The Impact of mTORC2 Signaling on the Initiation and Progression of KRAS-Driven Pancreatic Neoplasias: A Dissertation

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, develops through progression of premalignant pancreatic intraepithelial neoplasias (PanINs). In mouse-models, KRAS-activation in acinar cells induced an acinar-to-ductal metaplasia (ADM), and mutation of the Kras oncogene is believed to initiate PanIN formation. ADM is also promoted by pancreatic injury, which cooperates with activated KRAS to stimulate PanIN and PDAC formation from metaplastic ducts. Our lab, and others, have shown that the downstream PI3K/AKT pathway is important for KRAS-mediated proliferation and survival in vitro and in vivo. Prior studies have demonstrated that full activation of AKT requires both PDK1- mediated phosphorylation of AKTT308 and mTOR complex 2 (mTORC2)-mediated phosphorylation of AKTS473. Given the importance of the PI3K/AKT signaling axis, I hypothesized that mTORC2 is required for KRAS-driven pancreatic tumorigenesis and investigated this relationship in mice by combining pancreasspecific expression of an activated KRASG12D molecule with deletion of the essential mTORC2 subunit RICTOR. In the context of activated KRAS, Rictor-null pancreata developed fewer PanIN lesions; these lesions lacked mTORC2 signaling and their proliferation and progression were impaired. Higher levels of nuclear cyclin dependent kinase inhibitors (CDKIs) were maintained in Rictor-null lesions, and nuclear BMI1, a known regulator of the CDKI Cdkn2a, inversely correlated with their expression.Rictor was not required for KRAS-driven ADM following acute pancreatitis, however the inverse correlation between CDKIs and BMI1 was maintained in this system. Treatment of PDX-Cre;KRASG12D/+;Trp53R172H/+ mice with an mTORC1/2 inhibitor delayed tumor formation, and prolonged the survival of mice with late stage PDAC. Knockdown of Rictor in established PDAC cell lines impaired proliferation and anchorage independent growth supporting a role for mTORC2 in fully transformed cells. These data suggest that mTORC2 cooperates with activated KRAS in the initiation and progression of PanIN lesions and is required for the transformation and maintenance of PDAC. My work illustrates phenotypic differences between pancreatic loss of Rictor and PDK1 in the context of KRAS, broadens our understanding of this signaling node and suggests that mTORC2 may potentially be a viable target for PDAC therapies

The Age of Reason: Financial Decisions Over the Lifecycle

In cross-sectional data sets from ten credit markets, we find that middle-aged adults borrow at lower interest rates and pay fewer fees relative to younger and older adults. Fee and interest payments are minimized around age 53. The measured effects are not explained by observed risk characteristics. We discuss several leading factors that may contribute to these effects, including age-related changes in experience and cognitive function, selection effects, and cohort effects.

The age of reason: financial decisions over the lifecycle

The sophistication of financial decisions varies with age: middle-aged adults borrow at lower interest rates and pay fewer fees compared to both younger and older adults. We document this pattern in ten financial markets. The measured effects cannot be explained by observed risk characteristics. The sophistication of financial choices peaks around age 53 in our cross-sectional data. Our results are consistent with the hypothesis that financial sophistication rises and then falls with age, although the patterns that we observe represent a mix of age effects and cohort effects.Financial institutions ; Loans

Student Evaluation Instruments: The Interactive Impact Of Course Requirement, Student Level, Department And Anticipated Grade

The examination of Student Evaluation Instruments (SEI) has generated a considerable literature. Interestingly, this extensive literature provides no clear guidance on how to interpret SEI results in order to make comparative evaluations of instructors’ performances. The research presented in this paper draws upon six semesters worth of SEI responses for all courses in our school of business – a database of nearly 30,000 responses. The paper examines how core measures of teaching effectiveness – student evaluation of instructor’s teaching ability and willingness to recommend the instructor – are affected by several factors. These factors include:  the department from which the course was offered; whether the course was required by the core, the department or was an elective; the status of the student and the anticipated grade. Statistical analyses are conducted to examine and determine the impact of these factors and their interactions. The goal is to develop a system that can more accurately gauge instructors’ performances as measured by the student evaluation instrument

A Method to Image Flame Index in Partially Premixed Flames

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97145/1/AIAA2012-972.pd

Descriptions of WHOI sediment cores : volume 5

This report supplements Volumes 1-4 of the core descriptions published previously in this sequence (Johnson and Driscoll, 1975). It contains visual descriptions and smear slide analyses for all cores received in the geological samples collection of the Woods Hole Oceanographic Institution between November, 1973 and November, 1976. Approximately 368 sample localities from the North Atlantic, Mediterranean, and South Atlantic are represented. Charts of ships' tracks and updated computer listings of all cores in the W.H.O.I. collection are also included.Prepared for the Office of Naval Research under Contract N00014-74-C0262, NR 083-004; and for the National Science Foundation under Grant OCE76-81488

Descriptions of WHOI sediment cores

Prepared by the Staff of the Sea Floor Samples LaboratoryThis report presents visual core descriptions and smear slide analyses for all cores in the Woods Hole Oceanographic Institution geological samples collection which were obtained prior to November 1973. Approximately 1000 coring stations from the Atlantic, Indian and Pacific oceans and adjacent seas are represented. Charts of ships' track and computer listings of all cores are also included.ONR N00014-74-C0262, NR 083-004, NSF DES73-0646