Exploring New Strategies to Overcome Resistance in Glioblastoma Multiforme: A Dissertation

Glioblastoma multiforme (GBM) tumors are highly malignant in nature and despite an aggressive therapy regimen, long–term survival for glioma patients is uncommon as cells with intrinsic or acquired resistance to treatment repopulate the tumor. This creates the need to investigate new therapies for enhancing GBM treatment outside of the standard of care, which includes Temozolomide (TMZ). Our lab focused on two novel strategies to overcome resistance in GBMs. In our first approach, the cellular responses of GBM cell lines to two new TMZ analogues, DP68 and DP86, are reported. The efficacy of these compounds was independent of DNA repair mediated by Methyl Guanine Methyl Transferase (MGMT) and the mismatch repair (MMR) pathway. DP68 or DP86 treated cells do not give rise to secondary spheres, demonstrating that they are no longer capable of self-renewal. DP68-induced damage includes interstrand DNA crosslinks and exhibits a distinct S-phase accumulation before G2/M arrest; a profile that is not observed for TMZ-treated cells. DP68 induces a strong DNA damage response and suppression of FANCD2 expression or ATR expression/kinase activity enhanced the anti-GBM effects of DP68. Collectively, these data demonstrate that DP68, and to a lesser extent DP86, are potent anti-GBM compounds that circumvent TMZ resistance and inhibit recovery of cultures. Our second approach stems from a previous discovery in our lab which demonstrated that the combination of TMZ with Notch inhibition, using a gamma secretase inhibitor (GSI), enhances GBM therapy. Efficacy of TMZ + GSI treatment is partially due to GBM cells shifting into a permanent senescent state. We sought to identify a miR signature that mimics the effects of TMZ + GSI as an alternative vi approach to enhance GBM therapy. MiR-34a expression was highly upregulated in response to TMZ or TMZ + GSI treatment. Exogenous expression of miR-34a revealed that it functions as a tumor suppressor and mimicked the in vitro effects of TMZ + GSI treatment. Additionaly, miR-34a overexpression leads to the downregulation of Notch family members. Together these two studies contribute to our understanding of the complex mechanisms driving resistance in GBM tumors and suggest strategies to develop more effective therapies

ILC Reference Design Report Volume 1 - Executive Summary

The International Linear Collider (ILC) is a 200-500 GeV center-of-mass high-luminosity linear electron-positron collider, based on 1.3 GHz superconducting radio-frequency (SCRF) accelerating cavities. The ILC has a total footprint of about 31 km and is designed for a peak luminosity of 2x10^34 cm^-2s^-1. This report is the Executive Summary (Volume I) of the four volume Reference Design Report. It gives an overview of the physics at the ILC, the accelerator design and value estimate, the detector concepts, and the next steps towards project realization.The International Linear Collider (ILC) is a 200-500 GeV center-of-mass high-luminosity linear electron-positron collider, based on 1.3 GHz superconducting radio-frequency (SCRF) accelerating cavities. The ILC has a total footprint of about 31 km and is designed for a peak luminosity of 2x10^34 cm^-2s^-1. This report is the Executive Summary (Volume I) of the four volume Reference Design Report. It gives an overview of the physics at the ILC, the accelerator design and value estimate, the detector concepts, and the next steps towards project realization

ILC Reference Design Report Volume 4 - Detectors

This report, Volume IV of the International Linear Collider Reference Design Report, describes the detectors which will record and measure the charged and neutral particles produced in the ILC's high energy e+e- collisions. The physics of the ILC, and the environment of the machine-detector interface, pose new challenges for detector design. Several conceptual designs for the detector promise the needed performance, and ongoing detector R&D is addressing the outstanding technological issues. Two such detectors, operating in push-pull mode, perfectly instrument the ILC interaction region, and access the full potential of ILC physics.This report, Volume IV of the International Linear Collider Reference Design Report, describes the detectors which will record and measure the charged and neutral particles produced in the ILC's high energy e+e- collisions. The physics of the ILC, and the environment of the machine-detector interface, pose new challenges for detector design. Several conceptual designs for the detector promise the needed performance, and ongoing detector R&D is addressing the outstanding technological issues. Two such detectors, operating in push-pull mode, perfectly instrument the ILC interaction region, and access the full potential of ILC physics

ILC Reference Design Report Volume 3 - Accelerator

The International Linear Collider (ILC) is a 200-500 GeV center-of-mass high-luminosity linear electron-positron collider, based on 1.3 GHz superconducting radio-frequency (SCRF) accelerating cavities. The ILC has a total footprint of about 31 km and is designed for a peak luminosity of 2x10^34 cm^-2 s^-1. The complex includes a polarized electron source, an undulator-based positron source, two 6.7 km circumference damping rings, two-stage bunch compressors, two 11 km long main linacs and a 4.5 km long beam delivery system. This report is Volume III (Accelerator) of the four volume Reference Design Report, which describes the design and cost of the ILC.The International Linear Collider (ILC) is a 200-500 GeV center-of-mass high-luminosity linear electron-positron collider, based on 1.3 GHz superconducting radio-frequency (SCRF) accelerating cavities. The ILC has a total footprint of about 31 km and is designed for a peak luminosity of 2x10^34 cm^-2 s^-1. The complex includes a polarized electron source, an undulator-based positron source, two 6.7 km circumference damping rings, two-stage bunch compressors, two 11 km long main linacs and a 4.5 km long beam delivery system. This report is Volume III (Accelerator) of the four volume Reference Design Report, which describes the design and cost of the ILC

International Linear Collider Reference Design Report Volume 2: PHYSICS AT THE ILC

This article reviews the physics case for the ILC. Baseline running at 500 GeV as well as possible upgrades and options are discussed. The opportunities on Standard Model physics, Higgs physics, Supersymmetry and alternative theories beyond the Standard Model are described.This article reviews the physics case for the ILC. Baseline running at 500 GeV as well as possible upgrades and options are discussed. The opportunities on Standard Model physics, Higgs physics, Supersymmetry and alternative theories beyond the Standard Model are described