all except 1 of the professionals discussing housing-related issues. Participants described ways in which unsuitable housing and housing insecurity impacted practical aspects of dying but also emotional and social well-being at end of life. Housing-related issues affected both patients and their families, though families found it difficult to air these concerns when their relative was dying., Conclusion: The paper demonstrates how trusted professionals are able to advocate or address the issues faced by bereaved individuals and suggests implications for policy and practice. A greater awareness of the potential impact of housing status across public services, including healthcare practitioners, welfare support, and housing providers, could better support patients and practitioners to address these issues proactively. Housing providers and policy-makers should be included as key partners in collaborative public health approaches to palliative care., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: Involving patients, service users, carers and members of the public in research has been part of health policy and practice in the UK for the last 15 years. However, low-income communities tend to remain marginalized from the co-design and delivery of mental health research, perpetuating the potential for health inequalities. Greater understanding is therefore needed on how to meaningfully engage low-income communities in mental health research., Objectives: To explore and articulate whether and how an engaged research approach facilitated knowledge coproduction relating to poverty and mental distress., Setting: A reflective evaluation of community and researcher engagement in the DeStress study that took place in two low-income areas of South-west England., Design: Reflective evaluation by the authors through on-going feedback, a focus group and first-person writing and discussion on experiences of working with the DeStress project, and how knowledge coproduction was influenced by an engaged research approach., Results: An engaged research approach influenced the process and delivery of the DeStress project, creating a space where community partners felt empowered to coproduce knowledge relating to poverty-related mental distress, treatment and the training of health professionals that would otherwise have been missed. We examine motivations for involvement, factors sustaining engagement, how coproduction influenced research analysis, findings and dissemination of outputs, and what involvement meant for different stakeholders., Conclusion: Engaged research supported the coproduction of knowledge in mental health research with low-income communities which led to multiple impacts., (© 2020 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Narratives of self-responsibility are pervasive in neoliberally oriented contexts, and have been found to engender feelings of shame and failure amongst those affected by poverty. Here, we use findings from research in two low-income communities in south-west England to examine how these narratives become embodied within people's daily lives when they intersect with systems of welfare support and the current political drive to upscale treatment for common mental health conditions. Drawing on Bourdieu's notion of symbolic violence, we examine how narratives of self-responsibility and associated welfare reform strategies impact on the mental health of people living in economic hardship. The data show how such narratives inflict, sustain and exacerbate mental distress and suffering, and how they become naturalised and normalised by individuals themselves. We demonstrate how this situation pushes people to seek support from General Practitioners, and how clinical interactions can normalise, and in turn, medicalise, poverty-related distress. Whilst some people actively resist dominant narratives around self-responsibility, we argue that this is insufficient under broader sociocultural and political circumstances, to free themselves from the harms perpetuated by symbolic violence., (© 2020 The Authors. Sociology of Health & Illness published by John Wiley & Sons Ltd on behalf of Foundation for SHIL (SHIL).)

Background: The Incredible Years ® (IY) Teacher Classroom Management (TCM) programme may be an effective way to reduce teacher stress levels, improve child behaviour, and promote positive socio-emotional development. However, few studies have considered what teachers think of the course and how it might work., Aims: In this paper, we examine teachers' perceptions of the impact of the TCM programme and how it might work in the classroom., Sample(s): Forty-four UK primary school teachers who attended the TCM programme as part of the STARS trial (Ford et al., 2018, Psychol. Med., 49, 828)., Methods: Focus groups and interviews were held with teachers two months after completing the TCM programme. Thematic analysis (Braun & Clarke, 2006, Qual. Res. Psychol., 3, 77) was employed to explore the subsequent data., Results: Three main themes were identified: impact on the teacher; on children; and on parent-teacher relationships. Impact on the teacher included a positive change in their ethos. Teachers reported being more able to see things from the child's perspective; placing a greater focus on building positive relationships; thinking before responding; feeling calmer, more confident, and in control; and employing strategies to create positive interactions with children. Teachers felt this had had a positive impact on their pupils' development and relationships with parents. Feedback on whether or not TCM was effective in tackling particularly challenging behaviour was more mixed., Conclusions: Our findings suggest that teachers experience the TCM programme as beneficial. This is discussed alongside other qualitative and quantitative studies in this field., (© 2019 The British Psychological Society.)

