Patient-derived models: Advanced tools for precision medicine in neuroblastoma

Neuroblastoma is a childhood cancer derived from the sympathetic nervous system. High-risk neuroblastoma patients have a poor overall survival and account for ~15% of childhood cancer deaths. There is thus a need for clinically relevant and authentic models of neuroblastoma that closely resemble the human disease to further interrogate underlying mechanisms and to develop novel therapeutic strategies. Here we review recent developments in patient-derived neuroblastoma xenograft models and in vitro cultures. These models can be used to decipher mechanisms of metastasis and treatment resistance, for drug screening, and preclinical drug testing. Patient-derived neuroblastoma models may also provide useful information about clonal evolution, phenotypic plasticity, and cell states in relation to neuroblastoma progression. We summarize current opportunities for, but also barriers to, future model development and application. Integration of patient-derived models with patient data holds promise for the development of precision medicine treatment strategies for children with high-risk neuroblastoma

Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma

The PI3K pathway is a major driver of cancer progression. However, clinical resistance to PI3K inhibition is common. IBL-302 is a novel highly specific triple PIM, PI3K, and mTOR inhibitor. Screening IBL-302 in over 700 cell lines representing 47 tumor types identified neuroblastoma as a strong candidate for PIM/PI3K/mTOR inhibition. IBL-302 was more effective than single PI3K inhibition in vitro, and IBL-302 treatment of neuroblastoma patient-derived xenograft (PDX) cells induced apoptosis, differentiated tumor cells, and decreased N-Myc protein levels. IBL-302 further enhanced the effect of the common cytotoxic chemotherapies cisplatin, doxorubicin, and etoposide. Global genome, proteome, and phospho-proteome analyses identified crucial biological processes, including cell motility and apoptosis, targeted by IBL-302 treatment. While IBL-302 treatment alone reduced tumor growth in vivo, combination therapy with low-dose cisplatin inhibited neuroblastoma PDX growth. Complementing conventional chemotherapy treatment with PIM/PI3K/mTOR inhibition has the potential to improve clinical outcomes and reduce severe late effects in children with high-risk neuroblastoma.This work was supported by funding from the Swedish Cancer Society (to SM, DB), the Swedish Research Council (to DB), the Swedish Childhood Cancer Fund (to SM, KvS, DB), Region Skåne and the research funds of Skåne University Hospital (to DB), the Mary Bevé Foundation (to SM, KvS, DB), Magnus Bergvalls stiftelse (to SM, DB), the Thelma Zoéga Foundation (to SM), Hans von Kantzow Foundation (to SM), Crafoord Foundation (to DB), Åke Wiberg Foundation (to DB), Jeanssons Stiftelser (to DB), Ollie och Elof Ericssons stiftelser (to DB), Berth von Kantzows stiftelse (to DB), the Royal Physiographic Society of Lund (to SM, DB), and the Spanish Ministry of Health and Social Policy (ADE 08 / 90038 ) and the Spanish Ministry of Science and Innovation (CIT- 090000 - 2008 - 14 ) (to JP, SMa, CBA). We would like to thank the Local MS Support at Medical Faculty, Lund University. The authors would like to acknowledge support of the National Genomics Infrastructure (NGI)/Uppsala Genome Center and UPPMAX for providing assistance in massive parallel sequencing and computational infrastructure. Work performed at NGI/Uppsala Genome Center has been funded by RFI/VR and Science for Life Laboratory, SwedenS

Under the magnifying glass: critical moments in virtual exchange

Virtual Exchange (VE) is a form of experiential learning that relies heavily on learning-by-doing and reflection. The present study draws on visual data comprising students’ perceptions of critical learning incidents presented under an imaginary magnifying glass. To complete this project-closing reflective activity, the students had to describe a critical moment that they had experienced during VE and present it in a visual form. Data was collected longitudinally, in three projects (2019, 2020, and 2021) that followed the same pedagogical design and focused on the theme of tourism. The collaborating universities were from three countries: Poland, Finland, and the Netherlands. We used the methods of qualitative content analysis and social semiotic analysis to investigate the students’ reflections. The findings show that the most frequently expressed themes were related to participation in the first meeting, joint production, use of a foreign language, and adaptation to change. The study contributes to a better understanding of the role of multimodal reflection in VE.peerReviewe

