p53 and the CNS: Tumors and developmental abnormalities

This article reviews the recent molecular and clinical studies that characterize the role of p53 in pathologies of the central nervous system, p53 has many important biological functions, notably, maintenance of DNA stability and regulation of apoptosis. These features are essential to avoid cellular transformation and ensure normal brain development. Lack of p53 function in the brain results in tumor formation in the astrocytic and lymphoid lineages and in severe neurodevelopmental diseases, such as exencephal

The in vivo therapeutic efficacy of the oncolytic adenovirus Delta24-RGD is mediated by tumor-specific immunity

The oncolytic adenovirus Delta24-RGD represents a new promising therapeutic agent for patients with a malignant glioma and is currently under investigation in clinical phase I/II trials. Earlier preclinical studies showed that Delta24-RGD is able to effectively lyse tumor cells, yielding promising results in various immune-deficient glioma models. However, the role of the immune response in oncolytic adenovirus therapy for glioma has never been explored. To this end, we assessed Delta24-RGD treatment in an immune-competent orthotopic mouse model for glioma and evaluated immune responses against tumor and virus. Delta24-RGD treatment led to long-term survival in 50% of mice and this effect was completely lost upon administration of the immunosuppressive agent dexamethasone. Delta24-RGD enhanced intra-tumoral infiltration of F4/80+ macrophages, CD4+ and CD8+ T-cells, and increased the local production of pro-inflammatory cytokines and chemokines. In treated mice, T cell responses were directed to the virus as well a

Economic Policy Program and Economic Performance in U.K.

Purpose: To (a) evaluate whether the lysine-rich protein (LRP) magnetic resonance (MR) imaging reporter gene can be engineered into G47Δ, a herpes simplex-derived oncolytic virus that is currently being tested in clinical trials, without disrupting its therapeutic effectiveness and (b) establish the ability of chemical exchange saturation transfer (CEST) MR imaging to demonstrate G47Δ-LRP. Materials and Methods: The institutional subcommittee for research animal care approved all in vivo procedures. Oncolytic herpes simplex virus G47Δ, which carried the LRP gene, was constructed and tested for its capacity to replicate in cancer cells and express LRP in vitro. The LRP gene was detected through CEST imaging of lysates derived from cells infected with G47Δ-LRP or the control G47Δ-empty virus. G47Δ-LRP was then tested for its therapeutic effectiveness and detection with CEST MR imaging in vivo. Images of rat gliomas were acquired before and 8-10 hours after injection of G47Δ-LRP (n = 7) or G47Δ-empty virus (n = 6). Group comparisons were analyzed with a paired t test. Results: No significant differences were observed in viral replication or therapeutic effectiveness between G47Δ-LRP and G47Δ-empty virus. An increase in CEST image contrast was observed in cell lysates (mean ± standard deviation, 0.52% ± 0.06; P = .01) and in tumors (1.1% ± 0.3, P = .02) after infection with G47Δ-LRP but not G47Δ-empty viruses. No histopathologic differences were observed between tumors infected with G47Δ-LRP and G47Δ-empty virus. Conclusion: This study has demonstrated the ability of CEST MR imaging to show G47Δ-LRP at acute stages of viral infection. The introduction of the LRP transgene had no effect on the viral replication or therapeutic effectiveness. This can aid in development of the LRP gene as a reporter for the real-time detection of viral spread

Secondary Beams at High-Intensity Electron Accelerator Facilities

The interaction of a high-current $O$(100~\textmu A), medium energy $O$(10\,GeV) electron beam with a thick target $O$(1m) produces an overwhelming shower of standard matter particles in addition to hypothetical Light Dark Matter particles. While most of the radiation (gamma, electron/positron, and neutron) is contained in the thick target, deep penetrating particles (muons, neutrinos, and light dark matter particles) propagate over a long distance, producing high-intense secondary beams. Using sophisticated Monte Carlo simulations based on FLUKA and GEANT4, we explored the characteristics of secondary muons and neutrinos and (hypothetical) dark scalar particles produced by the interaction of Jefferson Lab 11 GeV intense electron beam with the experimental Hall-A beam dump. Considering the possible beam energy upgrade, this study was repeated for a 20 GeV CEBAF beam

