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International audience; Simple Summary Radioembolization is a kind of internal radiation therapy which is currently used in non-operable HCC. Several radiolabeled product can be used as Y-90-loaded microspheres or less frequently radiolabeled lipiodol either with iodine 131 (in the past) or currently with rhenium 188 (Re-188). Currently used Re-188-labeled compounds are limited by in vivo instability. This study sought to evaluate the safety, bio-distribution, and response to Re-188-SSS lipiodol, a new and more stable compound. Method: Lip-Re-01 was an activity-escalation Phase 1 study involving HCC patients progressing after sorafenib. The primary endpoint was safety. Secondary endpoints included bio-distribution and response evaluation. Results: Fourteen heavily pre-treated HCC patients were treated in Level 1 (n = 6), Level 2 (n = 6), and Level 3 (n = 2). Safety was acceptable with only 1/6 of Level 1 and 1/6 of Level 2 patients experiencing limiting toxicity. The study was prematurely discontinued unrelated to clinical outcomes. Cumulative urinary elimination and fecal eliminations at 72 h were very low, confirming high in vivo stability. Partial response occurred in 37.5% of the patients receiving 3.6 GBq of Re-188-SSS lipiodol or more. Conclusion: As the 3.6 GBq activity proved to be safe, it will be used in an ongoing Phase 2 study. Background: Despite the wide development of Y-90-loaded microspheres, Re-188-labeled lipiodol is still being used for radioembolization of hepatocellular carcinoma (HCC). However, the use of this latter compound is limited by in vivo instability. This study sought to evaluate the safety, bio-distribution, and response to Re-188-SSS lipiodol, a new and more stable compound. Method: Lip-Re-01 was an activity-escalation Phase 1 study involving HCC patients progressing after sorafenib. The primary endpoint was safety based on Common Terminology Criteria for Adverse Events (AEs) of Grade >= 3 within 2 months. Secondary endpoints included bio-distribution assessed by scintigraphy quantification from 1 to 72 h, tumor to non-tumor uptake ratio (T/NT), as well as blood, urine and feces collection over 72 h, dosimetry, and response evaluation (mRECIST). Results: Overall, 14 heavily pre-treated HCC patients were treated using a whole liver approach. The mean injected activity was 1.5 +/- 0.4 GBq for activity Level 1 (n = 6), 3.6 +/- 0.3 GBq for Level 2 (n = 6), and 5.0 +/- 0.4 GBq for Level 3 (n = 2). Safety was acceptable with only 1/6 of Level 1 and 1/6 of Level 2 patients experiencing limiting toxicity (one liver failure; one lung disease). The study was prematurely discontinued unrelated to clinical outcomes. Uptake occurred in the tumor, liver, and lungs, and only sometimes in the bladder. The T/NT ratio was high with a mean of 24.9 +/- 23.4. Cumulative urinary elimination and fecal eliminations at 72 h were very low, 4.8 +/- 3.2% and 0.7 +/- 0.8%, respectively. Partial response occurred in 21% of patients (0% in the first activity level; 37.5% in the others). Conclusion: The high in vivo stability of Re-188-SSS lipiodol was confirmed, resulting in encouraging responses for a Phase 1 study. As the 3.6 GBq activity proved to be safe, it will be used in a future Phase 2 study.

International audience; Sexual development is a complex process relying on numerous genes. Disruptions in some of these genes are known to cause differences of sexual development (DSDs). Advances in genome sequencing allowed the discovery of new genes implicated in sexual development, such as PBX1. We present here a fetus with a new PBX1 NM_002585.3: c.320G>A,p.(Arg107Gln) variant, presenting with severe DSD along with renal and lung malformations. Using CRISPR-Cas9 gene editing on HEK293T cells, we generated a KD cell line for PBX1. The KD cell line showed reduced proliferation and adhesion properties compared with HEK293T cells. HEK293T and KD cells were then transfected plasmids coding either PBX1 WT or PBX1-320G>A (mutant). WT or mutant PBX1 overexpression rescued cell proliferation in both cell lines. RNA-seq analyses showed less than 30 differentially expressed genes, in ectopic mutant-PBX1-expressing cells compared with WT-PBX1. Among them, U2AF1, encoding a splicing factor subunit, is an interesting candidate. Overall, mutant PBX1 seems to have modest effects compared with WT PBX1 in our model. However, the recurrence of PBX1 Arg107 substitution in patients with closely related phenotypes calls for its impact in human diseases. Further functional studies are needed to explore its effects on cellular metabolism.

International audience; Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its action is complex, since TGFβ exhibits tumor-suppressive or oncogenic properties, depending on the tumor stage. At an early stage TGFβ exhibits cytostatic features, but at a later stage it promotes cell growth and metastasis, as a potent inducer of epithelial to mesenchymal transition (EMT). Here, we evaluated DNA methylation as a possible molecular mechanism switching TGFβ activity toward tumor progression in hepatocellular carcinoma (HCC). We report that decitabine, a demethylating agent already used in the clinic for the treatment of several cancers, greatly impairs the transcriptional response of SNU449 HCC cells to TGFβ. Importantly, decitabine was shown to induce the expression of EMT-related transcription factors (e.g., SNAI1/2, ZEB1/2). We also report that the promoter of SNAI1 was hypomethylated in poor-prognosis human HCC, i.e., associated with high grade, high AFP level, metastasis and recurrence. Altogether, the data highlight an epigenetic control of several effectors of the TGFβ pathway in human HCC possibly involved in switching its action toward EMT and tumor progression. Thus, we conclude that epidrugs should be carefully evaluated for the treatment of HCC, as they may activate tumor promoting pathways.

Non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH) result as a consequence of diverse conditions, mainly unbalanced diets. Particularly, high-fat and cholesterol content, as well as carbohydrates, such as those commonly ingested in Western countries, frequently drive adverse metabolic alterations in the liver and promote NAFLD development. Lipid liver overload is also one of the main risk factors for initiation and progression of hepatocellular carcinoma (HCC), but detailed knowledge on the relevance of high nutritional cholesterol remains elusive. We were aimed to characterize HCC development in mice fed with a Western diet (high in lipids and cholesterol) and to identify molecular alterations that define a subtype of liver cancer induced by lipid overload. Mice under western or high cholesterol diets more frequently developed tumors with a more aggressive phenotype than animals fed with a chow diet. Associated changes involved macrophage infiltration, angiogenesis, and stemness features. RNA-seq revealed a specific gene expression signature (Slc41a, Fabp5, Igdcc4 and Mthfd1l) resembling the adverse phenotypic features and poor clinical outcomes seen in patients with HCC. In conclusion, consumption of lipid enriched diets, particularly cholesterol, could accelerate HCC development with an aggressive phenotype and poor prognosis