Magnetic force imaging and handling of cancer cells on the nanoscale

A thesis submitted to the University of Bedfordshire in partial fulfilment of the requirements for the degree of Doctor of PhilosophyCancer treatment has become one of the top priorities in health. Great efforts have been devoted to the diagnosis and therapy of cancers. Culturing cells with drugs is a common method used to investigate cancer therapy in experiments. However, this method has limitations in cancer treatment because of the lack of capabilities of handling cells, targeting specific cells and measuring the nanoscale changes in cell structures. Magnetic nanoparticles (MNPs) and magnetic force microscopes (MFMs) have been used to study biological samples due to their advantages in tracing, manipulating and measuring, which has motivated to research the method for implanting MNPs into cancer cells, to target the cancer cells and to measure their changes during the treatment. Research reported in this thesis focuses on magnetic force imaging and handling of targeted cancer cells on the nanoscale for possible new cancer therapies. A new differential MFM imaging method and a new compensation MFM imaging method were developed in this research to improve the MFM imaging quality. The former reverses the magnetized direction of probe from upward to downward and the latter scans the samples with three scanning directions of 0°, 45° and 90°. With these methods, the obtained MFM images achieve a high resolution, SNR, image contrast and accuracy. A pair of innovative MNPs picking up method and MNPs releasing method were developed in this research to achieve flexible MNPs picking up and releasing. The picking up method handles the magnetic tip following a helical structure as the capture path when approaching to the target MNPs. The MNPs releasing method uses a biaxiably-oriented polypropylene (BOPP) film together with a magnet allowing MNPs to separate from the MFM tip surface. With these methods, the target MNPs can be picked up by the MFM tip and released from the tip surface successfully. This research discovered, for the first time in the world to the author knowledge, the differences in morphological features (height, length, width and roughness) and mechanical properties (adhesive force and Young‟s modulus) between multinuclear and mononuclear colon cancer cells after treating the cells with fullerenol. This discovery provides guidance to the selection of cells for target treatment. The results indicate that the mononuclear SW480 cells are more sensitive to fullerenol than the multinuclear SW480 cells and the multinuclear SW480 cells exhibit a stronger drug-resistance than the mononuclear SW480 cells. A new MNPs implantation method was developed in this research, which enables the FITC-MNPs functioned tip to insert into cells so that MNPs are implanted into the target cells. Fluorescence microscope images show that the FITC-MNPs are released into the cells successfully. Cells being treated with MNPs (Cell-MNPs) manipulation III methods are explored by magnet and controllable electromagnets to manipulate the target cancer cells. The results show that the cell-MNPs have magnetic force manipulated capability and they can be manipulated to have the leftward, rightward, upward and downward flexibilities

