The Persisting Burden of Intracerebral Haemorrhage: Can Effective Treatments Be Found?

Colin Josephson, Rustam Al-Shahi Salman, and colleagues discuss the effectiveness of treatments for intracerebral haemorrhage

Repair of 3-methyladenine and abasic sites by base excision repair mediates glioblastoma resistance to temozolomide

Alkylating agents have long played a central role in the adjuvant therapy of glioblastoma multiforme (GBM). More recently, inclusion of temozolomide (TMZ), an orally administered methylating agent with low systemic toxicity, during radiotherapy and afterward has markedly improved survival. Extensive in vitro and in vivo evidence has shown that TMZ-induced O6-methylguanine (O6-meG) mediates GBM cell killing. Moreover, low or absent expression of O6-methylguanine-DNA methyltransferase (MGMT), the sole human repair protein that removes O6-meG from DNA, is frequently associated with longer survival in GBMs treated with TMZ, promoting interest in developing inhibitors of MGMT to counter resistance. However, the clinical efficacy of TMZ is unlikely to be due solely to O6-meG, as the agent produces approximately a dozen additional DNA adducts, including cytotoxic N3-methyladenine (3-meA) and abasic sites. Repair of 3-meA and abasic sites, both of which are produced in greater abundance than O6-meG, is mediated by the base excision repair (BER) pathway, and occurs independently of removal of O6-meG. These observations indicate that BER activities are also potential targets for strategies to potentiate TMZ cytotoxicity. Here we review the evidence that 3-meA and abasic sites mediate killing of GBM cells. We also present in vitro and in vivo evidence that alkyladenine-DNA–glycosylase, the sole repair activity that excises 3-meA from DNA, and Ape1, the major human abasic site endonuclease, mediate TMZ resistance in GBMs and represent potential anti-resistance targets

Minimally Cytotoxic Doses of Temozolomide Produce Radiosensitization in Human Glioblastoma Cells Regardless of MGMT Expression

Decedent, a Texas resident, provided that if his wife elected to take under his will she would receive one-third of the total community property and one-third of his separate estate. The remaining two-thirds of decedent\u27s total estate was devised in trust for the benefit of his children. The widow elected to take under the will, thereby allowing her interest in the community property to pass as provided in the will. The executors claimed a marital deduction for the one-third separate property passing to the widow. Since she received less under the will than the value of her relinquished community property, the government disallowed the deduction. After paying the deficiency, the executors brought suit for a refund. The district court held that the bequest of one-third separate property qualified for the marital deduction. On appeal, held, affirmed, one judge dissenting. In determining the amount of the marital deduction, the value of the separate property passing to the surviving spouse is not reduced by the value of her relinquished community property passing under the will to decedent\u27s children. United States v. Stapf, 309 F.2d 592 (5th Cir. 1962), cert. granted, 372 U.S. 928 (1963)