FGF2 Translationally Induced by Hypoxia Is Involved in Negative and Positive Feedback Loops with HIF-1α

BACKGROUND: Fibroblast growth factor 2 (FGF2) is a major angiogenic factor involved in angiogenesis and arteriogenesis, however the regulation of its expression during these processes is poorly documented. FGF2 mRNA contains an internal ribosome entry site (IRES), a translational regulator expected to allow mRNA expression during cellular stress. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we have developed a skin ischemia model in transgenic mice expressing a reporter transgene under the control of the FGF2 IRES. The results reveal that FGF2 is induced at the protein level during ischemia, concomitant with HIF-1alpha induction and a decrease in FGF2 mRNA. In addition, the FGF2 IRES is strongly activated under these ischemic conditions associated with hypoxia, whereas cap-dependent translation is repressed by 4E-BP hypophosphorylation. We also show that up-regulation of FGF2 protein expression in response to hypoxia correlates with the increase of FGF2 IRES activity in vitro, in human retinoblasts 911. The use of siRNAs targeting HIF or FGF2 indicates that FGF2 and HIF-1alpha reciprocally regulate their expression/accumulation, by a negative feedback loop in early hypoxia, followed by a positive feedback loop in late hypoxia. CONCLUSION/SIGNIFICANCE: FGF2 expression is up-regulated in vivo and in vitro in response to hypoxia. Strikingly, this up-regulation is not transcriptional. It seems to occur by an IRES-dependent mechanism, revealing new mechanistic aspects of the hypoxic response. In addition, our data show that FGF2 interacts with HIF-1alpha in a unique crosstalk, with distinct stages in early and late hypoxia. These data reveal the physiological importance of IRES-dependent translation during hypoxic stress and underline the complexity of the cellular response to hypoxia, suggesting a novel role of FGF2 in the regulation of HIF-1alpha during the induction of angiogenesis

Les grottes ornées de Domme (Dordogne) : La Martine, Le Mammouth et le Pigeonnier

Delluc Brigitte, Delluc Gilles, Bazile-Robert Evelyne, Galinat B., Guichard Francis, Ozanne M. Les grottes ornées de Domme (Dordogne) : La Martine, Le Mammouth et le Pigeonnier. In: Gallia préhistoire, tome 26, fascicule 1, 1983. pp. 7-80

CALCULS DES PROPRÉTÉS THERMODYNAMIQUES ET DE TRANSPORT DES PLASMAS Ar-N2 ET Ar-NH3 À LA PRESSION ATMOSPHÉRIQUE

Les propriétés thermodynamiques et de transport de mélanges Al-N2 et Al-NH3 pour la synthèse de nitrure d'aluminium par arc transféré plasma sont calculées. Dans le cas de vapeur d'aluminium métallique en présence de plasma d'azote ou d'ammoniac, une approche thermodynamique donne les conditions de composition initiale et de température qui conduisent à de bonnes conditions expérimentales pour la réaction en phase gazeuse. Les calculs des compositions des mélanges et des propriétés de transport (conductivité thermique, viscosité, coefficient de diffusion des différentes espèces...) permettent de prévoir le comportement des arcs transférés et le taux d'aluminium vaporisé.In this paper are calculated the thermodynamic and transport properties of Al-N2 and Al-NH3 mixtures to synthetize aluminium nitride under transferred arc plasma conditions. In the case of metallic aluminium vaporized in nitrogen or ammonia plasmas, a thermodynamic approach gives the conditions of composition, temperature and pressure which allow good operating conditions for reactions in the gaseous phase. The calculation of the mixtures composition and of the transport properties (thermal conductivity, viscosity, diffusion coefficient of the differents species...) allows to predict the behaviour of the transferred arcs and the rate of aluminium vaporisation

Serum-free light chain assessment in hepatitis C virus-related lymphoproliferative disorders.

