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Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Here, we report on gross, aberrant constitutive activation of DNA damage signalling in low- and high-grade human gliomas, and analyze the sources of such endogenous genotoxic stress. Based on analyses of human glioblastoma multiforme (GBM) cell lines, normal astrocytes and clinical specimens from grade II astrocytomas (n=41) and grade IV GBM (n=60), we conclude that the DDR machinery is constitutively activated in gliomas, as documented by phosphorylated histone H2AX (gammaH2AX), activation of the ATM-Chk2-p53 pathway, 53BP1 foci and other markers. Oxidative DNA damage (8-oxoguanine) was high in some GBM cell lines and many GBM tumors, while it was low in normal brain and grade II astrocytomas, despite the degree of DDR activation was higher in grade II tumors. Markers indicative of ongoing DNA replication stress (Chk1 activation, Rad17 phosphorylation, replication protein A foci and single-stranded DNA) were present in GBM cells under high- or low-oxygen culture conditions and in clinical specimens of both low- and high-grade tumors. The observed global checkpoint signaling, in contrast to only focal areas of overabundant p53 (indicative of p53 mutation) in grade II astrocytomas, are consistent with DDR activation being an early event in gliomagenesis, initially limiting cell proliferation (low Ki-67 index) and selecting for mutations of p53 and likely other genes that allow escape (higher Ki-67 index) from the checkpoint and facilitate tumor progression. Overall, these results support the potential role of the DDR machinery as a barrier to gliomagenesis and indicate that replication stress, rather than oxidative stress, fuels the DNA damage signalling in early stages of astrocytoma development.

Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Here, we report on gross, aberrant constitutive activation of DNA damage signalling in low- and high-grade human gliomas, and analyze the sources of such endogenous genotoxic stress. Based on analyses of human glioblastoma multiforme (GBM) cell lines, normal astrocytes and clinical specimens from grade II astrocytomas (n=41) and grade IV GBM (n=60), we conclude that the DDR machinery is constitutively activated in gliomas, as documented by phosphorylated histone H2AX (gammaH2AX), activation of the ATM-Chk2-p53 pathway, 53BP1 foci and other markers. Oxidative DNA damage (8-oxoguanine) was high in some GBM cell lines and many GBM tumors, while it was low in normal brain and grade II astrocytomas, despite the degree of DDR activation was higher in grade II tumors. Markers indicative of ongoing DNA replication stress (Chk1 activation, Rad17 phosphorylation, replication protein A foci and single-stranded DNA) were present in GBM cells under high- or low-oxygen culture conditions and in clinical specimens of both low- and high-grade tumors. The observed global checkpoint signaling, in contrast to only focal areas of overabundant p53 (indicative of p53 mutation) in grade II astrocytomas, are consistent with DDR activation being an early event in gliomagenesis, initially limiting cell proliferation (low Ki-67 index) and selecting for mutations of p53 and likely other genes that allow escape (higher Ki-67 index) from the checkpoint and facilitate tumor progression. Overall, these results support the potential role of the DDR machinery as a barrier to gliomagenesis and indicate that replication stress, rather than oxidative stress, fuels the DNA damage signalling in early stages of astrocytoma development.

Biochemical responses to cadmium (Cd2+) and copper (Cu2+) exposure were compared in two strains of the aquatic hyphomycete (AQH) Heliscus lugdunensis. One strain (H4-2-4) had been isolated from a heavy metal polluted site, the other (H8-2-1) from a moderately polluted habitat. Conidia of the two strains differed in shape and size. Intracellular accumulation of Cd2+ and Cu2+ was lower in H4-2-4 than in H8-2-1. Both?strains synthesized significantly more glutathione (GSH), cysteine (Cys) and ?-glutamylcysteine (?-EC) in the presence of 25 and 50 µM Cd2+, but quantities and rates of synthesis were different. In H4-2-4, exposure to 50 µM Cd2+ increased GSH levels to 262% of the control; in H8-2-1 it increased to 156%. Mycelia of the two strains were analysed for peroxidase, dehydroascorbate reductase, glutathione reductase and glucose-6-phosphate dehydrogenase. With Cd2+ exposure, peroxidase activity increased in both strains. Cu2+ stress increased dehydroascorbate reductase activity in H4-2-4 but not in H8-2-1. Dehydroascorbate reductase and glucose-6-phosphate dehydrogenase activities progressively declined in the presence of Cd2+, indicating a correlation with Cd2+ accumulation in both strains. Cd2+ and Cu2+ exposure decreased glutathione reductase activity.

