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Background Despite significant endeavor having been applied to identify effective therapies to treat glioblastoma (GBM), survival outcomes remain intractable. The greatest nonsurgical benefit arises from radiotherapy, though tumors typically recur due to robust DNA repair. Patients could therefore benefit from therapies with the potential to prevent DNA repair and synergize with radiotherapy. In this work, we investigated the potential of salinomycin to enhance radiotherapy and further uncover novel dual functions of this ionophore to induce DNA damage and prevent repair. Methods In vitro primary GBM models and ex vivo GBM patient explants were used to determine the mechanism of action of salinomycin by immunoblot, flow cytometry, immunofluorescence, immunohistochemistry, and mass spectrometry. In vivo efficacy studies were performed using orthotopic GBM animal xenograft models. Salinomycin derivatives were synthesized to increase drug efficacy and explore structure-activity relationships. Results Here we report novel dual functions of salinomycin. Salinomycin induces toxic DNA lesions and prevents subsequent recovery by targeting homologous recombination (HR) repair. Salinomycin appears to target the more radioresistant GBM stem cell–like population and synergizes with radiotherapy to significantly delay tumor formation in vivo. We further developed salinomycin derivatives which display greater efficacy in vivo while retaining the same beneficial mechanisms of action. Conclusion Our findings highlight the potential of salinomycin to induce DNA lesions and inhibit HR to greatly enhance the effect of radiotherapy. Importantly, first-generation salinomycin derivatives display greater efficacy and may pave the way for clinical testing of these agents.

Glioblastoma (GBM) is an essentially incurable and rapidly fatal cancer, with few markers predicting a favourable prognosis. Here we report that the transcription factor NFIB is associated with significantly improved survival in GBM. NFIB expression correlates inversely with astrocytoma grade and is lowest in mesenchymal GBM. Ectopic expression of NFIB in low-passage, patient-derived classical and mesenchymal subtype GBM cells inhibits tumourigenesis. Ectopic NFIB expression activated phospho-STAT3 signalling only in classical and mesenchymal GBM cells, suggesting a mechanism through which NFIB may exert its context-dependent tumour suppressor activity. Finally, NFIB expression can be induced in GBM cells by drug treatment with beneficial effects.

The EphA3 receptor has recently emerged as a functional tumour-specific therapeutic target in glioblastoma (GBM). EphA3 is significantly elevated in recurrent disease, is most highly expressed on glioma stem cells (GSCs), and has a functional role in maintaining self-renewal and tumourigenesis. An unlabelled EphA3-targeting therapeutic antibody is currently under clinical assessment in recurrent GBM patients. In this study, we assessed the efficacy of EphA3 antibody drug conjugate (ADC) and radioimmunotherapy (RIT) approaches using orthotopic animal xenograft models. Brain uptake studies, using positron emission tomography/computed tomography (PET/CT) imaging, show EphA3 antibodies are effectively delivered across the blood-tumour barrier and accumulate at the tumour site with no observed normal brain reactivity. A robust anti-tumour response, with no toxicity, was observed using EphA3, ADC, and RIT approaches, leading to a significant increase in overall survival. Our current research provides evidence that GBM patients may benefit from pay-loaded EphA3 antibody therapies.