Background: Teaching is a stressful occupation with poor retention. The Incredible Years® Teacher Classroom Management (TCM) programme is a training programme that research has demonstrated may be an effective intervention for improving children's mental health, but little research has explored any impacts there may be on the teachers' own professional confidence and mental health., Aims: In this paper, we evaluate whether TCM may lead to changes in teachers' well-being, namely a reduction in burnout and an improvement in self-efficacy and mental health., Sample: Eighty schools across the South West of England were recruited between September 2012 and September 2014. Headteachers were asked to nominate one class teacher to take part., Methods: Eighty teachers were randomized to either attend a TCM course (intervention) or not (control). TCM was delivered to groups of up to 12 teachers in six whole-day workshops that were evenly spread between October and April. At baseline and 9-month follow-up, we measured teachers' mental health using the Everyday Feelings Questionnaire (EFQ), burnout using the Maslach Burnout Inventory-General Survey (MBI-GS), and self-efficacy using the Teachers' Sense of Efficacy Scale-Short (TSES-Short)., Results: Using linear regression models, there was little evidence of differences at follow-up between the intervention and control teachers on the outcomes (the smallest p-value was .09)., Conclusions: Our findings did not replicate previous research that TCM improved teachers' sense of efficacy. However, there were limitations with this study including low sample size., (© 2019 The British Psychological Society.)

Background: We evaluated the effectiveness and cost-effectiveness of the Incredible Years® Teacher Classroom Management (TCM) programme as a universal intervention, given schools' important influence on child mental health., Methods: A two-arm, pragmatic, parallel group, superiority, cluster randomised controlled trial recruited three cohorts of schools (clusters) between 2012 and 2014, randomising them to TCM (intervention) or Teaching As Usual (TAU-control). TCM was delivered to teachers in six whole-day sessions, spread over 6 months. Schools and teachers were not masked to allocation. The primary outcome was teacher-reported Strengths and Difficulties Questionnaire (SDQ) Total Difficulties score. Random effects linear regression and marginal logistic regression models using Generalised Estimating Equations were used to analyse the outcomes., Trial Registration: ISRCTN84130388., Results: Eighty schools (2075 children) were enrolled; 40 (1037 children) to TCM and 40 (1038 children) to TAU. Outcome data were collected at 9, 18, and 30-months for 96, 89, and 85% of children, respectively. The intervention reduced the SDQ-Total Difficulties score at 9 months (mean (s.d.):5.5 (5.4) in TCM v. 6.2 (6.2) in TAU; adjusted mean difference = -1.0; 95% CI-1.9 to -0.1; p = 0.03) but this did not persist at 18 or 30 months. Cost-effectiveness analysis suggested that TCM may be cost-effective compared with TAU at 30-months, but this result was associated with uncertainty so no firm conclusions can be drawn. A priori subgroup analyses suggested TCM is more effective for children with poor mental health., Conclusions: TCM provided a small, short-term improvement to children's mental health particularly for children who are already struggling.

Background: Presentation at an accident and emergency (A&E) department is a key opportunity to engage with a young person who self-harms. The needs of this vulnerable group and their fears about presenting to healthcare services, including A&E, are poorly understood., Aims: To examine young people's perceptions of A&E treatment following self-harm and their views on what constitutes a positive clinical encounter., Method: Secondary analysis of qualitative data from an experimental online discussion forum. Threads selected for secondary analysis represent the views of 31 young people aged 16-25 with experience of self-harm., Results: Participants reported avoiding A&E whenever possible, based on their own and others' previous poor experiences. When forced to seek emergency care, they did so with feelings of shame and unworthiness. These feelings were reinforced when they received what they perceived as punitive treatment from A&E staff, perpetuating a cycle of shame, avoidance and further self-harm. Positive encounters were those in which they received 'treatment as usual', i.e. non-discriminatory care, delivered with kindness, which had the potential to challenge negative self-evaluation and break the cycle., Conclusions: The clinical needs of young people who self-harm continue to demand urgent attention. Further hypothesis testing and trials of different models of care delivery for this vulnerable group are warranted., (© The Royal College of Psychiatrists 2016.)

Background: The 'Supporting Teachers And childRen in Schools' (STARS) study is a cluster randomised controlled trial evaluating the Incredible Years Teacher Classroom Management (TCM) programme as a public health intervention. TCM is a 6 day training course delivered to groups of 8-12 teachers. The STARS trial will investigate whether TCM can improve children's behaviour, attainment and wellbeing, reduce teachers' stress and improve their self-efficacy. This protocol describes the methodology of the process evaluation embedded within the main trial, which aims to examine the uptake and implementation of TCM strategies within the classroom plus the wider school environment and improve the understanding of outcomes., Methods/design: The STARS trial will work with eighty teachers of children aged 4-9 years from eighty schools. Teachers will be randomised to attend the TCM course (intervention arm) or to "teach as normal" (control arm) and attend the course a year later. The process evaluation will use quantitative and qualitative approaches to assess fidelity to model, as well as explore headteachers' and teachers' experiences of TCM and investigate school factors that influence the translation of skills learnt to practice. Four of the eight groups of teachers (n = 40) will be invited to participate in focus groups within one month of completing the TCM course, and again a year later, while 45 of the 80 headteachers will be invited to take part in telephone interviews. Standardised checklists will be completed by group leaders and each training session will be videotaped to assess fidelity to model. Teachers will also complete standardised session evaluations., Discussion: This study will provide important information about whether the Teacher Classroom Management course influences child and teacher mental health and well-being in both the short and long term. The process evaluation will provide valuable insights into factors that may facilitate or impede any impact., Trial Registration: The trial has been registered with ISCTRN (Controlled Trials Ltd) and assigned an ISRCTN number ISRCTN84130388 . Date assigned: 15 May 2012.

