La escritura de la historia de la Iglesia en Paraguay: algunos progresos recientes

This article examines the recent historiography of the Paraguayan Church –contexts of produc- tion, historical discourse and conceptual coordinates that underpin the main research in the area– in order to respond to particular questions: What are the issues that, in the last fifty years have been the main source of interest among scholars? Who were the writers and what approaches did they adopt? And to what extent is the practice of the history of the Church in Paraguay part of the current historiographical trends?Este artículo pretende revisar la historio- grafía reciente sobre la Iglesia paraguaya –contextos de producción, discursos históricos y coordenadas conceptuales que han sustentado principales investigaciones– con el propósito de responder a determinados interrogantes ¿Cuáles son los temas que, en los últimos cincuenta años, han despertado mayor interés entre los estudiosos? ¿Quiénes han escrito y cuáles han sido los enfoques que han adoptado? Y ¿Hasta qué punto la práctica de la historia de la Iglesia en Paraguay participa de las tendencias historiográficas actuales

La escritura de la historia de la Iglesia en Paraguay: algunos progresos recientes

This article examines the recent historiography of the Paraguayan Church –contexts of produc- tion, historical discourse and conceptual coordinates that underpin the main research in the area– in order to respond to particular questions: What are the issues that, in the last fifty years have been the main source of interest among scholars? Who were the writers and what approaches did they adopt? And to what extent is the practice of the history of the Church in Paraguay part of the current historiographical trends?Este artículo pretende revisar la historio- grafía reciente sobre la Iglesia paraguaya –contextos de producción, discursos históricos y coordenadas conceptuales que han sustentado principales investigaciones– con el propósito de responder a determinados interrogantes ¿Cuáles son los temas que, en los últimos cincuenta años, han despertado mayor interés entre los estudiosos? ¿Quiénes han escrito y cuáles han sido los enfoques que han adoptado? Y ¿Hasta qué punto la práctica de la historia de la Iglesia en Paraguay participa de las tendencias historiográficas actuales

Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications

Background & aims: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB. Methods: We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically annotated samples from 113 patients with HB, using high-throughput technologies. Results: We discovered a widespread epigenetic footprint of HB that includes hyperediting of the tumor suppressor BLCAP concomitant with a genome-wide dysregulation of RNA editing and the overexpression of mainly non-coding genes of the oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, we identified 2 epigenomic clusters (Epi-CA, Epi-CB) with distinct degrees of DNA hypomethylation and CpG island hypermethylation that are associated with the C1/C2/C2B transcriptomic subtypes. Based on these findings, we defined the first molecular risk stratification of HB (MRS-HB), which encompasses 3 main prognostic categories and improves the current clinical risk stratification approach. The MRS-3 category (28%), defined by strong 14q32 locus expression and Epi-CB methylation features, was characterized by CTNNB1 and NFE2L2 mutations, a progenitor-like phenotype and clinical aggressiveness. Finally, we identified choline kinase alpha as a promising therapeutic target for intermediate and high-risk HBs, as its inhibition in HB cell lines and patient-derived xenografts strongly abrogated tumor growth. Conclusions: These findings provide a detailed insight into the molecular features of HB and could be used to improve current clinical stratification approaches and to develop treatments for patients with HB. Lay summary: Hepatoblastoma is a rare childhood liver cancer that has been understudied. We have used cutting-edge technologies to expand our molecular knowledge of this cancer. Our biological findings can be used to improve clinical management and pave the way for the development of novel therapies for this cancer

Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications

Background & Aims: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB. Methods: We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically annotated samples from 113 patients with HB, using high-throughput technologies. Results: We discovered a widespread epigenetic footprint of HB that includes hyperediting of the tumor suppressor BLCAP concomitant with a genome-wide dysregulation of RNA editing and the overexpression of mainly non-coding genes of the oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, we identified 2 epigenomic clusters (Epi-CA, Epi-CB) with distinct degrees of DNA hypomethylation and CpG island hypermethylation that are associated with the C1/C2/C2B transcriptomic subtypes. Based on these findings, we defined the first molecular risk stratification of HB (MRS-HB), which encompasses 3 main prognostic categories and improves the current clinical risk stratification approach. The MRS-3 category (28%), defined by strong 14q32 locus expression and Epi-CB methylation features, was characterized by CTNNB1 and NFE2L2 mutations, a progenitor-like phenotype and clinical aggressiveness. Finally, we identified choline kinase alpha as a promising therapeutic target for intermediate and high-risk HBs, as its inhibition in HB cell lines and patient-derived xenografts strongly abrogated tumor growth. Conclusions: These findings provide a detailed insight into the molecular features of HB and could be used to improve current clinical stratification approaches and to develop treatments for patients with HB. Lay summary: Hepatoblastoma is a rare childhood liver cancer that has been understudied. We have used cutting-edge technologies to expand our molecular knowledge of this cancer. Our biological findings can be used to improve clinical management and pave the way for the development of novel therapies for this cancer