Evaluation of the oxygenation and vascularity of prostate cancer using magnetic resonance imaging.

The outcome of radical treatment for prostate cancer is appreciably influenced by the presence of hypoxia. Oxygenation status may therefore be another underlying biological parameter, beyond the classic prognostic factors (age, clinical stage, Gleason score and prostate specific antigen), that predicts for treatment failure in this malignancy. Angiogenesis plays a pivotal role in the growth, invasion, metastasis and survival of prostate tumours. Measurements of angiogenesis have been linked with clinical and pathological stage, histological grade and the potential for metastasis formation. They also provide prognostic information and have been correlated with disease-specific survival and progression after treatment. Magnetic resonance imaging techniques are capable of detecting the molecular, biochemical, physiological and metabolic changes that occur due to pathological processes within tissues. Experiments presented in this thesis have sought to evaluate the ability of Dynamic Contrast Enhanced MRI (DCE-MRI), Dynamic Susceptibility Contrast MRI (DSC-MRI), Intrinsic Susceptibility Weighted MRI (also known as Blood Oxygen Level Dependent (BOLD) MRI) and Diffusion Weighted Imaging (DWI) to characterise the oxygenation and vascular status of prostate tumours in animal models and in patients with prostate cancer. This research has demonstrated the feasibility of hypoxia imaging in prostate cancer. Although MRI can not precisely map tissue p02, the combination of BOLD-MRI and dynamic susceptibility contrast MRI provides a valuable surrogate and predicts the pattern of hypoxia, as determined by pimonidazole immunohistochemistry, with reasonable accuracy. The research has also shown that prostate cancer responds to carbogen gas breathing and that androgen deprivation causes profound vascular collapse within one month of starting therapy. These findings should help in the rational design of future studies that aim to target tumour vasculature and combat tumour hypoxia in prostate cancer

PD-0136: Hypoxia biomarkers for prognostic evaluation and the prediction of outcome following prostate radiotherapy

Hom Santolaia, Cinto; Casamor Maldonado, Carlo

Neutron Beta Decay Studies with Nab

Precision measurements in neutron beta decay serve to determine the coupling constants of beta decay and allow for several stringent tests of the standard model. This paper discusses the design and the expected performance of the Nab spectrometer.Comment: Submitted to Proceedings of the Conference CIPANP12, St.Petersburg, Florida, May 201

Nab: Measurement Principles, Apparatus and Uncertainties

The Nab collaboration will perform a precise measurement of 'a', the electron-neutrino correlation parameter, and 'b', the Fierz interference term in neutron beta decay, in the Fundamental Neutron Physics Beamline at the SNS, using a novel electric/magnetic field spectrometer and detector design. The experiment is aiming at the 10^{-3} accuracy level in (Delta a)/a, and will provide an independent measurement of lambda = G_A/G_V, the ratio of axial-vector to vector coupling constants of the nucleon. Nab also plans to perform the first ever measurement of 'b' in neutron decay, which will provide an independent limit on the tensor weak coupling.Comment: 12 pages, 6 figures, 1 table, talk presented at the International Workshop on Particle Physics with Slow Neutrons, Grenoble, 29-31 May 2008; to appear in Nucl. Instrum. Meth. in Physics Research

First Observation of PP-odd γ\gamma Asymmetry in Polarized Neutron Capture on Hydrogen

We report the first observation of the parity-violating 2.2 MeV gamma-ray asymmetry $A^{np}_\gamma$ in neutron-proton capture using polarized cold neutrons incident on a liquid parahydrogen target at the Spallation Neutron Source at Oak Ridge National Laboratory. $A^{np}_\gamma$ isolates the $\Delta I=1$, \mbox{$^{3}S_{1}\rightarrow {^{3}P_{1}}$} component of the weak nucleon-nucleon interaction, which is dominated by pion exchange and can be directly related to a single coupling constant in either the DDH meson exchange model or pionless EFT. We measured $A^{np}_\gamma = [-3.0 \pm 1.4 (stat) \pm 0.2 (sys)]\times 10^{-8}$, which implies a DDH weak $\pi NN$ coupling of $h_{\pi}^{1} = [2.6 \pm 1.2(stat) \pm 0.2(sys)] \times 10^{-7}$ and a pionless EFT constant of $C^{^{3}S_{1}\rightarrow ^{3}P_{1}}/C_{0}=[-7.4 \pm 3.5 (stat) \pm 0.5 (sys)] \times 10^{-11}$ MeV$^{-1}$. We describe the experiment, data analysis, systematic uncertainties, and the implications of the result.Comment: 6 pages, 5 figure

Carbogen breathing increases prostate cancer oxygenation: a translational MRI study in murine xenografts and humans

