Capture in the metabolic arena: co-selection of gamma and deltaretrovirus envelope glycoproteins and their receptors

International audiencen.

E4F1-mediated control of pyruvate dehydrogenase activity is essential for skin homeostasis.

The multifunctional protein E4 transcription factor 1 (E4F1) is an essential regulator of epidermal stem cell (ESC) maintenance. Here, we found that E4F1 transcriptionally regulates a metabolic program involved in pyruvate metabolism that is required to maintain skin homeostasis. E4F1 deficiency in basal keratinocytes resulted in deregulated expression of dihydrolipoamide acetyltransferase (Dlat), a gene encoding the E2 subunit of the mitochondrial pyruvate dehydrogenase (PDH) complex. Accordingly, E4f1 knock-out (KO) keratinocytes exhibited impaired PDH activity and a redirection of the glycolytic flux toward lactate production. The metabolic reprogramming of E4f1 KO keratinocytes associated with remodeling of their microenvironment and alterations of the basement membrane, led to ESC mislocalization and exhaustion of the ESC pool. ShRNA-mediated depletion of Dlat in primary keratinocytes recapitulated defects observed upon E4f1 inactivation, including increased lactate secretion, enhanced activity of extracellular matrix remodeling enzymes, and impaired clonogenic potential. Altogether, our data reveal a central role for Dlat in the metabolic program regulated by E4F1 in basal keratinocytes and illustrate the importance of PDH activity in skin homeostasis

Prévalence de l'obésité chez l'enfant dans la région PACA [Provence-Alpes-Côte d'azur], les causes, les conséquences possibles, et les modalités d'action

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

No Impact of Fluconazole to Echinocandins Replacement as First-Line Therapy on the Epidemiology of Yeast Fungemia (Hospital-Driven Active Surveillance, 2004–2017, Paris, France)

Part of this work has been presented at 8th Trends in Medical Mycology, October 6–9, 2017, Belgrade, Serbia (oral presentation S08.6).International audienceReplacement of fluconazole by echinocandins as the first-line therapy for yeast-related fungemia could have an impact on both the mortality rate and the epidemiology of yeast species responsible for candidemia. We analyzed the individual clinical and microbiological data collected through the active surveillance program on yeast fungemia (YEASTS program, 2004–2016, Paris area, France) within 14 University Hospitals. The cohort included 3,092 patients [male:female ratio: 1.56; median age 61.0 years (IQR: 23.8)]. The mean mortality rate within 30 days was 38.5% (1,103/2,868) and significantly higher in intensive care units (690/1,358, 50.8%) than outside (413/1,510, 27.4%, p < 0.0001) without significant change over time. The yeast species distribution [ Candida albicans ( n = 1,614, 48.0%), Candida glabrata ( n = 607, 18.1%), Candida parapsilosis ( n = 390, 11.6%), Candida tropicalis ( n = 299, 8.9%), Candida krusei ( n = 96, 2.9%), rare species ( n = 357, 10.6%)], minimal inhibitory concentration distribution, and the distribution between the patient populations (hematological malignancies, solid tumors, without malignancy) did not change either while the proportion of patients ≥60-years increased from 48.7% (91/187) in 2004 to 56.8% (133/234) in 2017 ( p = 0.0002). Fluconazole as first-line therapy dramatically decreased (64.4% in 2004 to 27.7% in 2017, p < 0.0001) with a corresponding increase in echinocandins (11.6% in 2004 to 57.8% in 2017, p < 0.0001). Survival rates did not differ according to the first antifungal therapy. The progressive replacement of fluconazole by echinocandins as the first-line antifungal therapy was not associated with change in global mortality, regardless of species involved and antifungal susceptibility profiles. Other factors remain to be uncovered to improve the prognosis of yeast fungemia

Predisposing factors and outcome of uncommon yeast species-related fungaemia based on an exhaustive surveillance programme (2002–14)

