MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis

Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors

YOUTH AND MENTAL HEALTH: LIFE SATISFACTION, WELLBEING, AND SOCIETAL PARTICIPATION IN THE CONTEXT OF A TRANSITIONING STATE

OBJECTIVE: The aim: Youth are important societal actors. This is especially relevant when considering countries in transition such as Ukraine. This study examines well-being and societal participation - both key signifiers of mental health - of youth in Ukraine. PATIENTS AND METHODS: Materials and methods: A descriptive, cross-sectional survey with open and closed questions was utilized (n= 1562). Participants were asked to reflect on social concerns and to evaluate their well-being in different life spheres and their own mental health through activities such as interpersonal communication, self-perception and relaxation. RESULTS: Results: Students showed positive mental health through their daily activities, but mental health indicated by life satisfaction ranged according to activities, age, gender and environment. Willingness to volunteer and connection to life can be attributed to feelings of learned helplessness in the face of problems deemed too complex, and participation in volunteering was linked to positive mental health and feelings of empowerment. CONCLUSION: Conclusions: The study contributes to understanding the status of Ukrainian youth's mental health and the ways in which mental health is expressed. The results of the research assist in identifying avenues to reduce the impact of social frustration, improve mental health of citizens of transitional countries, and encourage social stability

Clinical risk assessment of organ manifestations in systemic sclerosis: A report from the EULAR Scleroderma Trials and Research group database

Background: Systemic sclerosis (SSc) is a multisystem autoimmune disease, which is classified into a diffuse cutaneous (dcSSc) and a limited cutaneous (IcSSc) subset according to the skin involvement. In order to better understand the vascular, immunological and fibrotic processes of SSc and to guide its treatment, the EULAR Scleroderma Trials And Research (EUSTAR) group was formed in June 2004. Aims and methods: EUSTAR collects prospectively the Minimal Essential Data Set (MEDS) on all sequential patients fulfilling the American College of Rheumatology diagnostic criteria in participating centres. We aimed to characterise demographic, clinical and laboratory characteristics of disease presentation in SSc and analysed EUSTAR baseline visits. Results: In April 2006, a total of 3656 patients (1349 with dcSSc and 2101 with IcSSc) were enrolled in 102 centres and 30 countries. 1330 individuals had autoantibodies against Scl70 and 1106 against anticentromere antibodies. 87% of patients were women. On multivariate analysis, scleroderma subsets (dcSSc vs IcSSc), antibody status and age at onset of Raynaud's phenomenon, but not gender, were found to be independently associated with the prevalence of organ manifestations. Autoantibody status in this analysis was more closely associated with clinical manifestations than were SSc subsets. Conclusion: dcSSc and IcSSc subsets are associated with particular organ manifestations, but in this analysis the clinical distinction seemed to be superseded by an antibody-based classification in predicting some scleroderma complications. The EUSTAR MEDS database facilitates the analysis of clinical patterns in SSc, and contributes to the standardised assessment and monitoring of SSc internationally