Boy meets goal, boy loses goal, boy gets goal : the nature of feedback between goal-based simulation and understanding systems

We are designing a goal-based planning and simulation system called REACTOR for a multiple-actor world in which partially formulated plans are monitored during execution, providing feedback to the planner. Plan failures that occur are diagnosed by a combination of top-down (plan-synthesis) and bottom-up (plan-understanding) techniques, allowing an informed choice of response to the error. By maintaining separate belief spaces for each actor, we simulate planners who themselves simulate the planning and plan-understanding of other actors

Special Issue “Cancer Biomarker Research and Personalized Medicine”

While the term biomarker is thought to have first been used in the 1970s, the concept itself is considered to be much older [...

Empirical evidence on vertical foreclosure

Recent papers have shown conditions under which vertical, mergers can result in anticompetitive foreclosure of unintegrated rivals. These models imply that a necessary but not sufficient condition for anticompetitive foreclosure is that unintegrated rivals are less profitable after a vertical merger. We test this hypothesis by examining the stock prices of unintegrated rivals at the time of a vertical merger announcement and at the time of a government antitrust complaint. We find no evidence to support the foreclosure hypothesis.Consolidation and merger of corporations

Infected cell types in the ovine lung following exposure to bovine respiratory syncytial virus

Immunohistochemical and lung organ culture techniques were developed and used to detect bovine respiratory syncytial virus-infected cell types in ovine lung tissue. Lung tissue was evaluated from sheep inoculated with bovine respiratory syncytial virus (BRSV) and from lung organ slices inoculated with BRSV in vitro. Infected sheep were killed at intervals from 0.5 to 8 days post-inoculation. Histological changes consisted of bronchiolitis, interstitial pneumonitis and pneumonia with exudates of neutrophils, lymphocytes and macrophages. Interstitial infiltrates consisted of peribronchiolar and perivascular lymphocytes and macrophages which extended into alveolar septa. Foci of infection were very sparse as determined by immunohistochemistry. Bovine respiratory syncytial virus antigen was detected in alveolar macrophages in tissues from sheep killed at 0.5 day post-inoculation. Staining for viral antigen was restricted primarily to bronchiolar epithelium and Type I pneumocytes in tissues from sheep killed at 1-6 days post-inoculation. Viral antigen was detected in Type II pneumocytes in tissues from sheep killed at all time periods from 3-6 days post-inoculation. There was no viral antigen detected in tissues collected at 8 days post-inoculation. We failed to detect (BRSV) antigen immunohistochemically at the electron microscopic level because we were unsuccessful in attempts at immunogold staining of BRSV antigen. Virions, identified morphologically, were in association with bronchiolar and alveolar epithelium in tissues from infected sheep;The in vitro portion of this study involved the development of an organ culture technique which allowed viable lung tissue slices to be maintained in vitro for 4 days without histological evidence of tissue necrosis. Cultures of sheep lung slices were inoculated with either BRSV, parainfluenzavirus-3, or ovine adenovirus, immunohistochemical techniques were used to detect infected cells at 0-4 days post-inoculation. Parainfluenzavirus-3 infected the lung slices as determined by immunohistochemical staining. However, immunohistochemical techniques revealed no staining of BRSV or ovine adenovirus antigen in any of the lung slices

Inhibition of pH regulation as a therapeutic strategy in breast cancer

The abnormal regulation of H+ ions, leading to a reversed pH gradient in cancer cells when compared to normal cells, is considered to be one of the most distinctive features of cancer. However, this characteristic has yet to be fully exploited as a therapeutic target in cancer. This project assessed whether targeting pH regulating proteins, which permit cancer cells to survive in the hostile hypoxic and acidic tumour microenvironment, could produce an effective therapeutic response in breast cancer. The pH regulating proteins carbonic anhydrase IX (CAIX), Na+/H+ exchanger 1 (NHE1) and vacuolar (H+)-ATPase (V-ATPase) were the focus of this thesis. Initial experiments were conducted in 2D tissue culture before progressing into 3D, using models that more faithfully re-create the in vivo tumour microenvironment. Expression analysis conducted with MCF-7, MDA-MB-231 and HBL-100 human breast cancer cell lines cultured in 2D, and in 3D as multicellular tumour spheroids, showed that protein and mRNA levels of CAIX were very responsive to lower O2 concentrations. Both MDA-MB-231 and HBL-100 cells displayed large increases in CAIX expression levels in hypoxia, with the HBL-100 cell line exhibiting the largest change in CAIX mRNA (42-fold increase) and protein (78-fold increase) levels in 0.5% O2 conditions. Hypoxia inducible factor 1-α (HIF-1α) controls the expression of CAIX, but the induction of CAIX in hypoxic MCF-7 cells was lower in comparison to the other cell lines, despite the presence of similar levels of HIF-1α. The differences in CAIX expression observed between the cell lines was consistent with a varying activity of factor inhibiting HIF-1 (FIH-1), an oxygen sensor that controls signalling through HIF-1α, as siRNA targeting FIH-1 led to increased levels of CAIX in hypoxic MCF-7 cells. While NHE1 protein levels did increase in hypoxic conditions in MCF-7 cells in 3D, overall, the expression levels of both NHE1 and V-ATPase were not as responsive to changes in O2 concentrations when compared to CAIX across differing O2 conditions in each of the cell lines. Inhibitors targeting CAIX, NHE1 and V-ATPase were all shown to reduce cancer cell number in 2D culture conditions. Differing O2 conditions changed the sensitivity of these cell lines to CAIX inhibition. Cells cultured in 20% O2 conditions were responsive to CAIX inhibition, while acute hypoxic cells cultured in 0.5% O2 displayed an increased resistance to drug treatment. Chronically hypoxic cells, which had spent over 10 weeks in 0.5% O2 before treatment, exhibited a re-sensitisation to CAIX inhibition. 3D invasion assays demonstrated that CAIX inhibition significantly reduced the invasion of cells from MDA-MB-231 spheroids into collagen type 1 in both 20% O2 and 0.5% O2 conditions, while drugs targeting either NHE1 or V-ATPase had no such inhibitory effects. Preliminary clonogenic assays, used to assess radiation sensitivity and performed with MDA-MB-231 spheroids, indicated that inhibitors targeting CAIX and NHE1 led to a significant decrease in colony formation when combined with irradiation, compared to either drug treatment or irradiation alone. Further invasion assays, carried out with primary tissue derived from human patients, showed that drugs targeting CAIX retained their inhibitory effects when tested on heterogeneous cancer material of varying tumour subtypes. CAIX inhibition also exhibited anti-cancer effects in vivo on mouse MDA-MB-231 xenografts, significantly reducing the proliferation and growth of tumours within mice. Together, this work demonstrates that inhibitors targeting the pH regulation mechanisms of cancer cells have potential in the treatment of breast cancer, highlighted by their capacity to affect cancer cell number, cancer cell invasion, and their ability to combine with irradiation. Of the 3 pH regulatory molecules studied, CAIX appears to be the target with the most therapeutic potential

Numerical methods for contingent claims analysis of investment decisions

Thesis (M.S.)--Massachusetts Institute of Technology, Sloan School of Management, 1988In this thesis I examine the numerical methods used in option valuation with analysis focusing on the more complex options associated with investment decisions. Two options implicit in many projects are identified and analyzed: i) the option to halt construction of a project, and ii) the option to shut down the production lines once the project is complete. The partial differential equations governing the values of these two options are derived, discretized, and solved using numerical techniques