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The electron cyclotron (EC) system of ITER for the initial configuration is designed to provide 20MW of RF power into the plasma during 3600s and a duty cycle of up to 25% for heating and (co and counter) non-inductive current drive, also used to control the MHD plasma instabilities. The EC system is being procured by 5 domestic agencies plus the ITER Organization (IO). F4E has the largest fraction of the EC procurements, which includes 8 high voltage power supplies (HVPS), 6 gyrotrons, the ex-vessel waveguides (includes isolation valves and diamond windows) for all launchers, 4 upper launchers and the main control system. F4E is working with IO to improve the overall design of the EC system by integrating consolidated technological advances, simplifying the interfaces, and doing global engineering analysis and assessments of EC heating and current drive physics and technology capabilities. Examples are the optimization of the HVPS and gyrotron requirements and performance relative to power modulation for MHD control, common qualification programs for diamond window procurements, assessment of the EC grounding system, and the optimization of the launcher steering angles for improved EC access. Here we provide an update on the status of Europe’s contribution to the ITER EC system, and a summary of the global activities underway by F4E in collaboration with IO for the optimization of the subsystems.

Our research laboratory has a longstanding interest in developmental disorders and embryonic tumors, and recent efforts have focused on the pathogenesis of pediatric liver tumors. This review focuses on hepatoblastoma (HB), the most common pediatric liver malignancy. Despite advances in treatment, patients with metastatic HB have a poor prognosis, and survivors often have permanent side effects attributable to chemotherapy. In an effort to improve survival and lessen long-term complications of HB, we have searched for novel molecular vulnerabilities using a combination of patient derived cell lines, metabolomics, and RNA sequencing of human samples at diagnosis and follow-up. These studies have shed light on pathogenesis and identified putative targets for future therapies in children with advanced HB., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hepatoblastoma (HB) is the most common malignant liver tumor among children. To gain insight into the pathobiology of HB, we performed RNA sequence analysis on 5 patient-derived xenograft lines (HB-243, HB-279, HB-282, HB-284, HB-295) and 1 immortalized cell line (HUH6). Using cultured hepatocytes as a control, we found 2,868 genes that were differentially expressed in all of the HB lines on mRNA level. The most upregulated genes were ODAM , TRIM71 , and IGDCC3 , and the most downregulated were SAA1 , SAA2 , and NNMT . Protein-protein interaction analysis identified ubiquitination as a key pathway dysregulated in HB. UBE2C , encoding an E2 ubiquitin ligase often overexpressed in cancer cells, was markedly upregulated in 5 of the 6 HB cell lines. Validation studies confirmed UBE2C immunostaining in 20 of 25 HB tumor specimens versus 1 of 6 normal liver samples. The silencing of UBE2C in two HB cell models resulted in decreased cell viability. RNA sequencing analysis showed alterations in cell cycle regulation after UBE2C knockdown. UBE2C expression in HB correlated with inferior patient survival. We conclude that UBE2C may hold prognostic utility in HB and that the ubiquitin pathway is a potential therapeutic target in this tumor., Competing Interests: Author SC is employed by Champions Oncology and was previously employed by XenTech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nousiainen, Eloranta, Isoaho, Cairo, Wilson, Heikinheimo and Pihlajoki.)

Background: In response to hypoxia, tumor cells undergo transcriptional reprogramming including upregulation of carbonic anhydrase (CA) IX, a metalloenzyme that maintains acid-base balance. CAIX overexpression has been shown to correlate with poor prognosis in various cancers, but the role of this CA isoform in hepatoblastoma (HB) has not been examined., Methods: We surveyed the expression of CAIX in HB specimens and assessed the impact of SLC-0111, a CAIX inhibitor, on cultured HB cells in normoxic and hypoxic conditions., Results: CAIX immunoreactivity was detected in 15 out of 21 archival pathology HB specimens. The CAIX-positive cells clustered in the middle of viable tumor tissue or next to necrotic areas. Tissue expression of CAIX mRNA was associated with metastasis and poor clinical outcome of HB. Hypoxia induced a striking upregulation of CAIX mRNA and protein in three HB cell models: the immortalized human HB cell line HUH6 and patient xenograft-derived lines HB-295 and HB-303. Administration of SLC-0111 abrogated the hypoxia-induced upregulation of CAIX and decreased HB cell viability, both in monolayer and spheroid cultures. In addition, SLC-0111 reduced HB cell motility in a wound healing assay. Transcriptomic changes triggered by SLC-0111 administration differed under normoxic vs. hypoxic conditions, although SLC-0111 elicited upregulation of several tumor suppressor genes under both conditions., Conclusion: Hypoxia induces CAIX expression in HB cells, and the CAIX inhibitor SLC-0111 has in vitro activity against these malignant cells., Competing Interests: Author Stefano Cairo has formerly been employed by the company XenTech and is currently employed by the company Champions Oncology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Eloranta, Pihlajoki, Liljeström, Nousiainen, Soini, Lohi, Cairo, Wilson, Parkkila and Heikinheimo.)

The neuropilins NRP1 and NRP2 are multifunctional glycoproteins that have been implicated in several cancer-related processes including cell survival, migration, and invasion in various tumor types. Here, we examine the role of neuropilins in hepatoblastoma (HB), the most common pediatric liver malignancy. Using a combination of immunohistochemistry, RNA analysis and western blotting, we observed high level expression of NRP1 and NRP2 in 19 of 20 HB specimens and in a majority of human HB cell lines (HUH6 and five cell lines established from patient-derived xenografts) studied but not in normal hepatocytes. Silencing of NRP2 expression in HUH6 and HB-282 HB cells resulted in decreased cell viability, impaired cytoskeleton remodeling, and reduced cell motility, suggesting that NRP2 contributes to the malignant phenotype. We propose that neuropilins warrant further investigation as biomarkers of HB and potential therapeutic targets., Competing Interests: SC is employed by the company XenTech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Eloranta, Nousiainen, Cairo, Pakarinen, Wilson, Pihlajoki and Heikinheimo.)

Twelve insulin-dependent diabetic patients were deprived of insulin for 12 h, and thereafter given an 8-h i.v. infusion of insulin. Lipoprotein lipase (LPL) activity was determined from heparin eluates of adipose tissue and skeletal muscle before and after insulin infusion. In spite of development of marked hyperglycemia and hyperketonaemia during the insulin deprivation the LPL activity of the two tissues remained mostly within normal range. During the subsequent insulin administration the LPL activity of adipose tissue increased by 36% (p less than 0.05) whereas the skeletal muscle LPL remained unchanged. The result is compatible with the view that human adipose tissue LPL is more sensitive to insulin than the corresponding enzyme of muscle.