18F-C2Am: a targeted imaging agent for detecting tumor cell death in vivo using positron emission tomography.

INTRODUCTION: Trialing novel cancer therapies in the clinic would benefit from imaging agents that can detect early evidence of treatment response. The timing, extent and distribution of cell death in tumors following treatment can give an indication of outcome. We describe here an 18F-labeled derivative of a phosphatidylserine-binding protein, the C2A domain of Synaptotagmin-I (C2Am), for imaging tumor cell death in vivo using PET. METHODS: A one-pot, two-step automated synthesis of N-(5-[18F]fluoropentyl)maleimide (60 min synthesis time, > 98% radiochemical purity) has been developed, which was used to label the single cysteine residue in C2Am within 30 min at room temperature. Binding of 18F-C2Am to apoptotic and necrotic tumor cells was assessed in vitro, and also in vivo, by dynamic PET and biodistribution measurements in mice bearing human tumor xenografts treated with a TRAILR2 agonist or with conventional chemotherapy. C2Am detection of tumor cell death was validated by correlation of probe binding with histological markers of cell death in tumor sections obtained immediately after imaging. RESULTS: 18F-C2Am showed a favorable biodistribution profile, with predominantly renal clearance and minimal retention in spleen, liver, small intestine, bone and kidney, at 2 h following probe administration. 18F-C2Am generated tumor-to-muscle (T/m) ratios of 6.1 ± 2.1 and 10.7 ± 2.4 within 2 h of probe administration in colorectal and breast tumor models, respectively, following treatment with the TRAILR2 agonist. The levels of cell death (CC3 positivity) following treatment were 12.9-58.8% and 11.3-79.7% in the breast and colorectal xenografts, respectively. Overall, a 20% increase in CC3 positivity generated a one unit increase in the post/pre-treatment tumor contrast. Significant correlations were found between tracer uptake post-treatment, at 2 h post-probe administration, and histological markers of cell death (CC3: Pearson R = 0.733, P = 0.0005; TUNEL: Pearson R = 0.532, P = 0.023). CONCLUSION: The rapid clearance of 18F-C2Am from the blood pool and low kidney retention allowed the spatial distribution of cell death in a tumor to be imaged during the course of therapy, providing a rapid assessment of tumor treatment response. 18F-C2Am has the potential to be used in the clinic to assess early treatment response in tumors

Magnetic Resonance Imaging Is More Sensitive Than PET for Detecting Treatment-Induced Cell Death-Dependent Changes in Glycolysis.

Metabolic imaging has been widely used to measure the early responses of tumors to treatment. Here, we assess the abilities of PET measurement of [18F]FDG uptake and MRI measurement of hyperpolarized [1-13C]pyruvate metabolism to detect early changes in glycolysis following treatment-induced cell death in human colorectal (Colo205) and breast adenocarcinoma (MDA-MB-231) xenografts in mice. A TRAIL agonist that binds to human but not mouse cells induced tumor-selective cell death. Tumor glycolysis was assessed by injecting [1,6-13C2]glucose and measuring 13C-labeled metabolites in tumor extracts. Injection of hyperpolarized [1-13C]pyruvate induced rapid reduction in lactate labeling. This decrease, which correlated with an increase in histologic markers of cell death and preceded decrease in tumor volume, reflected reduced flux from glucose to lactate and decreased lactate concentration. However, [18F]FDG uptake and phosphorylation were maintained following treatment, which has been attributed previously to increased [18F]FDG uptake by infiltrating immune cells. Quantification of [18F]FDG uptake in flow-sorted tumor and immune cells from disaggregated tumors identified CD11b+/CD45+ macrophages as the most [18F]FDG-avid cell type present, yet they represented <5% of the cells present in the tumors and could not explain the failure of [18F]FDG-PET to detect treatment response. MRI measurement of hyperpolarized [1-13C]pyruvate metabolism is therefore a more sensitive marker of the early decreases in glycolytic flux that occur following cell death than PET measurements of [18F]FDG uptake. SIGNIFICANCE: These findings demonstrate superior sensitivity of MRI measurement of hyperpolarized [1-13C]pyruvate metabolism versus PET measurement of 18F-FDG uptake for detecting early changes in glycolysis following treatment-induced tumor cell death

