Benchmark dose analyses of multiple genetic toxicity endpoints permit robust, cross-tissue comparisons of MutaMouse responses to orally delivered benzo[a]pyrene.

Genetic damage is a key event in tumorigenesis, and chemically induced genotoxic effects are a human health concern. Although genetic toxicity data have historically been interpreted using a qualitative screen-and-bin approach, there is increasing interest in quantitative analysis of genetic toxicity dose-response data. We demonstrate an emerging use of the benchmark dose (BMD)-approach for empirically ranking cross-tissue sensitivity. Using a model environmental carcinogen, we quantitatively examined responses for four genetic damage endpoints over an extended dose range, and conducted cross-tissue sensitivity rankings using BMD100 values and their 90% confidence intervals (CIs). MutaMouse specimens were orally exposed to 11 doses of benzo[a]pyrene. DNA adduct frequency and lacZ mutant frequency (MF) were measured in up to 8 tissues, and Pig-a MF and micronuclei (MN) were assessed in immature (RETs) and mature red blood cells (RBCs). The cross-tissue BMD pattern for lacZ MF is similar to that observed for DNA adducts, and is consistent with an oral route-of-exposure and differences in tissue-specific metabolism and proliferation. The lacZ MF BMDs were significantly correlated with the tissue-matched adduct BMDs, demonstrating a consistent adduct conversion rate across tissues. The BMD CIs, for both the Pig-a and the MN endpoints, overlapped for RETs and RBCs, suggesting comparable utility of both cell populations for protracted exposures. Examination of endpoint-specific response maxima illustrates the difficulty of comparing BMD values for a fixed benchmark response across endpoints. Overall, the BMD-approach permitted robust comparisons of responses across tissues/endpoints, which is valuable to our mechanistic understanding of how benzo[a]pyrene induces genetic damage.

PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress.

Mutations in PTEN-induced kinase 1 (PINK1) result in a recessive familial form of Parkinson's disease (PD). PINK1 loss is associated with mitochondrial Ca2+ mishandling, mitochondrial dysfunction, as well as increased neuronal vulnerability. Here we demonstrate that PINK1 directly interacts with and phosphorylates LETM1 at Thr192 in vitro. Phosphorylated LETM1 or the phospho-mimetic LETM1-T192E increase calcium release in artificial liposomes and facilitates calcium transport in intact mitochondria. Expression of LETM1-T192E but not LETM1-wild type (WT) rescues mitochondrial calcium mishandling in PINK1-deficient neurons. Expression of both LETM1-WT and LETM1-T192E protects neurons against MPP+-MPTP-induced neuronal death in PINK1 WT neurons, whereas only LETM1-T192E protects neurons under conditions of PINK1 loss. Our findings delineate a mechanism by which PINK1 regulates mitochondrial Ca2+ level through LETM1 and suggest a model by which PINK1 loss leads to deficient phosphorylation of LETM1 and impaired mitochondrial Ca2+ transport..

Cognitive function and its relationship to other psychosocial factors in lymphoma survivors.

PURPOSE: The purpose of this study was to estimate the prevalence of cognitive disturbance in lymphoma survivors and to explore relationships between cognitive function and other psychosocial factors. METHODS: A package of standardized questionnaires was sent to 622 lymphoma patients treated at the Ottawa Hospital in the preceding 5 years. Patients with central nervous system involvement were excluded. The questionnaires addressed cognitive function, pain, insomnia, fatigue, and mood. Of the patients in the sampling frame, 54 % responded to the survey and 42 % met inclusion/exclusion criteria. Sixteen percent (99/622) agreed to undergo computerized neuropsychological testing with CNS vital signs (CNSVS). Scores on the objective and subjective cognitive measures were compared to those of a healthy female control group from a previous study. RESULTS: The lymphoma group scored significantly lower than the controls on a cognitive rating scale (p = .018) and on CNSVS (p = .035). The difference on the CNSVS was primarily due to poorer attention and executive function scores in the lymphoma patients. The patients also had a higher frequency of impairment on both the objective (p = .009) and subjective (p < .001) cognitive measures. Among the lymphoma survivors, fatigue and anxiety were related to subjective cognitive disturbance (p < .001 for both), whereas pain was the only psychosocial measure associated with objective cognitive performance (p < .001). CONCLUSIONS: These results suggest that cognitive disturbance may be a significant survivorship issue for lymphoma patients and should be more thoroughly investigated in this population.