International audienceOBJECTIVE: To evaluate the relevance of serum-free light chain (FLC) assessment in hepatitis C virus (HCV)-related lymphoproliferative disorders, including mixed cryoglobulinemia (MC) and B cell non-Hodgkin lymphoma (B-NHL). PATIENTS AND METHODS: A total of 59 patients infected with HCV were prospectively followed, including patients without MC (n = 17), with asymptomatic MC (n = 7) and with MC vasculitis (n = 35, 9 of whom had B-NHL). Clinical and biological data were recorded at the time of the initial evaluation and at the end of follow-up. Serum FLC quantitation was carried out using a serum FLC assay. RESULTS: The mean (SD) serum kappa FLC level was higher in patients with asymptomatic MC (27.9 (8.6) mg/litre), MC vasculitis (36.7 (46.2) mg/litre) and B-NHL (51.3 (78.3) mg/litre) than without MC (21.7 (17.6) mg/litre) (p = 0.047, 0.025 and 0.045, respectively). The mean serum FLC ratio was higher in patients with MC vasculitis (2.08 (2.33)) and B-NHL (3.14 (3.49)) than in patients without MC (1.03 (0.26)) (p = 0.008). The rate of abnormal serum FLC ratio (>1.65) correlated with the severity of HCV-related B cell disorder: 0/17 (0%) without MC, 0/7 (0%) asymptomatic MC, 6/26 (23%) MC vasculitis without B-NHL and 4/9 (44%) B-NHL (p = 0.002). Serum kappa FLC levels and the serum FLC ratio correlated with the cryoglobulin level (r = 0.32, p<0.001 and r = 0.25, p = 0.002, respectively) and the severity of the B cell disorder (r = 0.26, p = 0.045 and r = 0.41, p = 0.001, respectively). Among patients with an abnormal serum FLC ratio at baseline, the FLC ratio correlated with the virological response to HCV treatment. CONCLUSIONS: In patients infected with HCV, an abnormal serum FLC ratio appears to be a very interesting marker, as it is consistently associated with the presence of MC vasculitis and/or B-NHL. After antiviral therapy, the serum FLC ratio could be used as a surrogate marker of the control of the HCV-related lymphoproliferation

Antipsychotic drugs and the risk of recurrent venous thromboembolism: A prospective cohort study

International audienc

Protein S Heerlen mutation heterozygosity is associated with venous thrombosis risk

International audienceHereditary Protein S (PS) deficiency is a rare coagulation disorder associated with an increased risk of venous thrombosis (VT). The PS Heerlen (PSH) mutation is a rare S501P mutation that was initially considered to be a neutral polymorphism. However, it has been later shown that PSH has a reduced half-life in vivo which may explain the association of PSH heterozygosity with mildly reduced levels of plasma free PS (FPS). Whether the risk of VT is increased in PSH carriers remains unknown. We analyzed the association of PSH (rs121918472 A/G) with VT in 4,173 VT patients and 5,970 healthy individuals from four independent case-control studies. Quantitative determination of FPS levels was performed in a subsample of 1257 VT patients. In the investigated populations, the AG genotype was associated with an increased VT risk of 6.57 [4.06–10.64] (p = 1.73 10−14). In VT patients in whom PS deficiency was excluded, plasma FPS levels were significantly lower in individuals with PSH when compared to those without [72 + 13 vs 91 + 21 UI/dL; p = 1.86 10−6, mean + SD for PSH carriers (n = 21) or controls (n = 1236) respectively]. We provide strong evidence that the rare PSH variant is associated with VT in unselected individuals

Ex vivo characterization of multiepitopic tumor-specific CD8 T cells in patients with chronic myeloid leukemia: implications for vaccine development and adoptive cellular immunotherapy

Identification of tumor-associated Ags is a prerequisite for vaccine-based and adoptive immune therapies. Some tumor-associated Ags elicit specific CD8 T cells in patients with chronic myeloid leukemia (CML). Here, we characterized ex vivo responses of CD8 T cells from CML patients to extrajunction bcr-abl peptides and telomerase 540-548 hTert, PR1, and WT1 peptides. CML-specific CD8 T cells were present in most treated patients and were usually multiepitopic: WT1, hTert, PR1, and bcr74 tetramer(+) cells were detected in 85, 82, 67, and 61% of patients, respectively. The breadth and magnitude of these responses did not differ significantly according to treatment or disease status. CML-specific tetramer(+) CD8 T cells had a predominantly memory phenotype, an intermediate perforin content, and low intracellular IFN-gamma accumulation in the presence of the relevant peptide. However, in short-term culture with HLA-matched leukemia cells, the patients' memory T cells were specifically reactivated to become IFN-gamma-producing effector cells, suggesting that CD8 T cell precursors with lytic potential are present in vivo and can be activated by appropriate stimulation. In conclusion, this study shows that multiepitopic tumor-specific CD8 T cell responses occur naturally in most CML patients, opening the way to new strategies for enhancing anti-CML immunity, in particular in patients with minimal residual disease

Fast Modeling of Phase Changes in a Particle Injected Within a d.c Plasma Jet

When spraying ceramic particles with a low thermal conductivity such as zirconia using Ar-H2 direct-current (d.c.) plasma jets where the heat transfer is important, heat propagation phenomena take place with the propagation of melting, evaporation or even solidification fronts. Most models neglect these heat propagation phenomena assuming the particle as a lumped media. This work is aimed at developing a model coupling the effect of heat propagation with the particle dynamic within plasma jets. It uses an adaptative grid in which the coordinates of the phase change fronts are fixed. It allows minimizing the calculation costs (approximately 10 seconds on PC under windows XP against 1hour with an enthalpy model). Such calculations are illustrated for dense and porous agglomerated zirconia as well as iron particles which evaporation in an Ar- H2 (25 vol %) plasma is importan