Multi-modal imaging of high-risk ductal carcinoma in situ of the breast using C2Am: a targeted cell death imaging agent

Abstract: Background: Ductal carcinoma in situ (DCIS) is a non-invasive form of early breast cancer, with a poorly understood natural history of invasive transformation. Necrosis is a well-recognized adverse prognostic feature of DCIS, and non-invasive detection of its presence and spatial extent could provide information not obtainable by biopsy. We describe here imaging of the distribution and extent of comedo-type necrosis in a model of human DCIS using C2Am, an imaging agent that binds to the phosphatidylserine exposed by necrotic cells. Methods: We used an established xenograft model of human DCIS that mimics the histopathological features of the disease. Planar near-infrared and optoacoustic imaging, using fluorescently labeled C2Am, were used to image non-invasively the presence and extent of lesion necrosis. Results: C2Am showed specific and sensitive binding to necrotic areas in DCIS tissue, detectable both in vivo and ex vivo. The imaging signal generated in vivo using near-infrared (NIR) fluorescence imaging was up to 6-fold higher in DCIS lesions than in surrounding fat pad or skin tissue. There was a correlation between the C2Am NIR fluorescence (Pearson R = 0.783, P = 0.0125) and optoacoustic signals (R > 0.875, P < 0.022) in the DCIS lesions in vivo and the corresponding levels of cell death detected histologically. Conclusions: C2Am is a targeted multi-modal imaging agent that could complement current anatomical imaging methods for detecting DCIS. Imaging the presence and spatial extent of necrosis may give better prognostic information than that obtained by biopsy alone

Optical Imaging of

dissertation

Relationships between the characteristics of soil and understory in a Pinus massoniana forest in southern China

Soil is the basis for vegetation growth, and vegetation in turn improves soil quality. Understanding the relationships between soil and vegetation characteristics is needed to rehabilitate degraded land and implement sustainable land use practices. In particular, it is important to uncover the relationship between natural vegetation restoration and key soil parameters for the improvement of restored ecological environments. This study analyzed the relationships between soil and understory characteristics of a P. massoniana forest in degraded red soil in southern China. Red soils in this area have been severely eroded. The soils were categorized into three groups whose attributes differed significantly and each group was distributed within a topographical type. Understory and soil characteristics were closely correlated, but restoration of the understory was only related to some key soil attributes (e.g. available potassium content, pH, soil water content, bacteria amounts, and urease and catalase activities). Our results provide insight into the relationships between soil and vegetation characteristics for natural revegetation in degraded land with severely eroded soil

Relationship between topography and the distribution of understory vegetation in a Pinus massoniana forest in Southern China

The poor growth of understory vegetation and the severe losses of soil and water in Pinus massoniana forests have recently become serious concerns in an area in southern China with eroded red soil. The influence of topography on the spatial distribution of vegetation, however, has received little attention. This study combined several multivariate analyses to discern the complicated relationship between understory vegetation and topography. Thirty-six plots (10 m×10 m) were sampled in a field survey of the vegetation and topography in the central red-soil region. The distributions of the understory vegetation differed significantly amongst the topographies. Most plants grew in gullies, and few grew on ridges. The low coverage (25.2%) and number of species (5 per plot) of the vegetation on ridges was due to serious soil erosion. Surface curvature and slope aspect were the first and second most important topographic factors, respectively, affecting the distribution of the vegetation. The relationship between topography and distribution could be described by a linear model. Surface curvature or slope aspect alone, however, could only explain 22.2–59.2% of the variance in distribution. The adaptation of vegetation to specific topographies should be considered for restorations of P. massoniana forests in the study area. The results of this study will be helpful for selecting potential sites for seeding and vegetation restoration to improve the ecology of the study area. Further studies will be needed to identify the mechanism of the distribution of the understory vegetation in these P. massoniana forests

Study on Physical and Mechanical Properties of High-Water Material Made by Seawater

