Frequent 4EBP1 Amplification Induces Synthetic Dependence on FGFR Signaling in Cancer

Simple Summary Our work establishes that amplification of 4EBP1, as a part of Chr. 8p11, creates a synthetic dependency on FGFR1 signaling in cancer. 4EBP1 is phosphorylated by FGFR1 and PI3K signaling, and accordingly cancer with 4EBP1-FGFR1 amplification is more sensitive to FGFR1 and PI3K inhibition due to inhibition of 4EBP1 phosphorylation. Moreover, we characterize the translational targets of 4EBP1 and identify that 4EBP1 specifically regulates the translation of genes involved in insulin signaling, glucose metabolism, and the inositol pathway that plays a role in cancer progression. The eIF4E translation initiation factor has oncogenic properties and concordantly, the inhibitory eIF4E-binding protein (4EBP1) is considered a tumor suppressor. The exact molecular effects of 4EBP1 activation in cancer are still unknown. Surprisingly, 4EBP1 is a target of genomic copy number gains (Chr. 8p11) in breast and lung cancer. We noticed that 4EBP1 gains are genetically linked to gains in neighboring genes, including WHSC1L1 and FGFR1. Our results show that FGFR1 gains act to attenuate the function of 4EBP1 via PI3K-mediated phosphorylation at Thr37/46, Ser65, and Thr70 sites. This implies that not 4EBP1 but instead FGFR1 is the genetic target of Chr. 8p11 gains in breast and lung cancer. Accordingly, these tumors show increased sensitivity to FGFR1 and PI3K inhibition, and this is a therapeutic vulnerability through restoring the tumor-suppressive function of 4EBP1. Ribosome profiling reveals genes involved in insulin signaling, glucose metabolism, and the inositol pathway to be the relevant translational targets of 4EBP1. These mRNAs are among the top 200 translation targets and are highly enriched for structure and sequence motifs in their 5 ' UTR, which depends on the 4EBP1-EIF4E activity. In summary, we identified the translational targets of 4EBP1-EIF4E that facilitate the tumor suppressor function of 4EBP1 in cancer

Reprogramming of Embryonic Human Fibroblasts into Fetal Hematopoietic Progenitors by Fusion with Human Fetal Liver CD34+ Cells

Experiments with somatic cell nuclear transfer, inter-cellular hybrid formation_ENREF_3, and ectopic expression of transcription factors have clearly demonstrated that cell fate can be dramatically altered by changing the epigenetic state of cell nuclei. Here we demonstrate, using chemical fusion, direct reprogramming of the genome of human embryonic fibroblasts (HEF) into the state of human fetal liver hFL CD34+ (hFL) hematopoietic progenitors capable of proliferating and differentiating into multiple hematopoietic lineages. We show that hybrid cells retain their ploidy and can differentiate into several hematopoietic lineages. Hybrid cells follow transcription program of differentiating hFL cells as shown by genome-wide transcription profiling. Using whole-genome single nucleotide polymorphism (SNP) profiling of both donor genomes we demonstrate reprogramming of HEF genome into the state of hFL hematopoietic progenitors. Our results prove that it is possible to convert the fetal somatic cell genome into the state of fetal hematopoietic progenitors by fusion. This suggests a possibility of direct reprogramming of human somatic cells into tissue specific progenitors/stem cells without going all the way back to the embryonic state. Direct reprogramming of terminally differentiated cells into the tissue specific progenitors will likely prove useful for the development of novel cell therapies

Cas publiés de salmonelloses chez les jeunes enfants secondaires à une exposition aux reptiles : revue bibliographique 1993-2013