CHARACTERIZATION OF TCL1-Tg:P53-/- MICE THAT RESEMBLE HUMAN CHRONIC LYMPHOCYTIC LEUKEMIA WITH 17P-DELETION

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United Statesand Europe. CLL patients with deletion of chromosome 17p, where the tumor suppressor p53 gene is located, often develop a more aggressive disease with poor clinical outcomes. However, the underlying mechanism remains unclear. In order to understand the underneath mechanism in vivo, I have recently generated mice with Eu-TCL1-Tg:p53-/- genotype and showed that these mice develop aggressive leukemia that resembles human CLL with 17p deletion. The Eu-TCL1-Tg:p53-/- mice developed CLL disease at 3-4 months, significantly earlier than the parental Eu-TCL1-Tg mice that developed CLL disease at 8-12 months. Flow cytometry analysis showed that the CD5+/ IgM+ cell population appeared in the peritoneal cavity, bone marrow, and the spleens of Eu-TCL1-Tg:p53-/- mice significantly earlier than that of the parental Eu-TCL1-Tg mice. Massive infiltration and accumulation of leukemia cells were found in the spleen and peritoneal cavity. In vitro study showed that the leukemia cells isolated from the Eu-TCL1-Tg:p53-/- mice were more resistant to fludarabine treatment than the leukemia cells isolated from spleens of Eu-TCL1-Tg mice. Interestingly, TUNEL assay revealed that there was higher apoptotic cell death found in the Eu-TCL1-Tg spleen tissue compared to the spleens of the Eu-TCL1-Tg:p53-/- mice, suggesting that the loss of p53 compromises the apoptotic process in vivo, and this might in part explain the drug resistant phenotype of CLL cells with 17p-deletion. In the present study, we further demonstrated that the p53 deficiency in the TCL1 transgenic mice resulted in significant down-regulation of microRNAs miR-15a and miR16-1, associated with a substantial up-regulation of Mcl-1, suggesting that the p53-miR15a/16-Mcl-1 axis may play an important role in CLL pathogenesis. Interestingly, we also found that loss of p53 resulted in a significant decrease in expression of the miR-30 family especially miR-30d in leukemia lymphocytes from the Eu-TCL1-Tg:p53-/- mice. Such down-regulation of those microRNAs and up-regulation of Mcl-1 were also found in primary leukemia cells from CLL patients with 17p deletion. To further exam the biological significance of decrease in the miR-30 family in CLL, we investigated the potential involvement of EZH2 (enhancer of zeste homolog 2), a component of the Polycomb repressive complex known to be a downstream target of miR-30d and plays a role in disease progression in several solid cancers. RT-PCR and western blot analyses showed that both EZH2 mRNA transcript and protein levels were significantly increased in the lymphocytes of Eu-TCL1-Tg:p53-/- mice relative to Eu-TCL1-Tg mice. Exposure of leukemia cells isolated from Eu-TCL1-Tg:p53-/- mice to the EZH2 inhibitor 3-deazaneplanocin (DZNep) led to induction of apoptosis, suggesting EZH2 may play a role in promoting CLL cell survival and this may contribute to the aggressive phenotype of CLL with loss of p53. Our study has created a novel CLL mouse model, and suggests that the p53/miR15a/16-Mcl-1 axis & p53/miR30d-EZH2 may contribute to the aggressive phenotype and drug resistance in CLL cells with loss of p53

Novel nanoparticle detection method using electrochemical device based on anodic aluminum oxide nanopore membrane

AbstractSome investigations suggest that nanoparticles are potentially the most dangerous because they can also penetrate deeper into lung tissue than other large particles. However, some researchers declare that the research on security of environmental nanoparticles should be on the basis of the standardization of investigation system. Therefore, it is significant to detect nanoparticles for both environmental evaluation and further treatment. In this paper, a method for iron oxide nanoparticle detection was investigated by a novel electrochemical device based on AAO nanopore membrane and preliminary results was taken out which may create novel avenues and applications for nanoparticle detection

Decadal Variation in Surface Characteristics over Xinjiang, Western China, from T/P Altimetry Backscatter Coefficients: Evidence of Climate Change

The backscatter coefficient, known as sigma0, is an important measurement of satellite radar altimetry and a key parameter for land altimetry because of its close relationship with the physical properties and geometric features of land coverage under global/regional climate change effects. Using the TOPEX/Poseidon GDR-M dataset from January 1993 to December 2004, we study the spatial and temporal distribution of sigma0 at bands Ku and C over Xinjiang, western China. The results show that the sigma0 is influenced by the water distribution over land and the time evolution of sigma0 has clear seasonal changes. River basins or deserts are classified over the spatial distribution based on different sigma0 values. For example, high sigma0 values are found in the Tarim River Basin and low values are found in the Taklimakan Desert. The periodic components of sigma0 time series are determined using the fast Fourier transformation method. The annual variation is the dominating cycle and the semi-annual variation is the secondary signal. The amplitudes of sigma0 time series at bands Ku and C are also given and most areas have quite low amplitudes except for the Tarim River Basin. Several areas including the Tarim River Basin, Tianshan Mountain and Taklimakan Desert are selected for sigma0 time series spacial analysis to discuss the reasons for variations in sigma0. The main factors are precipitation and vegetation growth, which are affected by the global/regional climate change. The correlation between the brightness temperature, which is related to the water-vapor content in the atmosphere measured by TMR at the 21 GHz channel and sigma0 at two bands, is analyzed

Mesoporous SnO2 sensor prepared by carbon nanotubes as template and its sensing properties to indoor air pollutants

