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The majority of chronic myeloid leukemia (CML) and some of acute lymphocytic leukemia (ALL) cases are associated with possessing the BCR-Abl fusion protein from an oncogenic translocation, resulting in a constantly active form of Abl and rapid proliferation. CML and ALL cells that possess the BCR-Abl fusion protein are known as Philadelphia chromosome positive (Ph+). Currently, Imatinib (selective Abl inhibitor) is used as therapy against CML and ALL. However, some patients may have malignancies which show resistance to Imatinib. Previous work displays that the transformation of progenitor B cells with the v-Abl oncogene of Abelson murine leukemia virus results in cell cycle progression, rapid proliferation, and potentially malignant transformation while preventing any further differentiation. Progenitor B cells transformed with the temperature-sensitive form of the v-Abl oncogene have served as a model to study cellular response to Imatinib treatment. After some manipulation, very few cells were forced to progress to malignancy, forming tumor in vivo. These cells were no long sensitive to v-Abl inactivation, resembling the Imatinib resistant ALL. Autophagy is the process by which proteins and organelles are broken-down and recycled within the eukaryotic cell and has been hypothesized to play a part in cancer cell survival and drug-resistance. LC3 processing is a widely accepted marker of autophagy induction and progression. It has also been shown that Imatinib treatment of Ph+ leukemia can induce autophagy. In this study, we examined the autophagy induction in response to v-Abl inactivation in a Ph+-B-ALL cell model that shows resistance to Imatinib. In particular, we wonder whether the tumor cell line resistant to v-Abl inactivation may acquire a high level of autophagy to become resistant to apoptosis induced by v-Abl inactivation, and thus become addicted to autophagy. Indeed, this tumor cell line displays a high basal levels of LC3 I and II expression, regardless of v-Abl activity. We further demonstrated that inhibition of the autophagy pathway enhances the tumor line's sensitivity to Imatinib, resulting in cell cycle arrest and massive apoptosis. The combination of autophagy and Abl inhibitions may serve as an effective therapy for BCR-Abl positive CML.
ContributorsArkus, Nohea (Author) / Chang, Yung (Thesis advisor) / Kusumi, Kenro (Committee member) / Lake, Douglas (Committee member) / Jacobs, Bertram (Committee member) / Arizona State University (Publisher)
Created2011
Description
Demand for biosensor research applications is growing steadily. According to a new report by Frost & Sullivan, the biosensor market is expected to reach $14.42 billion by 2016. Clinical diagnostic applications continue to be the largest market for biosensors, and this demand is likely to continue through 2016 and beyond. Biosensor technology for use in clinical diagnostics, however, requires translational research that moves bench science and theoretical knowledge toward marketable products. Despite the high volume of academic research to date, only a handful of biomedical devices have become viable commercial applications. Academic research must increase its focus on practical uses for biosensors. This dissertation is an example of this increased focus, and discusses work to advance microfluidic-based protein biosensor technologies for practical use in clinical diagnostics. Four areas of work are discussed: The first involved work to develop reusable/reconfigurable biosensors that are useful in applications like biochemical science and analytical chemistry that require detailed sensor calibration. This work resulted in a prototype sensor and an in-situ electrochemical surface regeneration technique that can be used to produce microfluidic-based reusable biosensors. The second area of work looked at non-specific adsorption (NSA) of biomolecules, which is a persistent challenge in conventional microfluidic biosensors. The results of this work produced design methods that reduce the NSA. The third area of work involved a novel microfluidic sensing platform that was designed to detect target biomarkers using competitive protein adsorption. This technique uses physical adsorption of proteins to a surface rather than complex and time-consuming immobilization procedures. This method enabled us to selectively detect a thyroid cancer biomarker, thyroglobulin, in a controlled-proteins cocktail and a cardiovascular biomarker, fibrinogen, in undiluted human serum. The fourth area of work involved expanding the technique to produce a unique protein identification method; Pattern-recognition. A sample mixture of proteins generates a distinctive composite pattern upon interaction with a sensing platform consisting of multiple surfaces whereby each surface consists of a distinct type of protein pre-adsorbed on the surface. The utility of the "pattern-recognition" sensing mechanism was then verified via recognition of a particular biomarker, C-reactive protein, in the cocktail sample mixture.
