137 research outputs found
Spotlight on zebrafish:translational impact
In recent years, the zebrafish has emerged as an increasingly prominent model in biomedical research. To showcase the translational impact of the model across multiple disease areas, Disease Models & Mechanisms has compiled a Special Issue that includes thought-provoking reviews, original research reporting new and important insights into disease mechanisms, and novel resources that expand the zebrafish toolkit. This Editorial provides a summary of the issueās contents, highlighting the diversity of zebrafish disease models and their clinical applications
The second European interdisciplinary Ewing sarcoma research summit ā A joint effort to deconstructing the multiple layers of a complex disease
Despite multimodal treatment, long term outcome for patients with Ewing
sarcoma is still poor. The second āEuropean interdisciplinary Ewing sarcoma research summitā assembled a large group of scientific experts in the field to discuss their latest unpublished findings on the way to the identification of novel therapeutic targets and strategies. Ewing sarcoma is characterized by a quiet genome with presence of an EWSR1-ETS gene rearrangement as the only and defining genetic aberration. RNA sequencing of recently described Ewing-like sarcomas with variant translocations identified them as biologically distinct diseases. Various presentations adressed mechanisms of EWS-ETS fusion protein activities with a focus on EWS-FLI1. Data were presented shedding light on the molecular underpinnings of genetic permissiveness
to this disease uncovering interaction of EWS-FLI1 with recently discovered
susceptibility loci. Epigenetic context as a consequence of the interaction between the oncoprotein, cell type, developmental stage, and tissue microenvironment emerged as dominant theme in the discussion of the molecular pathogenesis and inter- and intratumor heterogeneity of Ewing sarcoma, and the difficulty to generate animal models faithfully recapitulating the human disease. The problem of preclinical development of biologically targeted therapeutics was discussed and promising perspectives were
offered from the study of novel in vitro models. Finally, it was concluded that in order to facilitate rapid pre-clinical and clinical development of novel therapies in Ewing sarcoma, the community needs a platform to maintain knowledge of unpublished results, systems and models used in drug testing and to continue the open dialogue initiated at the first two Ewing sarcoma summits.UniĆ³n Europea 261743(ENCCA)UniĆ³n Europea 259348 (ASSET
Pediatric Germ Cell Tumors: A Developmental Perspective
Germ cell tumors (GCTs) arising in infants, children, and adolescents present a set of special challenges. GCTs make up about 3% of malignancies in children aged 0ā18 and nearly 15% of cancers in adolescents. Epidemiologic and molecular evidence suggests that GCTs in young children likely represent a distinct biologic group as compared to GCTs of older adolescents and adults. Despite this difference, pediatric GCTs are typically treated with cisplatin-based multiagent regimens similar to those used in adults. There is evidence that children are particularly vulnerable to late effects of conventional therapy, including ototoxicity, pulmonary abnormalities, and secondary malignancies, motivating the search for molecular targets for novel therapies. Evidence is accumulating that the genes and mechanisms controlling normal germ cell development are particularly relevant to the understanding of germ cell tumorigenesis. Perturbations in the epigenetic program of germ cell differentiation, with resulting effects on the regulation of pluripotency, may contribute to the marked histologic variability of GCTs. Perturbations in the KIT receptor signaling pathway have been identified via next-generation sequencing studies and in genome-wide association studies of testicular cancer susceptibility. Here, we review these and other biological insights that may fuel further translational and clinical research in childhood GCTs
Effect of Vascular Cadherin Knockdown on Zebrafish Vasculature during Development
Background: Vascular endothelial cadherin (VE-cad) is essential for endothelial barrier integrity and vascular sprouting. However, the role of this important protein in cardiovascular development is only recently becoming apparent. Methodology/Principal Findings: To characterize the role of VE-cadherin in cardiovascular development, we analyzed cardiovascular development in a zebrafish VE-cad knockdown model. Embryos deficient in VE-cad show profoundly impaired cardiac development despite having apparently normal peripheral vasculature. Initial formation of the heart proceeds normally in knockdown embryos, but subsequent looping morphogenesis is impaired. Consistent with these results, VE-cad knockdown embryos demonstrate impaired cardiac function and early circulatory arrest. Histologic examination of knockdown embryos shows persistent, abnormal separation of the endocardial and myocardial layers. Using transmission electron microscopy, we demonstrate that endocardial junctions form poorly in VE-cad knockdown embryos, with resulting leak across the endothelial layer and reduction in the density of the cardiac jelly. Conclusions: Our results demonstrate a significant role for VE-cadherin in cardiac development independent of its effects on the formation of the peripheral vasculature
C/EBPĪ²-1 promotes transformation and chemoresistance in Ewing sarcoma cells.
