Hamartia in hippocampal sclerosis-associated mesial temporal lobe epilepsy.

Hamartia are small collections of rounded glioneuronal cells that are thought to be due to aberrant cell migration. Their presence has been recognized in association with mesial temporal lobe epilepsy; their prevalence among cases of hippocampal sclerosis (HS) and any potential association with patient demographics and outcomes is unknown. This study examines hamartia in a series of 292 patients with pathologically confirmed HS. Medical records were reviewed for pertinent patient clinical information (follow-up mean 5years). Hamartia were identified in 96 cases (33%) and were seen primarily in the amygdala (n=88) and less commonly in the hippocampus (n=10) and temporal lobe (n=4). A statistically significant relationship was found between the presence of hamartia and male gender, younger age of seizure onset, and history of childhood febrile seizures and developmental delay. It is unclear if these associations represent a real association or are a result of the underlying pathologies related to chronic epilepsy. At follow-up, there were no significant differences between patients who had hamartia and those who lacked this finding. Hamartia were observed in all subtypes of HS and there was a significant difference found in subtype distribution as well as proportion of cases between subtypes, but no association with any specific subtype overall. The presence of hamartia was not associated with the coexistence of focal cortical dysplasia or any specific histologic pattern of dysplasia. Hamartia are a common concomitant finding in HS and indicates evidence of aberrant cell migration in the hippocampal and parahippocampal regions in these patients.

The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01.

A checkpoint operating in the G(2) phase of the cell cycle prevents entry into mitosis in the presence of DNA damage. UCN-01, a protein kinase inhibitor currently undergoing clinical trials for cancer treatment, abrogates G(2) checkpoint function and sensitizes p53-defective cancer cells to DNA-damaging agents. In most species, the G(2) checkpoint prevents the Cdc25 phosphatase from removing inhibitory phosphate groups from the mitosis-promoting kinase Cdc2. This is accomplished by maintaining Cdc25 in a phosphorylated form that binds 14-3-3 proteins. The checkpoint kinases, Chk1 and Cds1, are proposed to regulate the interactions between human Cdc25C and 14-3-3 proteins by phosphorylating Cdc25C on serine 216. 14-3-3 proteins, in turn, function to keep Cdc25C out of the nucleus. Here we report that UCN-01 caused loss of both serine 216 phosphorylation and 14-3-3 binding to Cdc25C in DNA-damaged cells. In addition, UCN-01 potently inhibited the ability of Chk1 to phosphorylate Cdc25C in vitro. In contrast, Cds1 was refractory to inhibition by UCN-01 in vitro, and Cds1 was still phosphorylated in irradiated cells treated with UCN-01. Thus, neither Cds1 nor kinases upstream of Cds1, such as ataxia telangiectasia-mutated, are targets of UCN-01 action in vivo. Taken together our results identify the Chk1 kinase and the Cdc25C pathway as potential targets of G(2) checkpoint abrogation by UCN-01.