Organotypic hippocampal slice cultures were used to model the effects of neuroinflammatory conditions following an epileptic state on functional P2X7 receptors (Rs) of subgranular zone (SGZ) neural progenitor cells (NPCs). The compound, 4-aminopyridine (4-AP), is known to cause pathological firing of neurons, consequently facilitating the release of various transmitter substances including ATP. Lipopolysaccharide (LPS) and interleukin-1(IL-1) both potentiated the dibenzoyl-ATP (Bz-ATP)-induced current amplitudes in NPCs, although via different mechanisms. Whereas LPS acted via promoting ATP release, IL-1 acted via its own receptor to directly influence P2X7Rs. Thus, the effect of LPS was inhibited by the ecto-ATPase inhibitor, apyrase, but not by the IL-1 antagonist, interleukin-1RA (IL-1RA); by contrast, the effect of IL-1 was inhibited by IL-1RA, but not by apyrase. Eventually, incubation with 4-AP upregulated the number of nestin/glial fibrillary acidic protein/P2X7R immunoreactive cells and their appropriate staining intensity, suggesting increased synthesis of P2X7Rs at NPCs. In conclusion, inflammatory cytokines accumulating after epilepsy-like neuronal firing may facilitate the effect of endogenous ATP at P2X7Rs of NPCs, thereby probably promoting necrosis/apoptosis and subsequent cell death.

Acute myeloid leukemia (AML) is a deadly cancer of the blood and bone marrow defined by the accumulation of immature and non-functional myeloid progenitor cells. While AML is associated with a high success of chemotherapy-induced remission, it is accompanied by high relapse rates with poor response to subsequent therapies. Therefore, relapsed AML patients only have a 10% probability of long-term survival. An effective postinduction therapy is allogeneic hematopoietic stem cell transplantation (HSCT). However, complications associated with HSCT can be more severe than the AML disease itself. To date, no robust methodology is available to prospectively identify and distinguish AML patients that are more likely to benefit from HSCT. Our group has shown that AML patients with high leukemic progenitor cell content (LPC+) have a significantly lower overall survival (OS) when compared to patients with lower LPC content (LPC-). The objective of this study was to determine whether the LPC assay can be used as a functional predictor of post-HSCT survival. We hypothesized that LPC content correlates to post-HSCT survival times. We performed LPC assays on over 100 primary AML patient samples, showing that HSCT significantly improved OS in both LPC+ and LPC- patients, but LPC+ patients benefited more strongly than LPC- patients. This provides an initial basis to suggest that HSCT can offset the negative prognostic impact associated with high LPC content. To understand the biology of LPCs, we employed the Infinium HumanMethylation450 BeadChip assay to determine whether there are any methylation patterns that distinguish LPC+ and LPC- patients. However, we were not able to discover any uniquely methylated regions that separate the two groups, suggesting for further studies with an increased patient cohort, or extending the analyses to the transcript level. Given the rarity of curative approaches to cancers, a prognostic measure that could determine whether any single patient will benefit from HSCT will have an immediate impact. / Thesis / Master of Science (MSc)

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