International audienceObjectives:Using registry data to compare fungaemia caused by uncommon yeast species (UYS; i.e. other than Candida albicans , Candida glabrata , Candida parapsilosis , Candida tropicalis and Candida krusei ) and C. albicans -related fungaemia can reveal specific predisposing factors of UYS with potential impact on treatment strategies.Methods:We analysed 338 episodes of UYS fungaemia prospectively collected from 27 hospitals (Paris, France; 1 October 2002-31 December 2014) and compared these with 1998 single episodes of C. albicans fungaemia using univariate and multivariate analyses.Results:The proportion of UYS fungaemia was stable over time. Thirty-five different species were identified (27 ascomycetes, 8 basidiomycetes), 11 had caspofungin MIC 50  >0.25 mg/L and 15 fluconazole MIC 50  >4 mg/L. Haematological malignancies [OR=2.39 (95% CI 1.79-3.18)] and prior exposure to antifungal drugs [OR=1.87 (1.30-2.69)] were independent predisposing factors for UYS infections upon multivariate analysis. However, when considering the genus/species complex level, only infections due to Candida kefyr -related species [OR=4.01 (2.42-6.64)] and to Trichosporon spp. [OR=5.38 (1.72-16.81)] remained associated with haematological malignancies, those due to the GEOTRICHUM group with acute leukaemia [OR=61.29 (19.23-195.36)], and infections with Trichosporon spp. or the GEOTRICHUM group with prior exposure to caspofungin [OR=15.67 (3.62-67.80) and OR=13.17 (3.33-52.03), respectively] but not to fluconazole. The global mortality at day 30 for UYS was similar to that for C. albicans (35.4%, and 39.9%, respectively), but very divergent results were observed according to the specific UYS.Conclusions:UYS encompass a high diversity of species, each with its own behaviour and predisposing factors for human infections. This variety makes it important to rapidly identify an isolate to the species level in order to optimize antifungal treatment

Recent Exposure to Caspofungin or Fluconazole Influences the Epidemiology of Candidemia: a Prospective Multicenter Study Involving 2,441 Patients▿

A prospective multicenter surveillance program on yeast bloodstream infections was implemented in the Paris, France, area without restrictions on ward of hospitalization (intensive care unit, hematology, and surgery) or age (adults and children). The present analysis concerns 2,618 isolates collected over 7 years from 2,441 patients. Centralized species identification and antifungal susceptibility testing using the EUCAST methodology were performed. Almost 10% (232/2,441) of the patients had recently (≤30 days) been treated with antifungal drugs. We analyzed the effect of recent exposure to fluconazole (n = 159) or caspofungin (n = 61) on the proportions of the five major Candida species. For both drugs, preexposure was associated with a decreased prevalence of Candida albicans in favor of less drug-susceptible species (C. glabrata and C. krusei for the former and C. parapsilosis and, to a lesser extent, C. glabrata and C. krusei for the latter; P = 0.001). In the multivariate analysis, the risk of being infected with an isolate with decreased susceptibility to fluconazole was independently associated with an age of ≥15 years (odds ratio [OR] = 2.45; 95% confidence interval [CI] = 1.39 to 4.31; P = 0.002) and with recent exposure to fluconazole (OR = 2.17; 95% CI = 1.51 to 3.13; P < 0.001), while the risk of being infected with an isolate with decreased susceptibility to caspofungin was independently associated with an age <15 years (OR = 2.53; 95% CI = 1.43 to 4.48; P = 0.001) and with recent exposure to caspofungin (OR = 4.79; 95% CI = 2.47 to 9.28; P < 0.001). These findings could influence future recommendations for the management of candidemia

Barhl2 maintient les facteurs de transcription T comme répresseurs et désactive ainsi la réponse de Wnt/β-Catenin entraînant la formation de l'organisateur de Spemann.