International audienceContact with animals including reptiles is a known source for Salmonella transmission. Cases of Salmonella infections transmitted by domestic reptiles have been described in the literature since the 1960s.A review of published cases of salmonellosis in young children secondary to reptiles’ exposure since 1993 was carried out in January 2013 in order to identify the most frequent clinical forms, the Salmonella serotypes involved, and the transmission of Salmonella.The 66 selected articles were 43 case-reports, 14 outbreak investigations, 5 case-control studies and 4 retrospective studies.Isolated cases reported were mostly cases of gastroenteritis (69%), and 31% were infections other than digestive. Serotypes of Salmonella strains were mostly enterica subspecies (I). Turtles were the reptiles the most frequently involved.Le contact avec des animaux, notamment avec les reptiles, est une source connue de transmission de Salmonella. Des cas d’infections à Salmonella transmises par des reptiles domestiques ont été décrits dans la littérature dès les années 1960.Une revue de la littérature scientifique des cas publiés de salmonellose chez les jeunes enfants secondaires à une exposition aux reptiles depuis 1993 a été réalisée en janvier 2013 afin de documenter les formes cliniques les plus fréquentes, les sérotypes de Salmonella impliqués ainsi que le mode de transmission des Salmonella.Les 66 articles retenus concernaient 43 études de cas isolés, 14 investigations d’épidémies, 5 études cas/témoins et 4 études rétrospectives descriptives.Les cas isolés rapportés étaient majoritairement des cas de gastro-entérites (69%) et 31% étaient des cas d’infections autres que digestives. Les sérotypes des souches de Salmonella étaient en majorité de la sous-espèce enterica (I). Les reptiles le plus fréquemment impliqués étaient des tortues

Abstract 878: Frequent 4EBP1 amplification induces synthetic dependence on FGFR signaling in cancer

Abstract The eIF4E translation initiation factor has oncogenic properties and concordantly, the inhibitory eIF4E-binding protein (4EBP1) is considered a tumor suppressor. The exact molecular effects of 4EBP1 activation in cancer are still unknown. Surprisingly, 4EBP1 is a target of genomic copy number gains (Chr. 8p11) in breast and lung cancer. We notice that 4EBP1 gains are genetically linked to gains in neighboring genes including WHSC1L1 and FGFR1. Our results show that FGFR1 gains act to attenuate the function of 4EBP1 via PI3K mediated phosphorylation at Thr37/46, Ser65, and Thr70 sites. This implies that not 4EBP1 but instead FGFR1 is the genetic target of Chr. 8p11 gains in breast and lung cancer. Accordingly, these tumors show increased sensitivity to FGFR1 and PI3K inhibition and this is a therapeutic vulnerability through restoring the tumor-suppressive function of 4EBP1. Ribosome profiling reveals genes involved in insulin signaling, glucose metabolism, and inositol pathway to be the relevant translational targets of 4EBP1. These mRNAs are among the top 200 translation targets and are highly enriched for structure and sequence motifs in their 5’UTR that depends on the 4EBP1-EIF4E activity. In summary, we identify the translational targets of 4EBP1-EIF4E that facilitate the tumor suppressor function of 4EBP1 in cancer. @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-536870145 1107305727 0 0 415 0;}@font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:swiss; mso-font-pitch:variable; mso-font-signature:-536859905 -1073732485 9 0 511 0;}p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:Calibri; mso-fareast-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;}.MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:Calibri; mso-fareast-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;}div.WordSection1 {page:WordSection1;} Citation Format: Kamini Singh, Prathibha Mohan, Viraj R. Sanghvi, Giovanni Ciriello, Nathalie Lailler, Elisa de Stanchina, Hans-Guido Wendel. Frequent 4EBP1 amplification induces synthetic dependence on FGFR signaling in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 878

Salmonelloses chez des jeunes enfants et exposition aux reptiles domestiques : investigation en France métropolitaine en 2012