Against all odds : Problem-solving as a skill critical to virtual exchange

Virtual Exchange (VE) brings together groups of learners from different geographical locations and cultural backgrounds to engage them in online intercultural collaboration and interaction. Although VE projects are designed and implemented by educators as part of the students’ educational programmes, they often go beyond the setting of traditional courses offered by higher education institutions. Because of their innovative nature, VEs require the students to leave their comfort zone and think outside the box to develop new creative strategies of communication and collaboration in order to find solutions to problems that crop up in this new learning environment. This presentation showcases the problem-solving strategies employed by the students  of Creative Business (the Netherlands), Tourism (Poland) and Language Studies (Finland) who were engaged in two interdisciplinary VE projects carried out in the times of Covid-19 pandemic in spring 2020 and 2021, City break in Europe: Understanding tourists' needs and motivations and City exploration: Emerging tourism trends in the Covid-19 era. During their six-week collaboration the Dutch, Polish, and Finnish students joined their forces and critically analysed the official websites of their municipalities (Utrecht, Poznań and Jyväskylä), focusing on the language, graphics, audience, marketing strategies and new attractive forms of sightseeing. As the final product, the students collaboratively designed an innovative tour of the three cities. To reach their project goals, the students, confronted with multiple collaborative hurdles and stuck in the Covid-19 pandemic, were forced to find effective ways of dealing with the physical distance, cultural differences, varying language levels, foreign accents, disciplinary gaps, malfunctioning technology and various security measures imposed in their countries to prevent the spread of the disease. Most studies addressing the challenges of VE offer tips and recommendations for teachers on how to improve the pedagogical design of the projects. Challenges are interpreted as problems that should be minimized to make the VE experience smooth for the students. In our study, we suggest that problems are affordances or even benefits because they provide a learning experience for the participants of VE. nonPeerReviewe

Bioaccumulation of Macronutrients in Edible Mushrooms in Various Habitat Conditions of NW Poland—Role in the Human Diet

Recently, the interest in mushroom consumption has been growing, since their taste and low calorific value are appreciated, but also due to their nutritional value. In determining the usefulness of mushrooms in the human diet, it is important to consider the conditions of their occurrence to perform the assessment of bioaccumulation of minerals. The aim of the study was: (a) to determine the content of selected macronutrients (P, K, Ca, Mg, Na) in fruiting bodies of Boletus edulis, Imleria badia, Leccinum scabrum and the soils, (b) to determine their bioaccumulation potential taking into account the habitat conditions, and (c) an attempt to estimate their role in covering the requirement for macronutrients of the human organism. The research material was obtained in the NW of Poland: Uznam and Wolin, the Drawa Plain and the Ińsko Lakeland. In the soil, we determined the content of organic matter, pH, salinity and the content of absorbable and general forms of macronutrients. The content of macronutrients in mushrooms was also determined. Chemical analyses were performed using the generally accepted test methods. The study showed that in NW Poland, B. edulis grew on the acidic soils of Arenosols, and I. badia and L. scabrum grew on Podzols. The uptake of K, Mg and Ca by the tested mushrooms was positively, and P and Na negatively correlated with the content of these elements in the soil. The acidity of the soil affected the uptake of K and Mg by mushrooms. There was no effect of the amount of organic matter in the soil noticed on the content of macronutrients (except sodium) in mushrooms. Among the studied macronutrients, none of the mushrooms accumulated Ca, while P and K were generally accumulated in the highest amounts, regardless of the species. Each of the other elements was usually accumulated at a similar level in the fruiting bodies of the species we studied. The exception was I. badia, which accumulated higher amounts of Mg compared to B. edulis and L. scabrum. Mushrooms can enrich the diet with some macronutrients, especially in P and K

Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma

Neuroblastoma is a childhood malignancy with often dismal prognosis; relapse is common despite intense treatment. Here, we used human tumor organoids representing multiple MYCN-amplified high-risk neuroblastomas to perform a high-throughput drug screen with approved or emerging oncology drugs. Tumor-selective effects were calculated using drug sensitivity scores. Several drugs with previously unreported anti-neuroblastoma effects were identified by stringent selection criteria. ARRY-520, an inhibitor of kinesin spindle protein (KSP), was among those causing reduced viability. High expression of the KSP-encoding gene KIF11 was associated with poor outcome in neuroblastoma. Genome-scale loss-of-function screens in hundreds of human cancer cell lines across 22 tumor types revealed that KIF11 is particularly important for neuroblastoma cell viability. KSP inhibition in neuroblastoma patient-derived xenograft (PDX) cells resulted in the formation of abnormal monoastral spindles, mitotic arrest, up-regulation of mitosis-associated genes, and apoptosis. In vivo, KSP inhibition caused regression of MYCN-amplified neuroblastoma PDX tumors. Furthermore, treatment of mice harboring orthotopic neuroblastoma PDX tumors resulted in increased survival. Our results suggested that KSP inhibition could be a promising treatment strategy in children with high-risk neuroblastoma.Peer reviewe

Anti-tumor effects of rigosertib in high-risk neuroblastoma

High-risk neuroblastoma has a poor prognosis despite intense treatment, demonstrating the need for new therapeutic strategies. Here we evaluated the effects of rigosertib (ON-01910.Na) in preclinical models of high-risk neuroblastoma. Among several hundred cancer cell lines representing 24 tumor types, neuroblastoma was the most sensitive to rigosertib. Treatment of MYCN-amplified neuroblastoma organoids resulted in organoid disintegration, decreased cell viability, and increased apoptotic cell death. Neuroblastoma response to rigosertib involved G2M cell cycle arrest and decreased phosphorylation of AKT (Ser473) and ERK1/2 (Thr202/Tyr204). Rigosertib delayed tumor growth and prolonged survival of mice carrying neuroblastoma MYCN-amplified PDX tumors (median survival: 31 days, treated; 22 days, vehicle) accompanied with increased apoptosis in treated tumors. We further identified vincristine and rigosertib as a potential promising drug combination treatment. Our results show that rigosertib might be a useful therapeutic agent for MYCN-amplified neuroblastomas, especially in combination with existing agents

The Role in the Human Diet of Bioaccumulation of Selenium, Copper, Zinc, Manganese and Iron in Edible Mushrooms in Various Habitat Conditions of NW Poland—A Case Study

The aim of the study was to determine the contents of microelements in Boletus edulis, Imleria badia and Leccinum scabrum, taking into account the soil conditions in selected forest areas of Northwest Poland and the bioaccumulation capacity of these fungi and their role in the human diet. Se, Cu, Zn, Mn and Fe contents were determined in the soil (organic and mineral layers) and mushrooms. The study showed that the soils on which fruiting bodies grew did not differ significantly in the contents of these trace elements. The concentrations of microelements in mushrooms in NW Poland were mostly at the lower range of the contents reported for these species in other regions of Poland and Europe. The uptake of microelements by the studied mushrooms was influenced by soil reaction, organic matter content, and bioavailable and total forms of the elements. B. edulis contained significantly more Se than other mushroom species and, together with I. badia, was much more abundant in Cu and Zn than L. scabrum. Fruiting bodies bioaccumulated Se (most strongly by B. edulis; BCF = 120.6), Cu and Zn. The contents of microelements in the tested mushrooms may be supplementary elements in the human diet