Hypoxia has been associated with poor local tumour control and relapse in many cancer sites, including carcinoma of the prostate. This translational study tests whether breathing carbogen gas improves the oxygenation of human prostate carcinoma xenografts in mice and in human patients with prostate cancer. A total of 23 DU145 tumour-bearing mice, 17 PC3 tumour-bearing mice and 17 human patients with prostate cancer were investigated. Intrinsic susceptibility-weighted MRI was performed before and during a period of carbogen gas breathing. Quantitative R2* pixel maps were produced for each tumour and at each time point and changes in R2* induced by carbogen were determined. There was a mean reduction in R2* of 6.4% (P=0.003) for DU145 xenografts and 5.8% (P=0.007) for PC3 xenografts. In all, 14 human subjects were evaluable; 64% had reductions in tumour R2* during carbogen inhalation with a mean reduction of 21.6% (P=0.0005). Decreases in prostate tumour R2* in both animal models and human patients as a result of carbogen inhalation suggests the presence of significant hypoxia. The finding that carbogen gas breathing improves prostate tumour oxygenation provides a rationale for testing the radiosensitising effects of combining carbogen gas breathing with radiotherapy in prostate cancer patients

Clinical management and research priorities for high-risk prostate cancer in the UK:meeting report of a multidisciplinary panel in conjunction with the NCRI Prostate Cancer Clinical Studies Localised Subgroup

The management of high-risk prostate cancer has become increasingly sophisticated, with refinements in radical therapy and the inclusion of adjuvant local and systemic therapies. Despite this, high-risk prostate cancer continues to have significant treatment failure rates, with progression to metastasis, castrate resistance and ultimately disease-specific death. In an effort to discuss the challenges in this field, the UK National Clinical Research Institute’s Prostate Cancer Clinical Studies localised subgroup convened a multidisciplinary national meeting in the autumn of 2014. The remit of the meeting was to debate and reach a consensus on the key clinical and research challenges in high-risk prostate cancer and to identify themes that the UK would be best placed to pursue to help improve outcomes. This report presents the outcome of those discussions and the key recommendations for future research in this highly heterogeneous disease entity

H-Prune through GSK-3β interaction sustains canonical WNT/β-catenin signaling enhancing cancer progression in NSCLC.

H-Prune hydrolyzes short-chain polyphosphates (PPase activity) together with an hitherto cAMP-phosphodiesterase (PDE), the latest influencing different human cancers by its overexpression. H-Prune promotes cell migration in cooperation with glycogen synthase kinase-3 (Gsk-3β). Gsk-3β is a negative regulator of canonical WNT/β-catenin signaling. Here, we investigate the role of Gsk-3β/h-Prune complex in the regulation of WNT/β-catenin signaling, demonstrating the h-Prune capability to activate WNT signaling also in a paracrine manner, through Wnt3a secretion. In vivo study demonstrates that h-Prune silencing inhibits lung metastasis formation, increasing mouse survival. We assessed h-Prune levels in peripheral blood of lung cancer patients using ELISA assay, showing that h-Prune is an early diagnostic marker for lung cancer. Our study dissects out the mechanism of action of h-Prune in tumorigenic cells and also sheds light on the identification of a new therapeutic target in non-small-cell lung cancer

Ciliary Neurotrophic Factor Stimulates Muscle Glucose Uptake by a PI3-Kinase–Dependent Pathway That Is Impaired With Obesity

OBJECTIVE: Ciliary neurotrophic factor (CNTF) reverses muscle insulin resistance by increasing fatty acid oxidation through gp130-LIF receptor signaling to the AMP-activated protein kinase (AMPK). CNTF also increases Akt signaling in neurons and adipocytes. Because both Akt and AMPK regulate glucose uptake, we investigated muscle glucose uptake in response to CNTF signaling in lean and obese mice. RESEARCH DESIGN AND METHODS: Mice were injected intraperitoneally with saline or CNTF, and blood glucose was monitored. The effects of CNTF on skeletal muscle glucose uptake and AMPK/Akt signaling were investigated in incubated soleus and extensor digitorum longus (EDL) muscles from muscle-specific AMPKalpha2 kinase-dead, gp130(DeltaSTAT), and lean and obese ob/ob and high-fat-fed mice. The effect of C2-ceramide on glucose uptake and gp130 signaling was also examined. RESULTS: CNTF reduced blood glucose and increased glucose uptake in isolated muscles in a time- and dose-dependent manner with maximal effects after 30 min with 100 ng/ml. CNTF increased Akt-S473 phosphorylation in soleus and EDL; however, AMPK-T172 phosphorylation was only increased in soleus. Incubation of muscles from AMPK kinase dead (KD) and wild-type littermates with the PI3-kinase inhibitor LY-294002 demonstrated that PI3-kinase, but not AMPK, was essential for CNTF-stimulated glucose uptake. CNTF-stimulated glucose uptake and Akt phosphorylation were substantially reduced in obesity (high-fat diet and ob/ob) despite normal induction of gp130/AMPK signaling--effects also observed when treating myotubes with C2-ceramide. CONCLUSIONS: CNTF acutely increases muscle glucose uptake by a mechanism involving the PI3-kinase/Akt pathway that does not require AMPK. CNTF-stimulated glucose uptake is impaired in obesity-induced insulin resistance and by ceramide