Radiosensitization with an inhibitor of poly(ADP-ribose) glycohydrolase: A comparison with the PARP1/2/3 inhibitor olaparib

Upon DNA binding the poly(ADP-ribose) polymerase family of enzymes (PARPs) add multiple ADP-ribose subunits to themselves and other acceptor proteins. Inhibitors of PARPs have become an exciting and real prospect for monotherapy and as sensitizers to ionising radiation (IR). The action of PARPs are reversed by poly(ADP-ribose) glycohydrolase (PARG). Until recently studies of PARG have been limited by the lack of an inhibitor. Here, a first in class, specific, and cell permeable PARG inhibitor, PDD00017273, is shown to radiosensitize. Further, PDD00017273 is compared with the PARP1/2/3 inhibitor olaparib. Both olaparib and PDD00017273 altered the repair of IR-induced DNA damage, resulting in delayed resolution of RAD51 foci compared with control cells. However, only PARG inhibition induced a rapid increase in IR-induced activation of PRKDC (DNA-PK) and perturbed mitotic progression. This suggests that PARG has additional functions in the cell compared with inhibition of PARP1/2/3, likely via reversal of tankyrase activity and/or that inhibiting the removal of poly(ADP-ribose) (PAR) has a different consequence to inhibiting PAR addition. Overall, our data are consistent with previous genetic findings, reveal new insights into the function of PAR metabolism following IR and demonstrate for the first time the therapeutic potential of PARG inhibitors as radiosensitizing agents

OPTIMIZATION OF TIN OXIDE THIN-FILM PREPARATION VIA GAS-PHASE TRANSPORT

International audienc

TRANSPORT PARAMETERS OF HOT-ELECTRONS IN GAAS AT 300-K

International audienc

DIFFUSION AND NOISE IN GAAS MATERIAL AND DEVICES

International audienceThe variation of the diffusion coefficent D(E) versus the electric field strength E, is determined at 300 K in n-type GaAs (N(D) = 3 x 10(-17) cm-3), using pulsed high-frequency noise measurements. D(E) is found to increase slightly at low field, then to decrease down to one tenth of its ohmic value near the threshold field. "Long" (greater-than-or-equal-to 4-mu-m) real n+-n-n+ Gunn diodes, with an arbitrary doping profile, can be modeled. Comparisons are made, and excellent agreement is found, between experimental and theoretical characteristics of two real diodes, with notch and with gradual doping profiles. The doping profile N(D)(x) is shown to have a considerable influence on the diode behavior, concerning the electric field profile as well as the noise characteristics. Using the impedance field method, the noise current is modeled and found to be very sensitive in the D(E) variation law, in particular in the range of 2.5-4 kV/cm. The agreement between the experimental noise and the computed noise of real diodes is found to be quite satisfactory when using D(E) determined in the present work, and important discrepancies occur when using other D(E) variations, both theoretical and experimental, found in the literature

OPTICAL AND ELECTRICAL-PROPERTIES OF SNO2 THIN-FILMS IN RELATION TO THEIR STOICHIOMETRIC DEVIATION AND THEIR CRYSTALLINE-STRUCTURE

International audienc

1/f noise measurements in n-channel MOSFET's processed in 0,25 µm technology- Extraction of BSIM3v3 noise parameters

International audienc

HIGH-FREQUENCY NOISE AND DIFFUSION-COEFFICIENT OF HOT-ELECTRONS IN BULK AL0.25GA0.75AS

International audienceWe present experimental results of hot electron noise in Si doped Al0.25Ga0.75As test structures using pulsed high-frequency noise measurements. Noise temperature and longitudinal diffusion coefficient as functions of field strength are compared with those of Si doped GaAs. We find significant changes at high fields. Results are discussed in regard of electron scattering mechanisms

Fragmentation radioinduite de l'ADN et réparation étudiée par immunomarquage anti poly(ADP-ribose)polymérase (PARP) dans les cellules de hamster chinois (CHO)

Le poly(ADP-ribose)polymérase est une enzyme nucléaire ubiquitaire capable de se fixer sur les cassures de l'ADN. Sur une lignée sauvage de cellules d'ovaire de hamster chinois (CHO-K1) cultivée sur lame et irradiée aux rayons γ à haut débit de dose (HD) 12,8 Gy/min ou à moyen débit de dose (MD) 5 Gy/min, nous avons réalisé un immunomarquage anti-polymères d'ADP-ribose immédiatement après l'irradiation γ ou après trois heures d'incubation à 37 °C. La quantification et la localisation des lésions radioinduites ont été réalisées par microscopie confocale. Les résultats montrent une relation dose-effet et un effet de débit de dose, ainsi qu'une disparition du signal après 3 heures à 37 °C. La présence de la PARP semble donc bien refléter la fragmentation radioinduite de l'ADN