Quantitative chemical exchange saturation transfer (CEST) MRI of glioma using Image Downsampling Expedited Adaptive Least-squares (IDEAL) fitting

Chemical Exchange Saturation Transfer (CEST) MRI is sensitive to dilute metabolites with exchangeable protons, allowing tissue characterization in diseases such as acute stroke and tumor. CEST quantification using multi-pool Lorentzian fitting is challenging due to its strong dependence on image signal-to-noise ratio (SNR), initial values and boundaries. Herein we proposed an Image Downsampling Expedited Adaptive Least-squares (IDEAL) fitting algorithm that quantifies CEST images based on initial values from multi-pool Lorentzian fitting of iteratively less downsampled images until the original resolution. The IDEAL fitting in phantom data with superimposed noise provided smaller coefficient of variation and higher contrast-to-noise ratio at a faster fitting speed compared to conventional fitting. We further applied the IDEAL fitting to quantify CEST MRI in rat gliomas and confirmed its advantage for in vivo CEST quantification. In addition to significant changes in amide proton transfer and semisolid macromolecular magnetization transfer effects, the IDEAL fitting revealed pronounced negative contrasts of tumors in the fitted CEST maps at 2 ppm and −1.6 ppm, likely arising from changes in creatine level and nuclear overhauser effects, which were not found using conventional method. It is anticipated that the proposed method can be generalized to quantify MRI data where SNR is suboptimal

Quantitative chemical exchange saturation transfer (CEST) MRI of glioma using Image Downsampling Expedited Adaptive Least-squares (IDEAL) fitting

Chemical Exchange Saturation Transfer (CEST) MRI is sensitive to dilute metabolites with exchangeable protons, allowing tissue characterization in diseases such as acute stroke and tumor. CEST quantification using multi-pool Lorentzian fitting is challenging due to its strong dependence on image signal-to-noise ratio (SNR), initial values and boundaries. Herein we proposed an Image Downsampling Expedited Adaptive Least-squares (IDEAL) fitting algorithm that quantifies CEST images based on initial values from multi-pool Lorentzian fitting of iteratively less downsampled images until the original resolution. The IDEAL fitting in phantom data with superimposed noise provided smaller coefficient of variation and higher contrast-to-noise ratio at a faster fitting speed compared to conventional fitting. We further applied the IDEAL fitting to quantify CEST MRI in rat gliomas and confirmed its advantage for in vivo CEST quantification. In addition to significant changes in amide proton transfer and semisolid macromolecular magnetization transfer effects, the IDEAL fitting revealed pronounced negative contrasts of tumors in the fitted CEST maps at 2 ppm and −1.6 ppm, likely arising from changes in creatine level and nuclear overhauser effects, which were not found using conventional method. It is anticipated that the proposed method can be generalized to quantify MRI data where SNR is suboptimal

The in vivo therapeutic efficacy of the oncolytic adenovirus Delta24-RGD is mediated by tumor-specific immunity.

The oncolytic adenovirus Delta24-RGD represents a new promising therapeutic agent for patients with a malignant glioma and is currently under investigation in clinical phase I/II trials. Earlier preclinical studies showed that Delta24-RGD is able to effectively lyse tumor cells, yielding promising results in various immune-deficient glioma models. However, the role of the immune response in oncolytic adenovirus therapy for glioma has never been explored. To this end, we assessed Delta24-RGD treatment in an immune-competent orthotopic mouse model for glioma and evaluated immune responses against tumor and virus. Delta24-RGD treatment led to long-term survival in 50% of mice and this effect was completely lost upon administration of the immunosuppressive agent dexamethasone. Delta24-RGD enhanced intra-tumoral infiltration of F4/80+ macrophages, CD4+ and CD8+ T-cells, and increased the local production of pro-inflammatory cytokines and chemokines. In treated mice, T cell responses were directed to the virus as well as to the tumor cells, which was reflected in the presence of protective immunological memory in mice that underwent tumor rechallenge. Together, these data provide evidence that the immune system plays a vital role in the therapeutic efficacy of oncolytic adenovirus therapy of glioma, and may provide angles to future improvements on Delta24-RGD therapy