In maritime engineering, marine-derived construction materials are seen as an efficient and cost-effective alternative. HWM is a novel inorganic cementitious material characterized by its high water content, rapid setting, and early strengthening. In this study, first, HWM was proposed to be produced from seawater and used in a maritime environment. Two groups of HWM samples with varied w/c ratios were prepared with fresh water and seawater, and their behavior was examined to assess the viability of HWM produced with seawater. The microstructures and chemical compositions were studied using SEM and XRD. Results indicated that as the w/c ratio increased from 3:1 to 6:1, the water content, density, and uniaxial compressive strength of HWM produced from seawater varied from 72.1% to 77.5%; 1.25 to 1.12 g/cm3, and 1.47 MPa to 0.39 MPa, respectively, which is 2–10% lower, 0.8–2.2% higher, and 13–45% stronger than that from fresh water. The chemical composition of HWM mixed with seawater is predominantly composed of ettringite, C-S-H gel, aluminum (Al(OH)3) glue, M-S-H gel, and Mg(OH)2. SO42− and Mg2+ in seawater participate in the hydration and hardening of HWM, resulting in an increase in the synthesis of ettringite and M-S-H gel, which makes the skeletal structure of HWM denser, hence increasing its strength. HWM derived from seawater retains excellent physical and mechanical properties. This work reveals the HWM-seawater interaction mechanism, elucidates the promising application prospect of HWM in maritime engineering, and paves the way to investigate its field performance

Effect of Material Inhomogeneity on the Crack Tip Mechanical Field and SCC Growth Rate of 52M/316L Dissimilar Metal Welded Joints

The stress–strain conditions at the crack tip in dissimilar metal welded joints (DMWJ) are a critical factor influencing stress corrosion cracking (SCC) behavior. The processing technology and working environment of DMWJ lead to a randomly inhomogeneous distribution of material mechanical properties, making the crack tip mechanical field more complex. An inhomogeneous model was obtained using a combination of physical experiments and the elastic–plastic finite element method to understand the effect of this inhomogeneous distribution of mechanical properties on the direction of SCC growth and the growth rate in DMWJ and the impact of inhomogeneity on the SCC growth behavior was compared and analyzed. The findings demonstrate that Type I (opening mode) cracks are more likely to form due to the inhomogeneity of mechanical properties and are more likely to deflect toward the Alloy 52M region at the interface between Alloy 52M and 316L stainless steel. Additionally, the strain gradient at the crack tip increases with the degree of inhomogeneity, which has a bigger impact on the accuracy of SCC growth rate predictions

Numerical Analysis of Motion Characteristics of Sliding or Rolling and Saltation of Sediment Particles under Turbulent Flow

The processes of sediment particle movement were studied through numerical simulation using a coupled method with focus on discussing the characteristics of sliding or rolling and saltation sediment particles, respectively. Turbulent flow was simulated using large eddy simulation (LES). The sediment particle was simulated using the combined finite-discrete element method (FDEM). The interaction forces of turbulent flow and sediment particle were calculated using the immersed boundary method (IBM). It indicated that the collisions of saltating particle with low concentration increase the saltation length and flight time. In response, sediment particle velocity also increases. The particle angular velocity is largest at the takeoff moment, and decreases gradually in the saltation progress. The drag and lift forces near the bed are large, and away from the bed decrease and trend to be a stable value, gradually. From the relative magnitudes of the drag and lift forces, the lift force plays a more important role than the drag force in the sediment saltation. The relative magnitudes of drag and lift forces influence the incident and takeoff angles. The sediment transport rate calculated based on the characteristics of saltation sediment particles is overestimated, ignoring the effect of sliding or rolling sediment particles and inter-particle collisions

Sensitivity analysis of a three-dimensional simulation of turbidity currents in a sloping flume

Sensitivity analysis is necessary in numerical models to establish the optimal model configuration and simulate turbidity currents accurately. The sensitivity of turbidity currents simulated by a three-dimensional numerical model named the semi-implicit cross-scale hydroscience integrated system model (SCHISM) was assessed using domain discretization, the turbulence closure model, and the transport scheme. The results show that a higher horizontal resolution with an appropriate aspect ratio, localized sigma coordinates with shaved cells (LSC2) grid with sufficient layers, a two-phase mixture turbulence closure model, and transport schemes with critical depth ratio lower than 1 could improve the model performance on the turbidity currents. The study can provide helpful guidance to establish accurate turbidity current simulations in complex water environments.</p