International audienceSalmonella transmission from reptiles has been reported in many countries, mostly among children. To describe cases of reptiles associated salmonellosis in young children in France, an investigation was conducted in 2012 among children under 5 years old with salmonellosis caused by a serotype confirmed by the National Reference Center and previously associated with reptiles in the literature.Children’s parents were surveyed by telephone using a questionnaire on the clinical symptoms, the onset of symptoms among family members, the history of recent travel and contacts with animals.Thirteen of the 41 children (32%) included had been exposed to reptiles, only one had direct contact with the animal. The isolates belonged to 9 different serotypes. The animals involved were mainly turtles (6 cases). Two children had meningitis. For one child, the same Salmonella was identified in the patient samples and in the domestic lizard samples. Twelve families of the 13 investigated were unaware of the risk of transmission of Salmonella from reptiles before the illness of their child.This investigation confirms that in France, even without direct contact, pet reptiles can sometimes lead to serious Salmonella infections in young children, and shows the importance of informing the public and physicians about this risk.La transmission de Salmonella par les reptiles a été rapportée dans de nombreux pays, le plus souvent chez des enfants. Afin de décrire les cas d’infections à Salmonella transmises par des reptiles chez des jeunes enfants en France, une investigation a été conduite en 2012 chez les enfants de moins de 5 ans atteints de salmonellose due à un sérotype confirmé par le Centre national de référence des Salmonella et déjà décrit en portage chez des reptiles dans la littérature.Les parents des enfants ont été interrogés par téléphone avec un questionnaire sur la clinique, la survenue de symptômes dans l’entourage, les voyages récents et les contacts avec des animaux.Treize des 41 enfants inclus (32%) avaient été exposés à des reptiles, dont un par contact direct. Les souches isolées appartenaient à 9 sérotypes différents. Les principaux animaux impliqués étaient des tortues (6 cas). Deux enfants ont présenté une méningite. Chez un de ces 2 cas, la même Salmonella a été identifiée chez le patient et chez son lézard domestique. Douze familles sur les 13 investiguées ignoraient le risque de transmission de Salmonella par les reptiles avant la maladie de l’enfant.Cette investigation confirme qu’en France les reptiles domestiques peuvent être à l’origine de salmonelloses parfois graves chez les jeunes enfants, même en l’absence de contact direct, et souligne l’importance d’une information sur ce risque

Complete Genome Phasing of Family Quartet by Combination of Genetic, Physical and Population-Based Phasing Analysis

<div><p>Phased genome maps are important to understand genetic and epigenetic regulation and disease mechanisms, particularly parental imprinting defects. Phasing is also critical to assess the functional consequences of genetic variants, and to allow precise definition of haplotype blocks which is useful to understand gene-flow and genotype-phenotype association at the population level. Transmission phasing by analysis of a family quartet allows the phasing of 95% of all variants as the uniformly heterozygous positions cannot be phased. Here, we report a phasing method based on a combination of transmission analysis, physical phasing by pair-end sequencing of libraries of staggered sizes and population-based analysis. Sequencing of a healthy Caucasians quartet at 120x coverage and combination of physical and transmission phasing yielded the phased genotypes of about 99.8% of the SNPs, indels and structural variants present in the quartet, a phasing rate significantly higher than what can be achieved using any single phasing method. A false positive SNP error rate below 10*E-7 per genome and per base was obtained using a combination of filters. We provide a complete list of SNPs, indels and structural variants, an analysis of haplotype block sizes, and an analysis of the false positive and negative variant calling error rates. Improved genome phasing and family sequencing will increase the power of genome-wide sequencing as a clinical diagnosis tool and has myriad basic science applications.</p></div

Human Annotation of ASR Error Regions: is "gravity" a Sharable Concept for Human Annotators?

International audienceThis paper is concerned with human assessments of the severity of errors in ASR outputs. We did not design any guidelines so that each annotator involved in the study could consider the " seriousness " of an ASR error using their own scientific background. Eight human annotators were involved in an annotation task on three distinct corpora, one of the corpora being annotated twice, hiding this annotation in duplicate to the annotators. None of the computed results (inter-annotator agreement, edit distance, majority annotation) allow any strong correlation between the considered criteria and the level of seriousness to be shown, which underlines the difficulty for a human to determine whether a ASR error is serious or not