MRI Characterization of Radiation Necrosis in an Animal Model: Time to Onset, Progression, and Therapeutic Response

Radiation necrosis is a severe, but late occurring type of injury to normal tissue, within and surrounding a radiation treatment field, which can lead to significant complications for neurooncology patients. Radiation necrosis is difficult to distinguish from recurrent tumor by either neurologic examination or clinical imaging protocols. Concerns for the development of radiation necrosis often limit therapeutic radiation doses. Current treatment options for radiation necrosis are limited. The development of solutions to these clinical challenges has been hampered by an appropriate animal model of radiation necrosis. With a novel mouse model of radiation necrosis developed in our lab employing a Gamma Knife, which enables high-dose, fractionated, hemispherical irradiation in the mouse brain, the objectives were to i) optimise radiation dosing schemes: total dose, fractionation) for this Gamma-Knife mouse-model of radiation necrosis; ii) determine the efficacy of bevacizumab: Avastin) and its murine analog B20-4.1.1, both vascular endothelial growth factor: VEGF) inhibitors, as mitigators of radiation necrosis in mice; iii) validate the neuroprotective effect of SB 415286, an inhibitor of glycogen synthase kinase 3β;: GSK-3β), in mouse brain following high-dose radiation treatment; and iv) identify and validate the quantitative blood oxygen level dependent: qBOLD) method as an imaging marker of radiation necrosis. For these purposes, a series of experiments were performed, including monitoring the onset and progression of radiation necrosis in mice receiving different dose schedules, comparing the development of radiation necrosis in irradiated mice with or without treatments, and mapping the irradiated and non-irradiated mouse brains using qBOLD method. It was found that i) radiation dose schedules affect the onset and progression of radiation necrosis; ii) anti-VEGF antibodies slow the progression of radiation necrosis in irradiated brain tissue; iii) SB 415286 protects against and mitigates radiation necrosis in irradiated brain tissue; and iv) a high SNR: 400 at least) is required to decouple oxygen extraction fraction: OEF) and deoxyhemoglombin cerebral blood volume: dCBV) in mouse brain using qBOLD method. In qBOLD, the voxel spread function: VSF) reduces the effect of macroscopic magnetic field inhomogeneities. However, with current shimming methods, imaging parameters, and post-processing algorithms, the resulting OEF and dCBV maps in the mouse brain are not reliable. These results demonstrated that the development of radiation necrosis in this Gamma Knife mouse model can be characterized by both anatomic MR imaging and histology. Both anti-VEGF therapy and GSK-3β inhibition could be potential therapeutic managements for radiation necrosis, but further studies are needed to optimize dosing schemes and treatment periods and elucidate mechanisms of action. Characterizing radiation necrosis in mouse brain using qBOLD remains a challenge due to the imperfect correction for macro magnetic field inhomogeneities

Dynamic Random Network Model for Human Papilloma Virus Transmission

Human Papilloma Virus (HPV) is a widespread sexually transmitted disease which can lead to cervical cancer. Understanding the factors influencing HPV transmission has been a challenge for scientists and policy makers. We have found that previous modeling studies have not sufficiently accounted for the structural and temporal features of the sexual networks underlying HPV transmission. The aim of this study is to investigate HPV transmission processes and vaccination strategies with a dynamic relationship-based transmission model. We calibrate the epidemic model with real-world network data, and study the transmission processes with different network parameters and transmission rates. We show that a pure vaccination strategy (vaccinating only one gender) is most efficient if female-to-male and male-to-female transmission rates are equal. However, there has been recent evidence in the literature indicating that female-to-male transmission rate might be higher. Incorporating these findings into our model lead to the conclusion that male vaccination is more effective. Finally, based on our simulation results, we provide some suggestions for optimal HPV vaccination strategies.Honor Thesi

Equalities and Inequalities for Norms of Block Imaginary Circulant Operator Matrices

Circulant, block circulant-type matrices and operator norms have become effective tools in solving networked systems. In this paper, the block imaginary circulant operator matrices are discussed. By utilizing the special structure of such matrices, several norm equalities and inequalities are presented. The norm τ in consideration is the weakly unitarily invariant norm, which satisfies τA=τ(UAV). The usual operator norm and Schatten p-norm are included. Furthermore, some special cases and examples are given

Vip And Host Immunity

The purpose of the current dissertation was to examine how VIP regulates host immunity and corneal healing, specifically, its control of growth factors and TLR expression in the P. aeruginosa infected cornea. Firstly, VIP treatment increased growth factor expression (EGF, GHF, FGF and VEGF) in infected cornea. Notably, treatment with a mixture of EGF, FGF and HGF prevented corneal perforation, reduced pro-inflammatory cytokines and bacterial plate count, while increasing anti-inflammatory cytokines and antimicrobials such as murine beta-defensin2 and 3. We also investigated the expression of TLR-signaling pathways in P. aeruginosa infected corneas with or without VIP treatment. PCR array and real-time RT-PCR data demonstrated that VIP treatment decreased pro-inflammatory, but increased anti-inflammatory TLRs. Immunohistochemistry, ELISA and western blot results further confirmed the PCR data. AC7 siRNA experiments indicated that VIP regulated TLR1, TRAF6 and ST2 in a cAMP dependent manner, but Chuk, IRAK1, 2, TLR4, 9 and SIGIRR were cAMP independent. In vitro, VIP down-regulated pro-inflammatory, but increased anti-inflamamtory TLRs in macrophages and Langerhans (XS52) cells. Exogenous VIP also decreased Langerhans cell number in the infected cornea. Furthermore, we used VIP-/- mice to asses whether VIP is required for expression of growth factors and their receptors in normal and infected cornea. VIP-/- vs WT B6 mice showed earlier corneal perforation. PCR array showed growth factors are differentially changed between groups. Real time RT-PCR and immunostaining studies revealed that the infected cornea of VIP-/- vs WT mice expressed higher EGF and HGF, reduced FGF, EGFR and HGFR and similar FGFR; no significant difference between the two groups of mice were seen in normal cornea. VIP antagonist treatment decreased protein levels for growth factor receptors at 5 days p.i. in both B6 and BALB/c mice, with no significant changes in normal cornea. In summary, these data provide evidence that VIP modulate growth factors, angiogenic molecules and beta defensins in the infected cornea; that it reduced pro-inflammatory, but increased anti-inflammatory TLRs after corneal infection; and that it is not required for growth factor production in the normal cornea but required in the infected cornea to delay perforation