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 highgrade 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 ¼ 41) and grade IV GBM (n ¼ 60), we conclude that the DDR machinery is constitutively activated in gliomas, as documented by phosphorylated histone H2AX (cH2AX), 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 lowoxygen 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.

The data of this study suggest that the majority of long-term survivors of brain tumours develop GH deficiency following radiotherapy in childhood and that the adverse effects of radiotherapy may be directly related to the biologically effective dose. With longer follow-up fewer patients might respond normally to GH stimulation tests.

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Gynaecomastic tissue from six patients were tested for oestrogen and testosterone sensitivity as measured by thymidine incorporation in tissue fragments in vitro. The DNA synthesis of the cultures was increased in tissue from five out of the six patients under the influence of oestrogen, whereas it was increased in tissue from only one patient under the influence of testosterone. The results are discussed in relation to the medical histories of the patients and hormonal excretion studies done by others.

Absence of association between oestrogen-receptor content and in vitro oestrogen sensitivity in human breast cancer. Acta path. microbiol. scand. Sect. A, 86: 169-172, 1978. Breast-cancer tissue from 25 consecutive patients was investigated for estrogen receptor content and for oestrogen-induced changes in tritiated thymidine uptake by explanted cells. A higher oestrogen receptor content was not associated with any statistically significant increase in oestrogen sensitivity. Neither the dissociation constants (& values), nor the oestrogen binding capacity (f mol oestrogen bound/mg supernatant protein) was found to be associated with in vitro oestrogen sensitivity. One receptor-negative tumour showed oestrogen sensitivity in vitro.