Patient derived xenograft models of small-cell lung cancer provide molecular insights into mechanisms of chemotherapy cross-resistance

Small Cell Lung Cancer (SCLC) is a highly aggressive neuroendocrine tumor with a 5% survival rate over 5 years. Though SCLC comprises 13% of all cases of lung cancer the median survival time of 14.5 months has seen little improvement over the last four decades. Standard treatment relies on DNA damaging agents such as Cisplatin/Etoposide (EP) which induce a high response rate of 60-70%. Despite this initial response, nearly all patients will relapse rendering first-line therapies ineffective. Furthermore, SCLC has been shown to develop chemotherapy cross-resistance in which resistance to first-line chemotherapies will confer resistance to additional DNA damaging agents thereby reducing treatment efficacy and duration of response. Cross-Resistance constitutes a major clinical issue whose underlying mechanisms remain a mystery. The modest improvements in SCLC patient outcomes over the decades may be partially explained by the existing systems of study. Current methodologies of SCLC study rely on cell lines, patient samples, and Genetically Engineered Mouse Models which have little functional correlation to clinical outcomes. While few sources have proposed Patient Derived Xenograft (PDX) systems as an improved alternative, significant data remains sparse. Without a robust model system which accurately recapitulates patient outcomes, molecular pathways driving resistance cannot be uncovered. Here we present the generation of 34 SCLC PDX models which maintain both genomic and functional fidelity. Furthermore, treatment of a 30-model subset with first-line chemotherapy EP and a novel chemotherapy Olaparib/Temozolomide (OT) allowed for functional and molecular comparison between groups. Our findings demonstrate incomplete independent resistance mechanisms between EP and OT treatment with a small overlap of 31 genes involved in glycolysis and xenobiotic metabolism

Grosse Ile and the Irish Memorial National Historic Site, Parks Canada: A Case Study

Focuses on values and their protection by examining the place of values in management. Grosse Ile's management is still evolving, and the eventful first phases of planning are still fresh in the minds of staff

Do Individual Investors Drive Post-Earnings Announcement Drift? Direct Evidence from Personal Trades

This study examines whether individual investors are the source of post- earnings announcement drift (PEAD). We provide evidence on how individual investors trade in response to extreme quarterly earnings surprises and on the relation between individual investors' trades and subsequent abnormal returns. We find no evidence that either individuals or any sub-category of individuals in our sample cause PEAD. Individuals are significant net buyers after both negative and positive earnings surprises. There is no indication that trading by any of our investor sub-categories explains the concentration of drift at subsequent earnings announcement dates. While post-announcement individual net buying is a significant negative predictor of stock returns over the next three quarters, individual investor trading fails to subsume any of the power of extreme earnings surprises to predict future abnormal returns.post earnings-announcement drift, trading activity, individual investors, market efficiency

Consistency Conditions for Brane Worlds in Arbitrary Dimensions

We consider ``brane world sum rules'' for compactifications involving an arbitrary number of spacetime dimensions. One of the most striking results derived from such consistency conditions is the necessity for negative tension branes to appear in five--dimensional scenarios. We show how this result is easily evaded for brane world models with more than five dimensions. As an example, we consider a novel realization of the Randall--Sundrum scenario in six dimensions involving only positive tension branes.Comment: 18 pages, LaTex, refs. adde