ContributorsChoi, Seokheun (Author) / Chae, Junseok (Thesis advisor) / Tao, Nongjian (Committee member) / Yu, Hongyu (Committee member) / Forzani, Erica (Committee member) / Arizona State University (Publisher)
Created2011
Description
A wireless hybrid device for detecting volatile organic compounds (VOCs) has been developed. The device combines a highly selective and sensitive tuning-fork based detector with a pre-concentrator and a separation column. The selectivity and sensitivity of the tuning-fork based detector is optimized for discrimination and quantification of benzene, toluene, ethylbenzene, and xylenes (BTEX) via a homemade molecular imprinted polymer, and a specific detection and control circuit. The device is a wireless, portable, battery-powered, and cell-phone operated device. The device has been calibrated and validated in the laboratory and using selected ion flow tube mass spectrometry (SFIT-MS). The capability and robustness are also demonstrated in some field tests. It provides rapid and reliable detection of BTEX in real samples, including challenging high concentrations of interferents, and it is suitable for occupational, environmental health and epidemiological applications.
ContributorsChen, Zheng (Author) / Tao, Nongjian (Thesis advisor) / Chae, Junseok (Committee member) / Forzani, Erica (Committee member) / Arizona State University (Publisher)
Created2011
Description
This thesis describes several approaches to next generation DNA sequencing via tunneling current method based on a Scanning Tunneling Microscope system. In chapters 5 and 6, preliminary results have shown that DNA bases could be identified by their characteristic tunneling signals. Measurements taken in aqueous buffered solution showed that single base resolution could be achieved with economic setups. In chapter 7, it is illustrated that some ongoing measurements are indicating the sequence readout by making linear scan on a piece of short DNA oligomer. However, to overcome the difficulties of controlling DNA especially ssDNA movement, it is much better to have the tunneling measurement incorporated onto a robust nanopore device to realize sequential reading of the DNA sequence while it is being translocated.
ContributorsHuang, Shuo (Author) / Lindsay, Stuart (Thesis advisor) / Sankey, Otto (Committee member) / Tao, Nongjian (Committee member) / Drucker, Jeff (Committee member) / Ros, Robert (Committee member) / Arizona State University (Publisher)
Created2011
Description
Dual-wavelength laser sources have various existing and potential applications in wavelength division multiplexing, differential techniques in spectroscopy for chemical sensing, multiple-wavelength interferometry, terahertz-wave generation, microelectromechanical systems, and microfluidic lab-on-chip systems. In the drive for ever smaller and increasingly mobile electronic devices, dual-wavelength coherent light output from a single semiconductor laser diode would enable further advances and deployment of these technologies. The output of conventional laser diodes is however limited to a single wavelength band with a few subsequent lasing modes depending on the device design. This thesis investigates a novel semiconductor laser device design with a single cavity waveguide capable of dual-wavelength laser output with large spectral separation. The novel dual-wavelength semiconductor laser diode uses two shorter- and longer-wavelength active regions that have separate electron and hole quasi-Fermi energy levels and carrier distributions. The shorter-wavelength active region is based on electrical injection as in conventional laser diodes, and the longer-wavelength active region is then pumped optically by the internal optical field of the shorter-wavelength laser mode, resulting in stable dual-wavelength laser emission at two different wavelengths quite far apart. Different designs of the device are studied using a theoretical model developed in this work to describe the internal optical pumping scheme. The carrier transport and separation of the quasi-Fermi distributions are then modeled using a software package that solves Poisson's equation and the continuity equations to simulate semiconductor devices. Three different designs are grown using molecular beam epitaxy, and broad-area-contact laser diodes are processed using conventional methods. The modeling and experimental results of the first generation design indicate that the optical confinement factor of the longer-wavelength active region is a critical element in realizing dual-wavelength laser output. The modeling predicts lower laser thresholds for the second and third generation designs; however, the experimental results of the second and third generation devices confirm challenges related to the epitaxial growth of the structures in eventually demonstrating dual-wavelength laser output.