Numérisation effectuée à partir d'un document de substitution : R 197865., DAHLER (J.-G.) : 10 mai 1785 ; 10 décembre 1788 ; 13 juin 1789 ; 24 janvier 1790 ; 9 avril 1790 ; 20 juin 1790 ; 12 décembre 1790 ; 9 mai 1808 ; 22 février 1808. (9 lettres.) — DECKER : 5 décembre 1795 ; 23 janvier 1796 ; 29 janvier 1796 ; 3 février 1796 ; 17 juin 1796 ; 4 janvier 1797 ; 9 frimaire an 4 (7 lettres.) — DEDON aîné : 5 germinal an 13 (1 lettre). — DEGUIGNES : 28 mars 1773 (1 lettre). — DEIMLING : 30 mai 1767 (1 lettre). — DELESSART : 9 juin 1773 ; 18 juillet 1783 (2 lettres). — DENNER : 10 décembre 1787. — DESAUNAY : 19 mars 1770 ; 3 juin 1771 (2 lettres). — DESBIEY (Abbé) : 1er novembre 1776 (1 lettre). — DESHAUTESRAYES : 18 février 1773 ; 22 avril 1773 (2 lettres). — DES ROTOURS : 1 lettre sans date. — DIEBOLT : 21 juillet 1807 ; 29 novembre 1807 (2 lettres). — DIETRICH (de) : 20 janvier 1771 ; 8 mai 1771 ; 6 juin 1774 ; 16 juin 1774 (4 lettres). — DOCEN (B.-J.) : 28 mars 1804 ; 19 août 1803 ; 8 mars 1804 ; 15 mai 1805 ; 30 juin 1806, 10 décembre (?) (6 lettres). — DOGEN : 14 décembre 1774 (1 lettre). — DOUAY : 26 septembre 1790 (1 lettre). — DROZ : 19 novembre 1776 (1 lettre). — DUBOIS DE FOSSEUX : 26 juin 1789 (1 lettre). — DUMAS (Mathieu) : 5 prairial an 5 (1 lettre). — DUMAS (de Toulouse) : 28 août 1777 ; 4 mai 1779 (2 lettres). — DUMONT (Chanoine) : 8 floréal an 13, 13 floréal an 13, 10 thermidor an 13, 13 thermidor an 13, 14 novembre 1804, 15 février (?) (6 lettres). — DUPAIN : 15 fructidor an 13 (1 lettre). — DUPRE : 1er janvier 1786 ; 16 août 1793 ; 27 août 1793 ; 8 nivôse an 8 ; 9 pluviose an 8, 10 germinal an 8, 23 floréal an 8 ; 18 prairial an 8 ; 13 messidor an 8 ; 15 thermidor an 8 ; 10 fructidor an 8 ; 5 vendémiaire an 9 ; 1er frimaire an 9 ; 28 frimaire an 9 ; 9 nivôse an 9 ; 23 vendémiaire an 10 ; 20 brumaire an 10 ; 22 frimaire an 10 ; 17 nivôse an 10 ; 5 germinal an 10 ; 12 floréal an 10 ; 20 floréal an 10 ; 17 prairial an 10 ; 19 prairial an 10 ; 10 messidor an 10 ; 22 messidor an 10 ; 29 messidor an 10 ; 4 thermidor an 10 ; 5 ther