International audienceA hallmark of Wnt/β-Catenin signaling is the extreme diversity of its transcriptional response, which varies depending on the cell and developmental context. What controls this diversity is poorly understood. In all cases, the switch from transcriptional repression to activation depends on a nuclear increase in β-Catenin, which detaches the transcription factor T cell factor 7 like 1 (Tcf7l1) bound to Groucho (Gro) transcriptional co-repressors from its DNA-binding sites and transiently converts Tcf7/Lymphoid enhancer binding factor 1 (Lef1) into a transcriptional activator. One of the earliest and evolutionarily conserved functions of Wnt/β-Catenin signaling is the induction of the blastopore lip organizer. Here, we demonstrate that the evolutionarily conserved BarH-like homeobox-2 (Barhl2) protein stabilizes the Tcf7l1-Gro complex and maintains the repressed expression of Tcf target genes by a mechanism that depends on histone deacetylase 1 (Hdac-1) activity. In this way, Barhl2 switches off the Wnt/β-Catenin-dependent early transcriptional response, thereby limiting the formation of the organizer in time and/or space. This study reveals a novel nuclear inhibitory mechanism of Wnt/Tcf signaling that switches off organizer fate determination.L'une des caractéristiques de la signalisation de Wnt/β-Catenin est l'extrême diversité de sa réponse transcriptionnelle, qui varie en fonction de la cellule et du contexte de développement. Ce qui contrôle cette diversité est mal compris. Dans tous les cas, le passage de la répression transcriptionnelle à l'activation dépend d'une augmentation nucléaire de la β-Caténine, qui détache le facteur de transcription T (Tcf7l1) lié aux co-répresseurs transcriptionnels de Groucho (Gro) de ses sites de liaison ADN et transforme temporairement Tcf7 en un activateur de la transcription. L'une des premières fonctions de signalisation de Wnt/β-Catenin, conservée au cours de l'évolution, est l'induction de l'organiseur de lSpemann. Nous démontrons ici que la protéine BarH-like Homeobox-2 (Barhl2), conservée au cours de l'évolution, stabilise le complexe Tcf7l1-Gro et maintient l'expression réprimée des gènes cibles du Tcf par un mécanisme qui dépend de l'activité des histone désacétylases 1 (Hdac-1). De cette façon, Barhl2 désactive la réponse transcriptionnelle précoce dépendante de Wnt/β-Catenin, limitant ainsi la formation de l'organisateur dans le temps et/ou l'espace. Cette étude révèle un nouveau mécanisme d'inhibition nucléaire de la signalisation Wnt/Tcf qui désactive la détermination du sort de l'organisateur

Prior Caspofungin Exposure in Patients with Hematological Malignancies Is a Risk Factor for Subsequent Fungemia Due to Decreased Susceptibility in Candida spp.: a Case-Control Study in Paris, France▿

Infections due to caspofungin-resistant Candida isolates in patients exposed to caspofungin therapy are increasing. We report here a nested case-control study which aimed at identifying factors associated with bloodstream infections caused by Candida spp. having reduced susceptibility to caspofungin (CRSC) in adults suffering from hematological malignancies. In univariate and multivariate analyses, infections with CRSC were associated with caspofungin exposure in the previous 30 days (odds ratio [OR] = 5.25; 95% confidence interval [95% CI], 1.68–16.35) and with an age of ≤65 years (OR = 3.27; 95% CI, 1.26–8.50)

The risk and clinical outcome of candidemia depending on underlying malignancy

International audiencePURPOSE:To assess the risk factors and outcomes associated with fungemia caused by the six most commonly occurring Candida species in patients with and without malignancies.METHODS:Analysis of the episodes of fungemia due to common Candida species in adults, based on an active hospital-based surveillance program (Paris area, France, 2002 to 2014).RESULTS:Of the 3417 patients (3666 isolates), 1164 (34.1%) had a solid tumor (45.7% digestive tract) and 586 (17.1%) a hematological malignancy (41.8% lymphoma, 33.5% acute leukemia). The hematology patients were significantly younger, more often pre-exposed to antifungals, more often infected by C. tropicalis, C. krusei, or C. kefyr, and more often treated in the first instance with an echinocandin. Compared with inpatients who were not in ICU at the time of fungemia, those in ICU were less frequently infected by C. parapsilosis (p < 0.02), had more recent surgery (p < 0.03), and died more frequently before day 8 and day 30 (p < 0.0001). An increase in crude mortality over time in ICU was observed only in oncology patients (p < 0.04). For all patients, lack of prescription of antifungals despite knowledge of positive blood culture increased the risk of death. The odds of being infected by a given Candida species compared with C. albicans were uneven regarding age, gender, type of malignancy, hospitalization in ICU, central venous catheter, HIV status, intravenous drug addiction, and previous exposure to antifungal drugs. Compared with C. albicans, C. glabrata (OR = 0.69 [0.54-0.89]) and C. parapsilosis (OR = 0.49 [0.35-0.67]) were associated with a decreased risk of death by day 8 and day 30.CONCLUSION:The clinical context of underlying malignancy and hospitalization in ICU may be relevant to the initial management of candidemia