Coping and wellbeing

The aim of this study was to investigate the association between children’s coping styles and emotional outcomes, with particular reference to family factors, and maternal mental health and coping. Although a conceptually problematic construct, coping has been found to play an important role in development and wellbeing. Coping, particularly coping in children and how it develops, remains, however, a relatively sparsely researched area of study. The study took a mixed method approach, employing large scale survey data collection (n=2557) and in depth interviews with 144 children and their carers A number of potential ethical issues were identified, particularly in relation to possible identification of high levels of symptomatology and a focus on potentially upsetting feelings and events in a vulnerable sample (children). A consultant child psychiatrist who agreed to act as research consultant to the main study provided medical cover in the event that worrying symptoms were identified. In addition, interviewers were fully briefed with details of appropriate local helping agencies and self-help organisations, and this information was available to children or their parents who requested it. Results indicated consistent relationships between children’s coping and children’s anxiety and somatic symptoms, and also between children's coping and family factors, such as maternal mental health, parent-child relationship quality and parent relationship quality

Dimensions of coping and anxiety symptoms in a community sample of young children

Coping style plays an important role in children’s wellbeing. This paper describes the patterns of associations between children’s self-reported coping styles and symptoms of anxiety in order to determine whether particular dimensions are associated with better adjustment. Participants were 2566 children (1268 girls, 1298 boys) aged 7–11 years attending 15 schools in the South East of England. Results showed that aspects of coping were differentially associated with children’s self-reported anxiety. Patterns of association also varied by age and gender. Dimensions of coping were shown to form distinct adaptive and maladaptive coping styles which were also differentially associated with anxiety. Analysis of these styles indicated that it is the absence of maladaptive coping strategies, rather than the presence of adaptive strategies, that is significant in emotional wellbeing. These findings suggest that interventions designed to reduce or extinguish maladaptive coping styles may be of particular benefit in facilitating emotional wellbeing

CRISPR activation screen identifies TGFβ-associated PEG10 as a crucial tumor suppressor in Ewing sarcoma

As the second most common pediatric bone and soft tissue tumor, Ewing sarcoma (ES) is an aggressive disease with a pathognomonic chromosomal translocation t(11;22) resulting in expression of EWS-FLI1, an "undruggable" fusion protein acting as transcriptional modulator. EWS-FLI1 rewires the protein expression in cancer cells by activating and repressing a multitude of genes. The role and contribution of most repressed genes remains unknown to date. To address this, we established a CRISPR activation system in clonal SKNMC cell lines and interrogated a custom focused library covering 871 genes repressed by EWS-FLI1. Among the hits several members of the TGFβ pathway were identified, where PEG10 emerged as prime candidate due to its strong antiproliferative effect. Mechanistic investigations revealed that PEG10 overexpression caused cellular dropout via induction of cell death. Furthermore, non-canonical TGFβ pathways such as RAF/MEK/ERK, MKK/JNK, MKK/P38, known to lead to apoptosis or autophagy, were highly activated upon PEG10 overexpression. Our study sheds new light onto the contribution of TGFβ signalling pathway repression to ES tumorigenesis and suggest that its re-activation might constitute a novel therapeutic strategy

Acceptance patterns and decision-making for human papillomavirus vaccination among parents in Vietnam: an in-depth qualitative study post-vaccination

