Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Its pathogenesis is frequently linked to liver inflammation. Gain-of-function mutations in the gene encoding β-catenin are frequent genetic modifications found in human HCCs. Thus, we investigated whether inflammation was a component of β-catenin-induced tumorigenesis using genetically modified mouse models that recapitulated the stages of initiation and progression of this tumoral process. Oncogenic β-catenin signaling was found to induce an inflammatory program in hepatocytes that involved direct transcriptional control by β-catenin and activation of the NF-κB pathway. This led to a specific inflammatory response, the intensity of which determined the degree of tumor aggressiveness. The chemokine-like chemotactic factor leukocyte cell-derived chemotaxin 2 (LECT2) and invariant NKT (iNKT) cells were identified as key interconnected effectors of liver β-catenin-induced inflammation. In genetic deletion models lacking the gene encoding LECT2 or iNKT cells, hepatic β-catenin signaling triggered the formation of highly malignant HCCs with lung metastasis. Thus, our results identify inflammation as a key player in β-catenin-induced liver tumorigenesis. We provide strong evidence that, by activating pro-and antiinflammatory mediators, β-catenin signaling produces an inflammatory microenvironment that has an impact on tumoral development. Our data are consistent with the fact that most β-catenin-activated HCCs are of better prognosis.

Fanny Chereau and colleagues assess the risk of the emergence and spread of antibiotic resistance in South East Asia and suggest it is the highest of the World Health Organization regions

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MU and DC are key elements in the control of tissue homeostasis and response to insult. In this work, we demonstrate that MU and DC are the major producers of the phenylalanine catabolizing enzyme IL-4-induced gene 1 (IL4I1) under inflammatory conditions. IL4I1 was first described in B cells, which indeed can produce IL4I1 in vitro, although at much lower levels. In vivo, IL4I1 is highly expressed by MU and DC of Th1 granulomas (sarcoidosis, tuberculosis) but poorly detected in Th2 granulomas (schistosomiasis). In vitro, expression of the enzyme is induced in mononuclear phagocytes by various proinflammatory stimuli through the activation of the transcription factors NF-jB and/or STAT1. B cells also express IL4I1 in response to NF-jB-activating stimuli such as CD40L; however, in contrast to myeloid cells, B cells are insensitive to IFN-c but respond to stimulation of the IL-4/STAT6 axis. As we show that the expression of IL4I1 by a monocytic cell line inhibits T-cell proliferation and production of IFN-c and inflammatory cytokines, we propose that IL4I1 participates in the downregulation of Th1 inflammation in vivo.

The spread of extended-spectrum-␤-lactamase-producing Enterobacteriaceae (ESBL-PE) in low-income countries, where the burden of neonatal sepsis is high, may have a serious impact on neonatal mortality rates. Given the potential for mother-to-child transmission of multiresistant bacteria, this study investigated the ESBL-PE rectal colonization among pregnant women at delivery in the community in Madagascar and estimated a prevalence of 18.5% (95% confidence interval, 14.5% to 22.6%). One strain of Klebsiella pneumoniae isolated was also a New Delhi metallo-␤-lactamase-1 (NDM-1) producer. Severe bacterial infections are responsible for a large number of neonatal deaths in low-income countries (LICs) (1, 2), with Enterobacteriaceae most frequently isolated in neonatal sepsis (3,4). The production of plasmid-borne extended-spectrum ␤-lactamases (ESBL) is the main mechanism of resistance against expanded-spectrum cephalosporins (ESC) among Enterobacteriaceae, with the CTX-M-15 variant being the most common enzyme (5). In LICs, where neonatal sepsis caused by ESBL-producing Enterobacteriaceae (ESBL-PE) may be associated with higher fatality rates (6), colonized mothers could represent a source of transmission to neonates. The objectives of this study were to estimate the prevalence of ESBL-PE rectal colonization among pregnant women in Madagascar in an urban area, Antananarivo, and a semirural area, Moramanga, and to identify associated risk factors.This study was conducted in the context of an international pediatric cohort, the BIRDY (bacterial infections and antibiotic resistance disease among young children in low-income countries) program, approved by the Ethics Committees of Ministry of Health, Madagascar, and Institut Pasteur, France. All pregnant women living in the study areas were identified by medical or community workers and enrolled after giving written informed consent. A stool sample was taken at delivery for ESBL-PE screening. Among the women enrolled, 356 gave birth between June 2013 and March 2014 and were included in the present study. A risk factor analysis was conducted on a subset of 231 women who delivered during a 6-month period (June to September 2013 and January to March 2014). Sociodemographic characteristics, previous health care exposure, and antibiotic consumption (collected with prescription documents, remaining tablets, or visual aid) were recorded. Fresh stools were plated onto Drigalski agar supplemented with 3 mg/liter of ceftriaxone at the clinical laboratory of Institut Pasteur of Madagascar. Plates were incubated for 24 to 48 h at 37°C. Every oxidase and Gram-negative colony type was Citation Chereau F, Herindrainy P, Garin B, Huynh B-T, Randrianirina F, Padget M, Piola P, Guillemot D, Delarocque-Astagneau E. 2015. Colonization of extendedspectrum-␤-lactamase-and NDM-1-producing Enterobacteriaceae among pregnant women in the community in a low-income country: a potential reservoir for transmission of multiresistant Enterobacteriaceae to neonates.

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GH is a pleiotropic hormone that plays a major role in proliferation, differentiation, and metabolism via its specific receptor. It has been previously suggested that GH signaling pathways are required for normal liver regeneration but the molecular mechanisms involved have yet to be determined. The aim of this study was to identify the mechanisms by which GH controls liver regeneration. We performed two thirds partial hepatectomies in GH receptor (GHR)-deficient mice and wild-type littermates and showed a blunted progression in the G(1)/S transition phase of the mutant hepatocytes. This impaired liver regeneration was not corrected by reestablishing IGF-1 expression. Although the initial response to partial hepatectomy at the priming phase appeared to be similar between mutant and wild-type mice, cell cycle progression was significantly blunted in mutant mice. The main defect in GHR-deficient mice was the deficiency of the epidermal growth factor receptor activation during the process of liver regeneration. Finally, among the pathways activated downstream of GHR during G(1) phase progression, namely Erk1/2, Akt, and signal transducer and activator of transcription 3, we only found a reduced Erk1/2 phosphorylation in mutant mice. In conclusion, our results demonstrate that GH signaling plays a major role in liver regeneration and strongly suggest that it acts through the activation of both epidermal growth factor receptor and Erk1/2 pathways.

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