Explore the vast range of titles available.

Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status. Immunohistochemistry and mRNA expression analysis in 30 PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation. In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A. The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293). In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones. The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate. Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors.

High-grade gliomas are one of the most lethal cancers and the leading cause of cancer-related mortality in children. Standard treatment typically involves resection, chemotherapy and radiation, yet offer limited improvement in survival rates. Targeted therapies are emerging to show effect in solid tumors harboring tyrosine-kinase activating fusion genes. Here, we present a thorough characterization of an epithelioid glioblastoma in a six-year-old patient, with four relapses and a variety of different treatment strategies. We identified a rare TRIM24::NTRK2 fusion in the primary tumor, which enabled a targeted TRK-inhibitor treatment. Our findings show that the TRIM24::NTRK2 fusion initially had oncogenic abilities, but this became less imperative as the tumor evolved. A general drug resistance to TRK-inhibition was documented. This study addresses the complex and adaptive nature of pediatric epithelioid glioblastomas and highlights the need for continued molecular profiling from relapses and various tumor regions to enable multitarget treatment approaches.

The outcome of pilocytic astrocytoma (PA) depends heavily on the success of surgery. In cases where surgery alone is not curative, genetic analysis can be used to identify treatment targets for precision medicine. Here, we report a pediatric PA case that underwent incomplete surgical resection due to the tumor location. Clinical routine analyses demonstrated that the tumor did not carry any BRAF alteration. After postoperative surveillance, according to the low-grade glioma (LGG) protocol, recurrent tumor progressions resulted in multiple chemotherapy regimens. Screening formalin-fixed paraffin-embedded tumor material using an open-ended RNA sequencing panel revealed a novel in-frame autophagy related 16 like 1-neurotrophic receptor tyrosine kinase 2 (ATG16L1::NTRK2) fusion gene. The NTRK2 rearrangement was subsequently confirmed by fluorescent in situ hybridization on tumor tissue sections. Functional validation was performed by in vitro transient transfection of HEK293 cells and showed the ATG16L1::TRKB fusion protein to activate both the mitogen-activated protein kinase pathway and the phosphoinositide 3-kinase oncogenic pathways through increased phosphorylation of extracellular signal-regulated kinase, AKT, and S6. As a result of the identification of the NTRK fusion, the patient was enrolled in a phase I/II clinical trial of the highly selective TRK inhibitor larotrectinib. The patient responded well without significant side effects, and 8 months after the start of treatment, the contrast-enhancing tumor lesions were no longer detectable, consistent with a complete response as per Response Assessment in Neuro-Oncology (RANO) criteria. Presently, after 22 months of treatment, the patient’s complete remission is sustained. Our findings highlight the importance of screening for other oncogenic drivers in BRAF-negative LGGs since rare fusion genes may serve as targets for precision oncology therapy.

Animal migrations are extensive, ubiquitous, and in decline. To effectively protect migratory species, it is often crucial to identify the interconnected sets of sites they rely upon. Gaps between primary ecological research and synthesised information that is useful to policymakers has limited effective conservation of long-distance migrants, particularly in the marine realm. By synthesising 1304 references to identify 1787 sites and develop model migratory networks for 109 species, we show the minimum extent of marine megafauna connectivity across the global oceans. Our analyses underscore the importance of transboundary cooperation for migratory species conservation at scales larger than current regional structures afford and provide a free online system that will enable policymakers to efficiently summarise how marine migrants use and connect their jurisdictions. Animal migrations are extensive and crucial for ecosystem health but are in decline. This study identifies 1,787 sites and links among them for 109 marine species, highlighting the need for international cooperation and providing policymakers with essential knowledge for effective conservation.

Green turtles are a widely distributed and highly migratory species, despite extensive data on the movement of green turtles, there is no global synthesis on the subject, limiting a holistic understanding of their movement. Based on three decades of published literature, we present the first global model of migratory connectivity for green turtles. Global. 1990–2022. Green Sea Turtle (Chelonia mydas) We conducted a structured literature review extracting georeferenced information on the movement of green turtles from 1990 to 2022, aggregating this information into a single connectivity model, defining sites and “metasites” as nodes of connectivity. We then evaluate the connectivity routes from nesting areas to foraging sites for each RMU, identifying those trajectories moving outside and across the boundaries of these areas. We found an increasing number of studies assessing movement of green turtles, with a total of 113 sources of migratory connectivity information. We identified 474 sites, representing locations where green turtles were observed (124 of these being nesting sites). Migratory connections from nesting sites ranged from resident turtles never leaving the area, to rookeries linked to 13 different sites, some over 5,000 km apart. This long-distance connectivity exposes populations to threats across disparate locations. Most connections traversed national jurisdictions, including crossing different Regional Management Units We compiled the largest available dataset describing movement of green turtles worldwide and present the first global model of their migratory connectivity. This model provides ecological insights into regional differences in life histories, identifies geographic and demographic gaps in sampling, and provides baseline information on connectivity to support transboundary management of green turtle populations. The study highlights the need for larger collaborative efforts to aggregate knowledge beyond local jurisdictions, to inform and align effective management measures to protect this threatened species.