Routine Outcome Monitoring (ROM) is held as a greatly important part of practice across many Health Care Services, both in the NHS and in private practice. Yet despite this, there has been little research into the attitudes of practitioners towards ROM. This paper looks at the attitudes of 50 clinicians from two Child and Adolescent Mental Health Services in greater London. The findings showed that although the practitioners were not overwhelming positive in their attitudes to ROM, neither were they overwhelming negative, and many of their concerns involved practical issues surrounding ROM that are potentially soluble. Practitioner engagement in ROM is key if ROM is to be used constructively to reflect on practice., (© The Author(s) 2013.)

Purpose: Cancer recurrence is one of the major setbacks in oncology. Maintaining telomeres is essential for sustaining the limitless replicative potential of such cancers. Because telomerase is thought to be active in all tumor cells and normal stem cells, telomerase inhibition may be nonspecific and have detrimental effects on tissue maintenance and development by affecting normal stem cell self-renewal., Methods: We examined telomerase activity, telomere maintenance, and stem cell maturation in tumor subpopulations from freshly resected gliomas, long-term, primary, neural tumor-initiating cells (TIC) and corresponding normal stem cell lines. We then tested the efficacy of the telomerase inhibitor Imetelstat on propagation and self-renewal capacity of TIC and normal stem cells in vitro and in vivo., Results: Telomerase was undetectable in the majority of tumor cells and specific to the TIC subpopulation that possessed critically short telomeres. In contrast, normal tissue stem cells had longer telomeres and undetectable telomerase activity and were insensitive to telomerase inhibition, which results in proliferation arrest, cell maturation, and DNA damage in neural TIC. Significant survival benefit and late tumor growth arrest of neuroblastoma TIC were observed in a xenograft model (P = 0.02). Furthermore, neural TIC exhibited irreversible loss of self-renewal and stem cell capabilities even after cessation of treatment in vitro and in vivo., Conclusions: TIC exhaustion with telomerase inhibition and lack of telomerase dependency in normal stem cells add new dimensions to the telomere hypothesis and suggest that targeting TIC with telomerase inhibitors may represent a specific and safe therapeutic approach for tumors of neural origin., (©2011 AACR.)

N-myc has emerged as a member of a transcriptional regulatory network which impinges directly on the machinery of cell growth and proliferation. Critical during neural crest embryogenesis, N-myc is rapidly down-regulated as tissues become terminally differentiated and growth-arrested. The involvement of N-myc in these fundamental cellular processes necessitates an intricate strategy for its regulation, which is still being elucidated. Deregulated N-myc over-expression has clear transforming ability in vitro and in vivo. The transcriptional target genes responsible for this activity are beginning to be unravelled.

We report the isolation and characterization of human contactin 4 (CNTN4), a brain-derived, immunoglobulin superfamily molecule-2 (alias BIG-2) as a candidate gene responsible for the differentiation potential of human neuroblastoma cells. Northern blot analysis showed highest CNTN4 expression in testes, thyroid, small intestine, uterus and brain. Induction of CNTN4 mRNA expression in human neuroblastoma tumor cells treated with retinoic acid correlated with a block in retinoid-induced neuritogenesis. Our findings suggest a role for human contactin 4 protein in the response of neuroblastoma cells to differentiating agents., (Copyright 2003 S. Karger AG, Basel)

Point mutations, deletions, and recombinations of the RET proto-oncogene are associated with several inherited human diseases of neural crest-derived cells: Hirschsprung's disease, familial medullary thyroid carcinoma, and the multiple endocrine neoplasia (MEN) syndromes, types 2A and 2B. RET expression is restricted to normal and malignant cells of neural crest origin, such as human neuroblastoma cells. To better understand the role of the activated RET oncogene in neural crest cells, we transfected two adherent human neuroblastoma tumor cell lines with oncogenic MEN2 mutant RET cDNAs. Transfectant clones from both cell lines overexpressing MEN2B RET demonstrated a marked increase in the cell fraction growing in suspension. Both control and MEN2B cells formed tumors at the site of injection in all cases. However, mice injected with MEN2B cells developed lung metastases at a much higher frequency than control mice. Only RET protein derived from MEN2A transfectant cells had increased autokinase activity, whereas MEN2B transfectant cells demonstrated selective activation of the mitogen-activated protein kinase, Jun kinase-1 (Jnk1). These results indicate a biochemical signaling pathway that may link oncogenic RET with the metastatic process.