BACKGROUND: The GAVI Alliance’s decision in late 2011 to invite developing countries to apply for funding for human papillomavirus (HPV) vaccine introduction underscores the importance of understanding levels of HPV vaccine acceptance in developing country settings. In this paper, we present findings from qualitative research on parents’ rationales for vaccinating or not vaccinating their daughters (vaccine acceptance) and their decision-making process in the context of an HPV vaccination demonstration project in Vietnam (2008–2009). METHODS: We designed a descriptive qualitative study of HPV vaccine acceptability among parents of girls eligible for vaccination in four districts of two provinces in Vietnam(a). The study was implemented after each of two years of vaccinations was completed. In total, 133 parents participated in 16 focus group discussions and 27 semi-structured interviews. RESULTS: Focus group discussions and in-depth interviews with parents of girls vaccinated revealed that they were generally very supportive of immunization for disease prevention and of vaccinating girls against HPV. The involvement of the National Expanded Program of Immunization in the demonstration project lent credibility to the HPV vaccine, contributing to high levels of acceptance. For parents who declined participation, concerns about side effects, the possibility that the vaccine was experimental, and the possible impact of the vaccine on future fertility rose to the surface. In terms of the decision-making process, many parents exhibited ‘active decision-making,’ reaching out to friends, family, and opinion leaders for guidance prior to making their decision. CONCLUSION: Vietnam’s HPV vaccination experience speaks to the importance of close collaboration with the government to make the most of high levels of trust, and to reduce suspicions about new vaccines that may arise in the context of vaccine introduction in developing country settings

Corrigendum to "Inhibition of HDACs reduces Ewing sarcoma tumor growth through EWS-FLI1 protein destabilization" [Neoplasia volume 27 (2022) pp. 100784/Number C]

Oncogenic transcription factors lacking enzymatic activity or targetable binding pockets are typically considered “undruggable”. An example is provided by the EWS-FLI1 oncoprotein, whose continuous expression and activity as transcription factor are critically required for Ewing sarcoma tumor formation, maintenance, and proliferation. Because neither upstream nor downstream targets have so far disabled its oncogenic potential, we performed a high-throughput drug screen (HTS), enriched for FDA-approved drugs, coupled to a Global Protein Stability (GPS) approach to identify novel compounds capable to destabilize EWS-FLI1 protein by enhancing its degradation through the ubiquitin-proteasome system. The protein stability screen revealed the dual histone deacetylase (HDAC) and phosphatidylinositol-3-kinase (PI3K) inhibitor called fimepinostat (CUDC-907) as top candidate to modulate EWS-FLI1 stability. Fimepinostat strongly reduced EWS-FLI1 protein abundance, reduced viability of several Ewing sarcoma cell lines and PDX-derived primary cells and delayed tumor growth in a xenograft mouse model, whereas it did not significantly affect healthy cells. Mechanistically, we demonstrated that EWS-FLI1 protein levels were mainly regulated by fimepinostat's HDAC activity. Our study demonstrates that HTS combined to GPS is a reliable approach to identify drug candidates able to modulate stability of EWS-FLI1 and lays new ground for the development of novel therapeutic strategies aimed to reduce Ewing sarcoma tumor progression

Inhibition of HDACs reduces Ewing sarcoma tumor growth through EWS-FLI1 protein destabilization

Oncogenic transcription factors lacking enzymatic activity or targetable binding pockets are typically considered "undruggable". An example is provided by the EWS-FLI1 oncoprotein, whose continuous expression and activity as transcription factor are critically required for Ewing sarcoma tumor formation, maintenance, and proliferation. Because neither upstream nor downstream targets have so far disabled its oncogenic potential, we performed a high-throughput drug screen (HTS), enriched for FDA-approved drugs, coupled to a Global Protein Stability (GPS) approach to identify novel compounds capable to destabilize EWS-FLI1 protein by enhancing its degradation through the ubiquitin-proteasome system. The protein stability screen revealed the dual histone deacetylase (HDAC) and phosphatidylinositol-3-kinase (PI3K) inhibitor called fimepinostat (CUDC-907) as top candidate to modulate EWS-FLI1 stability. Fimepinostat strongly reduced EWS-FLI1 protein abundance, reduced viability of several Ewing sarcoma cell lines and PDX-derived primary cells and delayed tumor growth in a xenograft mouse model, whereas it did not significantly affect healthy cells. Mechanistically, we demonstrated that EWS-FLI1 protein levels were mainly regulated by fimepinostat's HDAC activity. Our study demonstrates that HTS combined to GPS is a reliable approach to identify drug candidates able to modulate stability of EWS-FLI1 and lays new ground for the development of novel therapeutic strategies aimed to reduce Ewing sarcoma tumor progression. Keywords: EWS-FLI1; Ewing sarcoma; Fimepinostat; HDACi; Protein stabilit