Invest in the future: "Hands-on Radiology" summer school.

PURPOSE: The field of radiology is currently underestimated by undergraduate medical students. The "Hands-on Radiology" summer school was established to improve radiology knowledge and interest among undergraduates. The purpose of this questionnaire survey was to analyze whether a radiological hands-on course is an effective tool to reach and motivate undergraduate students. MATERIALS AND METHODS: The three-day course held in August 2022 included lectures, quizzes, and small group hands-on workshops focusing on practical work with simulators. All participants (n = 30) were asked to rate their knowledge and motivation to specialize in radiology at the beginning of the summer school (day 1) and the end (day 3). The questionnaires included multiple choice questions, 10-point scale questions and open comment questions. The second questionnaire (day 3) included additional questions regarding the program (topic choice, length, etc.). RESULTS: Out of 178 applicants, 30 students (16.8%) from 21 universities were selected to participate (50% female and 50% male students). All students completed both questionnaires. The overall rating was 9.47 on a 10-point scale. While the self-reported knowledge level increased from 6.47 (day 1) to 7.50 (day 3), almost all participants (96.7%, n = 29/30) mentioned an increased interest in the specialization of radiology after the event. Interestingly, most students (96.7%) preferred onsite teaching instead of online teaching and chose residents over board-certified radiologists as teachers. CONCLUSION: Intensive three-day courses are valuable tools to strengthen interest in radiology and increase knowledge among medical students. Particularly, students who already have a tendency to specialize in radiology are further motivated.

A direct comparison of selective BH3-mimetics reveals BCL-XL, BCL-2 and MCL-1 as promising therapeutic targets in neuroblastoma.

BACKGROUND: Despite advances in the treatment of neuroblastoma, patients with high-risk disease still have dismal survival prognosis. Neuroblastoma cells display elevated expression of the antiapoptotic BCL-2 proteins, suggesting that BH3-mimetics may be a promising treatment option. Here, we investigated the role of BCL-2, BCL-XL and MCL-1 in neuroblastoma. METHODS: A panel of neuroblastoma cell lines and primary patient-derived cells were exposed to BH3-mimetics targeting BCL-2 (ABT-199), BCL-XL (A1331852) or MCL-1 (S63845). In addition, protein expression and interaction patterns were analysed using Western blotting and immunoprecipitation. RESULTS: All tested BH3-mimetics were able to induce apoptosis in neuroblastoma cell lines, indicating that not only BCL-2 but also BCL-XL and MCL-1 may be promising therapeutic targets. Primary patient-derived cells displayed highest sensitivity to A1331852, highlighting the important role of BCL-XL in neuroblastoma. Further analysis into the molecular mechanisms of apoptosis revealed that A1331852 and S63845 displaced proapoptotic proteins like BIM and BAK from their antiapoptotic targets, subsequently leading to the activation of BAX and BAK and caspase-dependent apoptosis. CONCLUSIONS: By using selective BH3-mimetics, this study demonstrates that BCL-2, BCL-XL, and MCL-1 are all relevant therapeutic targets in neuroblastoma. A1331852 and S63845 induce rapid apoptosis that is initiated following a displacement of BAK from BCL-XL or MCL-1, respectively.

Targeting BCL-2 proteins in pediatric cancer: Dual inhibition of BCL-XL and MCL-1 leads to rapid induction of intrinsic apoptosis.

With the development of potent and selective inhibitors of MCL-1 (S63845) and BCL-XL (A-1331852) novel cancer treatment options have emerged. BCL-2 family proteins are important regulators of apoptosis in pediatric solid tumors. In the current study, we discover that rhabdomyosarcoma, Ewing sarcoma, osteosarcoma and neuroblastoma cell lines are co-dependent on BCL-XL and MCL-1 for survival. A-1331852/S63845 co-treatment, but not combinations of either inhibitor with ABT-199, synergistically induces rapid intrinsic apoptosis in vitro and demonstrates efficiency in an in vivo embryonic chicken model of rhabdomyosarcoma. Interestingly, A-1331852/S63845-induced apoptosis is BAX/BAK-dependent and mediated by displacement of BAK from BCL-XL and MCL-1, respectively. Moreover, BAK interacts with BAX to build a pore-forming complex in the outer mitochondrial membrane, leading to loss of mitochondrial outer membrane potential and caspase activation. Furthermore, in RD cells A-1331852/S63845 co-treatment disrupts BIM and NOXA in their interactions with BCL-XL and MCL-1, respectively, thereby contributing to apoptosis. Altogether, this study is the first to demonstrate the potency of A-1331852/S63845 in pediatric solid tumor cells and to describe the molecular mechanisms of A-1331852/S63845 co-treatment underlining the potential of BCL-XL and MCL-1 inhibition as treatment regime.