Developing a critical analysis of the relational and situated practices of social policy, this paper draws on an evaluation of an early intervention project in Scotland (UK) where volunteer adult mentors supported young people ‘at risk’ of offending or antisocial behaviour. Contributing to ‘enlivened’ accounts of social practice, we explore how practices of mentoring developed through the co-presence of mentor and young person in the often transitory spaces of care which characterized the ‘diversionary activities’ approach in the project. We expand the notion of the relational in social practice beyond the care-recipient dyad to include wider networks of care (families, programme workers, social institutions). The paper explores how such social interventions might both be ‘good’ for the young people involved, and yet recognize critiques that more individualized models of intervention inevitably have limitations which make them ‘not enough’ to deal with structural inequalities and disadvantages. Acknowledging the impacts of neoliberalism, we argue critical attention to diverse situated relational practices points to the excessive nature of engagement in social policy and provides scope for transformative practice where young people’s geographies can be ‘upscaled’ to connect to the realms of social policy and practice. Résumé Développant une analyse critique de la politique sociale des pratiques relationnelles en situation, cet article s’appuie sur une évaluation d’un ancien programme d’intervention en Ecosse (Royaume-Uni), où des mentors adultes bénévoles aidaient des jeunes « en danger » de commettre un délit ou d’adopter un comportement antisocial. En apportant une contribution aux comptes rendus « animés » de politique sociale, nous explorons comment les pratiques de mentorat se sont développées à travers la coprésence d’un mentor et d’un jeune pendant les périodes souvent transitoires de prise en charge qui caractérisaient les approches d’« activités de diversion » de ce programme. Nous élargissons la notion du relationnel dans la pratique sociale au-delà de la dyade prise en charge-bénéficiaire en incluant les réseaux plus vastes de prise en charge (famille, acteurs du programme, institutions sociales). L’article explore dans quelle mesure les interventions sociales peuvent être « bonnes » pour les jeunes concernés mais reconnaît aussi les critiques que les modèles d’intervention plus individualisés ont inévitablement des limites qui les rendent « insuffisantes » pour gérer les inégalités et désavantages structuraux. Reconnaissant les effets du néolibéralisme, nous avançons l’argument que l’attention critique envers les diverses pratiques relationnelles en situation suggère la nature excessive de l’engagement politique social et donne la possibilité d’une pratique transformative où les géographies des jeunes peuvent être « améliorées » pour être reliées aux domaines de la politique et de la pratique sociales. Resumen Desarrollando un análisis crítico de las prácticas relacionales y situadas de la política social, este documento se basa en una evaluación de un proyecto de intervención temprana en Escocia (Reino Unido), donde mentores adultos voluntarios apoyaron a jóvenes ‘en riesgo’ de ofender o de mostrar un comportamiento antisocial. Contribuyendo a informes ‘animados’ de política social, se explora cómo se desarrollaron las prácticas de tutoría a través de la co-presencia de mentores y jóvenes en espacios a menudo transitorios de atención que caracterizaron el enfoque de las ‘actividades de distracción’ en el proyecto. Se amplía la noción de lo relacional en la práctica social más allá de la díada cuidado-receptor para incluir redes más amplias de cuidado (familias, trabajadores del programa, instituciones sociales). El trabajo explora cómo este tipo de intervenciones sociales podrían ser ‘buenas’ para los jóvenes involucrados y, sin embargo, al mismo tiempo, reconocer las críticas de que los modelos más individualizados de intervención tienen inevitablemente limitaciones que los hacen ‘no suficientes’ para hacer frente a desigualdades y desventajas estructurales. Reconociendo los impactos del neoliberalismo, se argumenta que la atención crítica a diversas prácticas relacionales situadas apunta al carácter excesivo de la participación en la política social y proporciona espacio para una práctica transformadora donde las geografías de los jóvenes pueden ‘aumentar de escala’ para conectarse con los dominios de la política y la práctica social.

This paper explores the motivations and meanings of international student mobility. Central to the discussion are the results of a large questionnaire survey and associated in-depth interviews with UK students enrolled in universities in six countries from around the world. The results suggest, first, that several different dimensions of social and cultural capital are accrued through study abroad. It is argued that the search for ‘world class’ education has taken on new significance. Second, the paper argues that analysis of student mobility should not be confined to a framework that separates study abroad from the wider life-course aspirations of students. It is argued that these insights go beyond existing theorisations of international student mobility to incorporate recognition of diverse approaches to difference within cultures of mobility, including class reproduction of distinction, broader notions of distinction within the life-plans of individual students, and how ‘reputations’ associated with educational destinations are structured by individuals, institutions and states in a global higher education system that produces differentially mediated geographies of international student mobility

Examining the everyday practices and feelings of volunteering, in particular their situated, emotional and embodied nature, serves to place the experiences of volunteers centrally in accounts of what matters in the doing of volunteering and goes beyond service provision or active citizenship. Using qualitative evidence from three collaborative research projects, we present enlivened geographies of volunteering which focus on: the situatedness of formal volunteering in place and the negotiation of local ‘moral economies’ of norms and expectations surrounding access to volunteering opportunities and the practices of volunteering; complex positionings of informal volunteering in biographies of social participation; and intersections of embodiment and emotions in experiences among environmental volunteers. We contribute to the development of social geographies which are ‘more-than-representational’ and argue that connecting insights on everyday practices of volunteering with wider policy and practice...