ContributorsGreen, Benjamin C (Author) / Zhang, Yong-Hang (Thesis advisor) / Ning, Cun-Zheng (Committee member) / Tao, Nongjian (Committee member) / Roedel, Ronald J (Committee member) / Arizona State University (Publisher)
Created2011
Description
Nanofluidic devices in which one single-walled carbon nanotube (SWCNT) spans a barrier between two fluid reservoirs were constructed, enabling direct electrical measurement of the transport of ions and molecules. Ion current through these devices is about 2 orders of magnitude larger than that predicted from the bulk resistivity of the electrolyte. Electroosmosis drives excess current, carried by cations, and is found to be the origin of giant ionic current through SWCNT as shown by building an ionic field-effect transistor with a gate electrode embedded in the fluid barrier. Wetting of inside of the semi-conducting SWCNT by water showed the change of its electronic property, turning the electronic SWCNT field-effect transistor to "on" state. These findings provide a new method to investigate and control the ion and molecule behavior at nanoscale.
ContributorsPang, Pei (Author) / Lindsay, Stuart (Thesis advisor) / Ros, Robert (Committee member) / Shumway, John (Committee member) / Tao, Nongjian (Committee member) / Menéndez, Jose (Committee member) / Arizona State University (Publisher)
Created2011
Description
In this project, a novel method is presented for measuring the resistivity of nanoscale metallic conductors (nanowires) using a variable-spacing 2-point method with a modified ultrahigh vacuum scanning tunneling microscope. An auxiliary field emission imaging method that allows for scanning insulating surfaces using a large gap distance (20nm) is also presented. Using these methods, the resistivity of self-assembled endotaxial FeSi2 nanowires (NWs) on Si(110) was measured. The resistivity was found to vary inversely with NW width, being rhoNW = 200 uOhm cm at 12 nm and 300 uOhm cm at 2 nm. The increase at small w is attributed to boundary scattering, and is fit to the Fuchs-Sondheimer model, yielding values of rho0 = 150 uOhm cm and lambda = 2.4 nm, for specularity parameter p = 0.5. These results are attributed to a high concentration of point defects in the FeSi2 structure, with a correspondingly short inelastic electron scattering length. It is remarkable that the defect concentration persists in very small structures, and is not changed by surface oxidation.
ContributorsTobler, Samuel (Author) / Bennett, Peter (Thesis advisor) / McCartney, Martha (Committee member) / Tao, Nongjian (Committee member) / Doak, Bruce (Committee member) / Chen, Tingyong (Committee member) / Arizona State University (Publisher)
Created2011
Description
Obtaining local electrochemical (EC) information is extremely important for understanding basic surface reactions, and for many applications. Scanning electrochemical microscopy (SECM) can obtain local EC information by scanning a microelectrode across the surface. Although powerful, SECM is slow, the scanning microelectrode may perturb reaction and the measured signal decreases with the size of microelectrode. This thesis demonstrates a new imaging technique based on a principle that is completely different from the conventional EC detection technologies. The technique, referred to as plasmonic-based electrochemical imaging (PECI), images local EC current (both faradaic and non-faradaic) without using a scanning microelectrode. Because PECI response is an optical signal originated from surface plasmon resonance (SPR), PECI is fast and non-invasive and its signal is proportional to incident light intensity, thus does not decrease with the area of interest. A complete theory is developed in this thesis work to describe the relationship between EC current and PECI signal. EC current imaging at various fixed potentials and local cyclic voltammetry methods are developed and demonstrated with real samples. Fast imaging rate (up to 100,000 frames per second) with 0.2×3µm spatial resolution and 0.3 pA detection limit have been achieved. Several PECI applications have been developed to demonstrate the unique strengths of the new imaging technology. For example, trace particles in fingerprint is detected by PECI, a capability that cannot be achieved with the conventional EC technologies. Another example is PECI imaging of EC reaction and interfacial impedance of graphene of different thicknesses. In addition, local square wave voltammetry capability is demonstrated and applied to study local catalytic current of platinum nanoparticle microarray. This thesis also describes a related but different research project that develops a new method to measure surface charge densities of SPR sensor chips, and micro- and nano-particles. A third project of this thesis is to develop a method to expand the conventional SPR detection and imaging technology by including a waveguide mode. This innovation creates a sensitive detection of bulk index of refraction, which overcomes the limitation that the conventional SPR can probe only changes near the sensor surface within ~200 nm.