CEBPB copy number gain in Ewing sarcoma was previously shown to be associated with worse clinical outcome compared to tumors with normal CEBPB copy number, although the mechanism was not characterized. We employed gene knockdown and rescue assays to explore the consequences of altered CEBPB gene expression in Ewing sarcoma cell lines. Knockdown of EWS-FLI1 expression led to a decrease in expression of all three C/EBPĪ² isoforms while re-expression of EWS-FLI1 rescued C/EBPĪ² expression. Overexpression of C/EBPĪ²-1, the largest of the three C/EBPĪ² isoforms, led to a significant increase in colony formation when cells were grown in soft agar compared to empty vector transduced cells. In addition, depletion of C/EBPĪ² decreased colony formation, and re-expression of either C/EBPĪ²-1 or C/EBPĪ²-2 rescued the phenotype. We identified the cancer stem cell marker ALDH1A1 as a target of C/EBPĪ² in Ewing sarcoma. Furthermore, increased expression of C/EBPĪ² led to resistance to chemotherapeutic agents. In summary, we have identified CEBPB as an oncogene in Ewing sarcoma. Overexpression of C/EBPĪ²-1 increases transformation, upregulates expression of the cancer stem cell marker ALDH1A1, and leads to chemoresistance
Insulin action and binding in isolated hepatocytes from fasted, streptozotocin-diabetic, and older, spontaneously obese rats
Paediatric extracranial germ-cell tumours.
Management of paediatric extracranial germ-cell tumours carries a unique set of challenges. Germ-cell tumours are a heterogeneous group of neoplasms that present across a wide age range and vary in site, histology, and clinical behaviour. Patients with germ-cell tumours are managed by a diverse array of specialists. Thus, staging, risk stratification, and treatment approaches for germ-cell tumours have evolved disparately along several trajectories. Paediatric germ-cell tumours differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate, evidence-based care. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis, or platinum-resistant disease. Survivors have significant long-term toxicities. The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into improved patient outcomes. Future trials will be characterised by improved risk-stratification systems, biomarkers for response and toxic effects, rational reduction of therapy for low-risk patients and novel approaches for poor-risk patients, and improved international collaboration across paediatric and adult cooperative research groups.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/S1470-2045(15)00545-
DNA Methylation Analysis Reveals Distinct Methylation Signatures in Pediatric Germ Cell Tumors
Background: Aberrant DNA methylation is a prominent feature of many cancers, and may be especially relevant in germ cell tumors (GCTs) due to the extensive epigenetic reprogramming that occurs in the germ line during normal development. Methods: We used the Illumina GoldenGate Cancer Methylation Panel to compare DNA methylation in the three main histologic subtypes of pediatric GCTs (germinoma, teratoma and yolk sac tumor (YST); N = 51) and used recursively partitioned mixture models (RPMM) to test associations between methylation pattern and tumor and demographic characteristics. We identified genes and pathways that were differentially methylated using generalized linear models and Ingenuity Pathway Analysis. We also measured global DNA methylation at LINE1 elements and evaluated methylation at selected imprinted loci using pyrosequencing. Results: Methylation patterns differed by tumor histology, with 18/19 YSTs forming a distinct methylation class. Four pathways showed significant enrichment for YSTs, including a human embryonic stem cell pluripotency pathway. We identified 190 CpG loci with significant methylation differences in mature and immature teratomas (q \u3c 0.05), including a number of CpGs in stem cell and pluripotency-related pathways. Both YST and germinoma showed significantly lower methylation at LINE1 elements compared with normal adjacent tissue while there was no difference between teratoma (mature and immature) and normal tissue. DNA methylation at imprinted loci differed significantly by tumor histology and location. Conclusion: Understanding methylation patterns may identify the developmental stage at which the GCT arose and the at-risk period when environmental exposures could be most harmful. Further, identification of relevant genetic pathways could lead to the development of new targets for therapy
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Serum MicroRNA-371a-3p Levels Predict Viable Germ Cell Tumor in Chemotherapy-naĆÆve Patients Undergoing Retroperitoneal Lymph Node Dissection.
Comparison of carboplatin versus cisplatin in the treatment of paediatric extracranial malignant germ cell tumours: A report of the Malignant Germ Cell International Consortium.
PURPOSE: To compare the outcomes of paediatric and adolescent extracranial malignant germ cell tumour (GCT) patients treated with either carboplatin or cisplatin on clinical trials conducted by the Children's Oncology Group (COG) and the Children's Cancer and Leukaemia Group (CCLG). METHODS: The Malignant Germ Cell International Consortium (MaGIC) has created a database of the GCT clinical trials conducted since 1983 by COG (United States, CanadaĀ andĀ Australia), which used cisplatin-based regimens, and by CCLG (United Kingdom), which used carboplatin-based regimens. Using the parametric cure model, this study compared the overall 4-year event-free survival (EFS), stratified by age, stage, siteĀ and the a-priori defined MaGIC 'risk' groups: standard risk ((SR) 1 (EFS >80%; age 80%, age ā„ 11y)Ā and poor risk (PR) (EFS ā¤ 70%, age ā„ 11y). RESULTS: Cisplatin-based therapy was used in 620 patients; carboplatin was used in 163 patients. In the overall multivariate cure model, the two regimens did not differ significantly (cisplatin: 4-year EFS 86%; 95% confidence interval (CI) 83-89% versus carboplatin 4-year EFS 86%; 95% CI 79-90%; pĀ =Ā 0.87). No significant differences were noted in stratified analyses by site, stage, age and MaGIC risk groups: SR1 (pĀ =Ā 0.20), SR2 (pĀ =Ā 0.55) or PR (pĀ =Ā 0.72) patients. CONCLUSIONS: In these trials conducted contemporaneously, there is no significant difference in outcome observed overall, or any subset of patients, who were treated with regimens containing cisplatin versusĀ carboplatin These results suggested sufficient equipoise to justify a randomised trial to evaluate the effectiveness of carboplatin versus cisplatin in the treatment of children, adolescents and young adults with standard risk GCT, which is currently underway
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