Sténose du sinus transverse et hypertension intracrânienne idiopathique (aspects diagnostiques, pronostiques et thérapeutiques)

Lors de la réalisation d imagerie cérébrale, une sténose du sinus transverse (SST) est fréquemment découverte chez les sujets présentant une hypertension intracrânienne idiopathique (HII), pathologie d étiologie inconnue touchant préférentiellement les jeunes femmes obèses. Nous avons repris les données cliniques et radiologiques des 26 sujets ayant consulté pour HII dans le service de neurologie sur 69 mois. La prévalence de la SST était de 57% dont 38% à caractère bilatéral. Chez les sujets présentant une SST, la présentation clinique était plus sévère, sans corrélation avec les valeurs de pression d ouverture du liquide céphalo-rachidien. Parmi les 18 sujets suivis, il existait une amélioration clinique et une stabilité des signes radiologiques, la présence d une SST initiale n étant pas associée à un caractère évolutif spécifique. Malgré son caractère rétrospectif et sa puissance limitée, cette étude monocentrique et exhaustive confirme la prévalence significative de la SST dans l HII et sa possible association à des formes cliniques plus sévères. La SST est-elle cause ou conséquence de l HII ? Sa place dans la physiopathologie de l HII reste débattue. La présence d une SST fait néanmoins discuter de nouvelles approches thérapeutiques telles que le stenting, dont la place reste à définir dans le traitement de l HII.Transverse sinus stenosis (TSS) is a radiological sign identified in the majority of patients with idiopathic intracranial hypertension (IIH), pathology of unknown aetiology, typically affecting young obese women. We studied clinical and radiological data of 26 patients who consulted for IIH in our department of neurology during 69 months. The prevalence of TSS was 57%, 38% of these were bilateral TSS. Clinical signs were more severe among patients with TSS but these signs were not correlated with a highter opening pressure of cephalo-spinal fluid. Eighteen patients were followed, clinical signs improved whereas radiological signs did not change. The presence of TSS was not associated with specific evolution. Despite its retrospective nature, this exhaustive and monocentric study confirm the highter prevalence of TSS in IIH and a possible association with more severe clinical forms. Cause or result of IIH ? The place of TSS in the physiopathology of IIH is still discussed. The significative prevalence of TSS opens the way to new treatments such as stenting of TSS which place among more conventionnal treatments of IIH is not actually well-defined.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Antitumor activity of an inhibitor of miR-34a in liver cancer with β-catenin-mutations miR-34a oncogenicity in β-catenin-mutated liver cancer

International audienceObjective: Hepatocellular carcinoma (HCC) is the most prevalent primary tumor of the liver. About a third of these tumors presents activating mutations of the β-catenin gene. The molecular pathogenesis of HCC has been elucidated, but mortality remains high and new therapeutic approaches, including treatments based on microRNAs, are required. We aimed to identify candidate microRNAs, regulated by β-catenin, potentially involved in liver tumorigenesis. Design: We used a mouse model, in which β-catenin signaling was overactivated exclusively in the liver, by the tamoxifen-inducible and Cre-Lox-mediated inactivation of the Apc gene. This model develops tumors with properties similar to human HCC. Results: We found that miR-34a was regulated by β-catenin, and significantly induced by the overactivation of β-catenin signaling in mouse tumors and in HCC patients. An inhibitor of miR-34a (LNA-34a) exerted anti-proliferative activity in primary cultures of hepatocyte. This inhibition of proliferation was associated with a decrease in cyclin D1 levels, orchestrated principally by HNF-4α, a target of miR-34a considered to act as a tumor suppressor in the liver. In vivo, LNA-34a approximately halved progression rates for tumors displaying β-catenin activation together with an activation of caspases 2 and 3. Conclusion: This work demonstrates the key oncogenic role of miR-34a in liver tumors with β-catenin gene mutations. We suggest that patients diagnosed with HCC with β-catenin mutations could be treated with an inhibitor of miR-34a. The potential value of this strategy lies in the modulation of the tumor suppressor HNF-4α, which targets cyclin D1, and the induction of a pro-apoptotic program

The concomitant loss of APC and HNF 4α in adult hepatocytes does not contribute to hepatocarcinogenesis driven by β‐catenin activation

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Deleting the β-catenin degradation domain in mouse hepatocytes drives hepatocellular carcinoma or hepatoblastoma-like tumor growth

International audienceBackground and aims: One-third of hepatocellular carcinomas (HCCs) harbor mutations activating the β-catenin pathway predominantly via mutations in CTNNB1 gene itself. Mouse models of Apc loss-of-function are widely used to mimic β-catenin-dependent tumorigenesis. Given the low prevalence of APC mutations in human HCCs we aimed to generate liver tumors through CTNNB1 exon 3 deletion (βcatΔex3). We then compared βcatΔex3 liver tumors with liver tumors generated via frameshift in exon 15 of Apc (Apcfs-ex15).Methods: We used hepatocyte-specific and inducible mouse models generated through either a Cre-Lox or a CRISPR/Cas9 approach using AAV vectors. Tumors generated by the Cre-Lox models were phenotypically analyzed using immunohistochemistry and were selected for transcriptomic analysis by RNA-sequencing. Mouse RNAseq data were compared to human RNAseq data (8 normal tissues, 48 HCCs, 9 hepatoblastomas) in an integrative analysis. Tumors generated via CRISPR were analyzed using DNA sequencing and immunohistochemistry.Results: Mice with CTNNB1 exon 3 deletion in hepatocytes developed liver tumors indistinguishable from Apcfs-ex15 liver tumors. Both Apcfs-ex15 and βcatΔex3 mouse models induced growth of two phenotypically distinct tumors (differentiated or undifferentiated). Integrative analysis of human and mouse tumors showed that differentiated mouse tumors cluster with well-differentiated human CTNNB1-mutated tumors. Conversely, undifferentiated mouse tumors cluster with human mesenchymal hepatoblastomas and harbor activated YAP signaling.Conclusion: Apcfs-ex15 and βcatΔex3 mouse models both induce growth of tumors that are transcriptionally similar to either well-differentiated and β-catenin-activated human HCCs or mesenchymal hepatoblastomas.Lay summary: New and easy-to-use transgenic mouse models of liver primary cancers have been generated, with mutations in the gene coding beta-catenin, frequent in both adult and pediatric liver primary cancers. The mice develop both types of cancer, constituting a strong preclinical model

ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription

International audienceErythropoietin (EPO) is a key regulator of erythropoiesis. The embryonic liver is the main site of erythropoietin synthesis, after which the kidney takes over. The adult liver retains the ability to express EPO, and we discovered here new players of this transcription, distinct from the classical hypoxia-inducible factor pathway. In mice, genetically invalidated in hepatocytes for the chromatin remodeler Arid1a, and for Apc, the major silencer of Wnt pathway, chromatin was more accessible and histone marks turned into active ones at the Epo downstream enhancer. Activating b-catenin signaling increased binding of Tcf4/b-catenin complex and upregulated its enhancer function. The loss of Arid1a together with b-catenin signaling, resulted in cell-autonomous EPO transcription in mouse and human hepatocytes. In mice with Apc-Arid1a gene invalidations in single hepatocytes, Epo de novo synthesis led to its secretion, to splenic erythropoiesis and to dramatic erythrocytosis. Thus, we identified new hepatic EPO regulation mechanism stimulating erythropoiesis

Les effets du jumelage des infrastructures lourdes de transport sur les territoires : quels enseignements?

This article reports a research on the effects of pairing of heavy infrastructures such as motorways and high speed lines railways on the functioning and perception of the territory. The ecological impact, effects on the evolution and perception of landscapes as well as governance issues and social acceptability in nearby areas have been specifically studied in three representative of the major types of land pairing observed in France. The comparison of the different elements from the research shows an apparent contradiction on scales of analysis of the appropriateness of the pairing. If it offers an overall benefit for land management with space saving and limiting fragmentation, it also causes a consumption of land with the creation of interstitial spaces, and a strong polarization of space. From the societal perspective, the advantages and disadvantages of the pairing are also related on scales thinking and posture of the actors interviewed vis-à-vis spatial or organizational cuts, or perception of nuisances. Pairing is therefore more a process than a technical solution. Directed downstream, it does not allow for synergies with the territory, but only responds to some isolated subjects like space consumption

T-cell factor 4 and β-catenin chromatin occupancies pattern zonal liver metabolism in mice

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Les effets du jumelage des infrastructures lourdes de transport sur les territoires : quels enseignements?

This article reports a research on the effects of pairing of heavy infrastructures such as motorways and high speed lines railways on the functioning and perception of the territory. The ecological impact, effects on the evolution and perception of landscapes as well as governance issues and social acceptability in nearby areas have been specifically studied in three representative of the major types of land pairing observed in France. The comparison of the different elements from the research shows an apparent contradiction on scales of analysis of the appropriateness of the pairing. If it offers an overall benefit for land management with space saving and limiting fragmentation, it also causes a consumption of land with the creation of interstitial spaces, and a strong polarization of space. From the societal perspective, the advantages and disadvantages of the pairing are also related on scales thinking and posture of the actors interviewed vis-à-vis spatial or organizational cuts, or perception of nuisances. Pairing is therefore more a process than a technical solution. Directed downstream, it does not allow for synergies with the territory, but only responds to some isolated subjects like space consumption

Hepatocellular Carcinomas With Mutational Activation of Beta-Catenin Require Choline and Can Be Detected by Positron Emission Tomography

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DLK1/DIO3 locus upregulation by a β-catenin-dependent enhancer drives cell proliferation and liver tumorigenesis

International audienceThe CTNNB1 gene, encoding β-catenin, is frequently mutated in hepatocellular carcinoma (HCC, ∼30%) and in hepatoblastoma (HB, >80%), in which DLK1/DIO3 locus induction is correlated with CTNNB1 mutations. Here, we aim to decipher how sustained β-catenin activation regulates DLK1/DIO3 locus expression and the role this locus plays in HB and HCC development in mouse models deleted for Apc (ApcΔhep) or Ctnnb1-exon 3 (β-cateninΔExon3) and in human CTNNB1-mutated hepatic cancer cells. We identified an enhancer site bound by TCF-4/β-catenin complexes in an open conformation upon sustained β-catenin activation (DLK1-WRE) and increasing DLK1/DIO3 locus transcription in β-catenin-mutated human HB and mouse models. DLK1-WRE editing by CRISPR/Cas9 approach impaired DLK1/DIO3 locus expression and slowed tumor growth in subcutaneous CTNNB1-mutated tumor cell grafts, ApcΔhep HB and β-cateninΔExon3 HCC. Tumor growth inhibition resulted either from increased FADD expression and subsequent caspase-3 cleavage in the first case, or from decreased expression of cell cycle actors regulated by FoxM1 in the others. Therefore, the DLK1/DIO3 locus is an essential determinant of FoxM1-dependent cell proliferation during β-catenin-driven liver tumorigenesis. Targeting the DLK1-WRE enhancer to silence the DLK1/DIO3 locus might thus represent an interesting therapeutic strategy to restrict tumor growth in primary liver cancers with CTNNB1 mutations