Objective: Histamine is a chemical mediator that acts at four known types of histamine receptors and has been widely implicated in the development of nociception and neuropathic pain. Blocking histamine H1 and H2 receptors has been shown to reduce hyperalgesia following nerve injury, but the role of histamine H3 and H4 receptors in neuropathic pain has not been studied. Here, we used blockers of histamine H3 and H4 receptors to assess their effects on neuropathic pain behavior and mast cell numbers following peripheral nerve injury. In addition, we assessed the effect of activating H4 receptors on neuropathic pain behavior. Methods: Rats were subjected to a partial ligation of the sciatic nerve, a model of neuropathic pain, and were treated either systemically or locally (hindpaw) with the H3/H4 receptor inverse agonist thioperamide, the specific H4 receptor antagonist JNJ 7777120, or the H4 receptor agonist VUF 8430. Measurements of mechanical hyperalgesia were carried out by Randall-Selitto test for 1–3 weeks, and sciatic nerve tissues were analyzed for numbers of intact mast cells by histology at 9 h after surgery. Results: Rats treated with thioperamide or JNJ 7777120 showed significantly enhanced mechanical hyperalgesia after partial ligation of the sciatic nerve. The number of intact mast cells in the injured nerve of these rats was higher than in control rats suggesting reduced mast cell degranulation, but was still significantly lower than in intact nerves. Rats treated with VUF 8430 showed significantly reduced mechanical hyperalgesia. Conclusion: We propose that the increase in mechanical hyperalgesia produced by thioperamide and JNJ 7777120 and the decrease in mechanical hyperalgesia produced by VUF 8430 may represent a direct effect of these agents on mechanospecific primary afferents, or an indirect effect of these agents via injury-induced inflammation.

To investigate levels of eating pathology in female adolescents diagnosed with a chronic condition causing appearance change (adolescent-onset idiopathic scoliosis), a chronic condition affecting nutritional behavior (insulin-dependent diabetes mellitus), and healthy age-matched controls.Cross-sectional comparison of 192 females aged 11-19 years; 76 individuals diagnosed with scoliosis, 40 diagnosed with diabetes, and 76 control participants. Disordered eating behavior was quantified using the Eating Disorder Examination Questionnaire, and weight and body mass index (weight [kg]/height [m(2)]) measurements were taken for each participant.The scoliosis group weighed less and had lower BMI scores (p.001) than control participants. Of the participants with scoliosis, 25% were severely underweight, but only two met the behavioral criteria for anorexia nervosa; in others no association with disordered eating behaviour was found. Eating disorders were significantly more common (p.05) in the diabetes participants than in the control group, with 27.5% of the group classified as having bulimia or binge eating disorder. All those classified as overweight or obese in the diabetes group were classified as pathological in terms of eating behavior.The relationship between scoliosis and low body mass is a concern but is not a result of an eating disorder. Etiological mechanisms remain unclear and require further investigation. In the diabetes participants, bulimia and binge eating may prejudice effective condition management. Implications for successful adaptation, treatment intervention, and future research are discussed.

Background Friedreich’s Ataxia (FRDA) is a neurodegenerative disorder that causes progressive damage to the central and peripheral nervous systems having a significant impact upon quality of life. With little information in the literature, cross-sectional observational studies were conducted in the UK and Germany to collect data on resource use and the burden of the disease on individuals and their caregivers. Methods Cross-sectional observational studies were conducted in the UK and Germany to estimate the burden of FRDA on individuals and on the respective healthcare systems. A total of 75 individuals in the UK and 28 in Germany were recruited to the study. Participants in both countries were asked to complete a Patient and Caregiver Information Form (PCIF), regarding access to, and use of, healthcare resources, and the impact FRDA has on their lifestyle. In Germany, doctors were asked to complete a Patient Record Form (PRF). Analyses of annual direct and indirect resource utilization were conducted for both countries while costs were calculated for the UK only. These figures were compared to the costs associated with Parkinson’s disease; one of the most common neurodegenerative conditions and the one most similar in terms of disease progression. Results The results showed that the annual burden of FRDA is significant and falls on the health and social care sectors, on society, on caregivers and on the individuals themselves. In the UK FRDA had a total annual cost per person of between £11,818 and £18,774 depending on whether the cost of long-term unemployment was included. Typically the largest component of direct costs is associated with professional care. Given the high proportion of children and young adults recruited and the long disease duration, (typically 40-50 years for FRDA, compared with 20 years for Parkinson’s disease), these figures may underestimate the true burden of the disease. Conclusion It is hoped that these estimates of resource utilization, can help in understanding the previously unquantified burden of FRDA. Given the long disease duration, management strategies should seek to minimise the impact of the condition on individuals and their caregivers, while maximising quality of life.