Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis.

Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy.

Silica nanocapsules of fluorescent conjugated polymers and superparamagnetic nanocrystals for dual-mode cellular imaging.

We describe here a facile and benign synthetic strategy to integrate the fluorescent behavior of conjugated polymers and superparamagnetic properties of iron oxide nanocrystals into silica nanocapsules, forming a new type of bifunctional magnetic fluorescent silica nanocapsule (BMFSN). The resultant BMFSNs are uniform, colloidally stable in aqueous medium, and exhibit the desired dual functionality of fluorescence and superparamagnetism in a single entity. Four conjugated polymers with different emissions were used to demonstrate the versatility of employing this class of fluorescent materials for the preparation of BMFSNs. The applicability of BMFSNs in cellular imaging was studied by incubating them with human liver cancer cells, the result of which demonstrated that the cells could be visualized by dual-mode fluorescence and magnetic resonance imaging. Furthermore, the superparamagnetic behavior of the BMFSNs was exploited for in vitro magnetic-guided delivery of the nanocapsules into the cancer cells, thereby highlighting their potential for targeting biomedical applications.

Simvastatin augments revascularization and reperfusion in a murine model of hind limb ischemia - Multimodal imaging assessment.

INTRODUCTION: Peripheral artery disease can lead to severe disability and limb loss. Therapeutic strategies focussing on macrovascular repair have shown benefit but have not significantly reduced amputation rates in progressive PAD. Proangiogenic small molecule therapies may substantially improve vascularisation in limb ischemia. The purpose of the current study was to assess the proangiogenic effects of simvastatin in a murine model of hind limb ischemia using longitudinal multimodal imaging. METHODS: Mice underwent surgical intervention to induce hind limb ischemia, and were treated with simvastatin orally for 28days. Neovascularisation was assessed using 99mTc-RGD SPECT imaging, and macrovascular volume was assessed by quantitative time of flight MRI. At each imaging time point, VEGF expression and capillary vessel density were quantified using immunohistochemical analysis. RESULTS: Simvastatin significantly increased 99mTc-RGD retention in the ischemic hind limb by day 3 post-surgery, with maximal retention at day 8. Vascular volume was significantly increased in the ischemic hind limb of simvastatin treated animals, but only by day 22. Immunohistochemical analysis shows that simvastatin significantly augmented tissue VEGF expression from day 8 with increase in capillary density (CD31+) from day 14. CONCLUSIONS: Early assessment of proangiogenic therapy efficacy can be identified using 99mTc-RGD SPECT, which displays significant increases in retention before macrovascular volume changes are measureable with MRI. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Simvastatin offers an effective proangiogenic therapy as an adjunct for management of limb ischemia. Simvastatin induces integrin expression and vascular remodeling leading to neovascularisation and improved perfusion.

A New Variational Method for Bias Correction and Its Applications to Rodent Brain Extraction.

Brain extraction is an important preprocessing step for further analysis of brain MR images. Significant intensity inhomogeneity can be observed in rodent brain images due to the high-field MRI technique. Unlike most existing brain extraction methods that require bias corrected MRI, we present a high-order and L0 regularized variational model for bias correction and brain extraction. The model is composed of a data fitting term, a piecewise constant regularization and a smooth regularization, which is constructed on a 3-D formulation for medical images with anisotropic voxel sizes. We propose an efficient multi-resolution algorithm for fast computation. At each resolution layer, we solve an alternating direction scheme, all subproblems of which have the closed-form solutions. The method is tested on three T2 weighted acquisition configurations comprising a total of 50 rodent brain volumes, which are with the acquisition field strengths of 4.7 Tesla, 9.4 Tesla and 17.6 Tesla, respectively. On one hand, we compare the results of bias correction with N3 and N4 in terms of the coefficient of variations on 20 different tissues of rodent brain. On the other hand, the results of brain extraction are compared against manually segmented gold standards, BET, BSE and 3-D PCNN based on a number of metrics. With the high accuracy and efficiency, our proposed method can facilitate automatic processing of large-scale brain studies.

Silica-F127 nanohybrid-encapsulated manganese oxide nanoparticles for optimized T1 magnetic resonance relaxivity.

To properly engineer MnO nanoparticles (MONPs) of high r1 relaxivity, a nanohybrid coating consisting of silica and F127 (PEO106PPO70PEO106) is designed to encapsulate MONPs. Achieved by an interfacial templating scheme, the nanohybrid encapsulating layer is highly permeable and hydrophilic to allow for an optimal access of water molecules to the encapsulated manganese oxide core. Hence, the efficacy of MONPs as MRI contrast agents is significantly improved, as demonstrated by an enhancement of the MR signal measured with a pre-clinical 7.0 T MRI scanner. The nanohybrid encapsulation strategy also confers high colloidal stability to the hydrophobic MONPs by the surface decoration of PEO chains and a small overall diameter (<100 nm) of the PEO-SiO2 nanohybrid-encapsulated MONPs (PEOMSNs). The PEOMSNs are not susceptible to Mn-ion leaching, and their biocompatibility is affirmed by a low toxicity profile. Moreover, these hybrid nanocapsules exhibit a nano-rattle structure, which would favor the facile loading of various therapeutic reagents for theranostic applications.