AbstractAn effort has been made to develop a kind of mesoporous SnO2 gas sensor for detecting indoor air pollutants such as ethanol, benzene, meta-xylene. Mesoporous SnO2 material has been prepared by sol-gel method joined into multiwall carbon nanotubes as template. The field emission scanning electron microscope (FSEM) was used to characterize the samples, by which the mesoporous structure of SnO2 was obviously observed. The investigation results suggest that the as-prepared mesoporous SnO2 has a good response and reversibility to indoor environmental air pollutants. At last, the selectivity of the mesoporous sensor was investigated

AdaptDHM: Adaptive Distribution Hierarchical Model for Multi-Domain CTR Prediction

Large-scale commercial platforms usually involve numerous business domains for diverse business strategies and expect their recommendation systems to provide click-through rate (CTR) predictions for multiple domains simultaneously. Existing promising and widely-used multi-domain models discover domain relationships by explicitly constructing domain-specific networks, but the computation and memory boost significantly with the increase of domains. To reduce computational complexity, manually grouping domains with particular business strategies is common in industrial applications. However, this pre-defined data partitioning way heavily relies on prior knowledge, and it may neglect the underlying data distribution of each domain, hence limiting the model's representation capability. Regarding the above issues, we propose an elegant and flexible multi-distribution modeling paradigm, named Adaptive Distribution Hierarchical Model (AdaptDHM), which is an end-to-end optimization hierarchical structure consisting of a clustering process and classification process. Specifically, we design a distribution adaptation module with a customized dynamic routing mechanism. Instead of introducing prior knowledge for pre-defined data allocation, this routing algorithm adaptively provides a distribution coefficient for each sample to determine which cluster it belongs to. Each cluster corresponds to a particular distribution so that the model can sufficiently capture the commonalities and distinctions between these distinct clusters. Extensive experiments on both public and large-scale Alibaba industrial datasets verify the effectiveness and efficiency of AdaptDHM: Our model achieves impressive prediction accuracy and its time cost during the training stage is more than 50% less than that of other models

Robust control for a tracked mobile robot based on a finite-time convergence zeroing neural network

IntroductionSince tracked mobile robot is a typical non-linear system, it has been a challenge to achieve the trajectory tracking of tracked mobile robots. A zeroing neural network is employed to control a tracked mobile robot to track the desired trajectory.MethodsA new fractional exponential activation function is designed in this study, and the implicit derivative dynamic model of the tracked mobile robot is presented, termed finite-time convergence zeroing neural network. The proposed model is analyzed based on the Lyapunov stability theory, and the upper bound of the convergence time is given. In addition, the robustness of the finite-time convergence zeroing neural network model is investigated under different error disturbances.Results and discussionNumerical experiments of tracking an eight-shaped trajectory are conducted successfully, validating the proposed model for the trajectory tracking problem of tracked mobile robots. Comparative results validate the effectiveness and superiority of the proposed model for the kinematical resolution of tracked mobile robots even in a disturbance environment

Mechanically manipulating glymphatic transport by ultrasound combined with microbubbles

The glymphatic system is a perivascular fluid transport system for waste clearance. Glymphatic transport is believed to be driven by the perivascular pumping effect created by the pulsation of the arterial wall caused by the cardiac cycle. Ultrasound sonication of circulating microbubbles (MBs) in the cerebral vasculature induces volumetric expansion and contraction of MBs that push and pull on the vessel wall to generate a MB pumping effect. The objective of this study was to evaluate whether glymphatic transport can be mechanically manipulated by focused ultrasound (FUS) sonication of MBs. The glymphatic pathway in intact mouse brains was studied using intranasal administration of fluorescently labeled albumin as fluid tracers, followed by FUS sonication at a deep brain target (thalamus) in the presence of intravenously injected MBs. Intracisternal magna injection, the conventional technique used in studying glymphatic transport, was employed to provide a comparative reference. Three-dimensional confocal microscopy imaging of optically cleared brain tissue revealed that FUS sonication enhanced the transport of fluorescently labeled albumin tracer in the perivascular space (PVS) along microvessels, primarily the arterioles. We also obtained evidence of FUS-enhanced penetration of the albumin tracer from the PVS into the interstitial space. This study revealed that ultrasound combined with circulating MBs could mechanically enhance glymphatic transport in the brain