ContributorsShan, Xiaonan (Author) / Tao, Nongjian (Thesis advisor) / Chae, Junseok (Committee member) / Christen, Jennifer Blain (Committee member) / Hayes, Mark (Committee member) / Arizona State University (Publisher)
Created2011
Description
An imaging measurement technique is developed using surface plasmon resonance. Plasmonic-based electrochemical current imaging (P-ECi) method has been developed to image the local electrochemical current optically, it allows us to measure the current density quickly and non-invasively [1, 2]. In this thesis, we solve the problems when we extand the P-ECi technique to the field of thin film system. The P-ECi signal in thin film structure was found to be directly proportional to the electrochemical current. The upper-limit of thin film thickness to use the proportional relationship between P-ECi signal and EC current was discussed by experiment and simulation. Furthermore, a new algorithm which can calculate the current density from P-ECi signal without any thickness limitation is developed and tested. Besides, surface plasmon resonance is useful phenomenon which can be used to detect the changes in the refractive index near the gold sensing surface. With the assistance of pH indicator, by applied EC potential on the gold film as the working electrode, the detection of H2 evolution reaction can be enhanced. This measurement technique is useful in analyzing local EC information and H2 evolution. References [1] S. Wang, et al., "Electrochemical Surface Plasmon Resonance: Basic Formalism and Experimental Validation," Analytical Chemistry, vol. 82, pp. 935-941, 2010/02/01 2010. [2] X. Shan, et al., "Imaging Local Electrochemical Current via Surface Plasmon Resonance," Science, vol. 327, pp. 1363-1366, March 12, 2010 2010.
ContributorsZhao, Yanjun (Author) / Tao, Nongjian (Thesis advisor) / Wang, Shaopeng (Committee member) / Tsow, Tsing (Committee member) / Arizona State University (Publisher)
Created2013
Description
Infertility has become an increasing problem in developed countries and in many cases can be attributed to compromised sperm quality. Assessment of male fertility typically utilizes semen analysis which mainly examines sperm morphology, however many males whose sperm appear normal are sub- or infertile, suggesting that sperm from these males may be deficient in a protein or suite of proteins. To date, very little is known about the composition of sperm or the complex maturation process that confers motility and fertilization competency to sperm. Chapter 1 discusses the use of whole cell mass spectrometry to identify 1247 proteins comprising the Rhesus macaque (Macaca mulatta) sperm proteome, a commonly used model of human reproduction. This study provides a more robust proxy of human sperm composition than was previously available and facilitates studies of sperm using the rhesus macaque as a model. Chapters 2 & 3 provide a systems level overview of changes in sperm proteome composition that occurs during epididymal transit. Chapter 2 reports the proteomes of sperm collected from the caput, corpus and cauda segments of the mouse epididymis, identifying 1536, 1720 and 1234 proteins respectively. Chapter 3 reports the sperm proteome from four distinct segments of the Rhesus macaque epididymis, including the caput, proximal corpus, distal corpus and cauda, identifying 1951, 2014, 1764 and 1423 proteins respectively. These studies identify a number of proteins that are added and removed from sperm during epididymal transit which likely play an important role in the sperm maturation process. To date no comparative evolutionary studies of sperm proteomes have been undertaken. Chapter 4 compares four mammalian sperm proteomes including the human, macaque, mouse and rat. This study identified 98 proteins common to all four sperm proteomes, 82 primate and 90 rodent lineage-specific proteins and 494, 467, 566, and 193 species specific proteins in the human, macaque, mouse and rat sperm proteomes respectively and discusses how differences in sperm composition may ultimately lead to functional differences across species. Finally, chapter 5 uses sperm proteome data to inform the preliminary design of a rodent contraceptive vaccine delivered orally using recombinant attenuated Salmonella vaccine vectors.
ContributorsSkerget, Sheri Jo (Author) / Karr, Timothy L. (Thesis advisor) / Lake, Douglas (Committee member) / Petritis, Konstantinos (Committee member) / Arizona State University (Publisher)
Created2013