Matching Items (144)
Description
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
Infections caused by the Hepatitis C Virus (HCV) are very common worldwide, affecting up to 3% of the population. Chronic infection of HCV may develop into liver cirrhosis and liver cancer which is among the top five of the most common cancers. Therefore, vaccines against HCV are under intense study in order to prevent HCV from harming people's health. The envelope protein 2 (E2) of HCV is thought to be a promising vaccine candidate because it can directly bind to a human cell receptor and plays a role in viral entry. However, the E2 protein production in cells is inefficient due to its complicated matured structure. Folding of E2 in the endoplasmic reticulum (ER) is often error-prone, resulting in production of aggregates and misfolded proteins. These incorrect forms of E2 are not functional because they are not able to bind to human cells and stimulate antibody response to inhibit this binding. This study is aimed to overcome the difficulties of HCV E2 production in plant system. Protein folding in the ER requires great assistance from molecular chaperones. Thus, in this study, two molecular chaperones in the ER, calreticulin and calnexin, were transiently overexpressed in plant leaves in order to facilitate E2 folding and production. Both of them showed benefits in increasing the yield of E2 and improving the quality of E2. In addition, poorly folded E2 accumulated in the ER may cause stress in the ER and trigger transcriptional activation of ER molecular chaperones. Therefore, a transcription factor involved in this pathway, named bZIP60, was also overexpressed in plant leaves, aiming at up-regulating a major family of molecular chaperones called BiP to assist protein folding. However, our results showed that BiP mRNA levels were not up-regulated by bZIP60, but they increased in response to E2 expression. The Western blot analysis also showed that overexpression of bZIP60 had a small effect on promoting E2 folding. Overall, this study suggested that increasing the level of specific ER molecular chaperones was an effective way to promote HCV E2 protein production and maturation.
ContributorsHong, Fan (Author) / Mason, Hugh (Thesis advisor) / Gaxiola, Roberto (Committee member) / Chang, Yung (Committee member) / Chen, Qiang (Committee member) / Arizona State University (Publisher)
Created2011
Description
2D fetal echocardiography (ECHO) can be used for monitoring heart development in utero. This study’s purpose is to empirically model normal fetal heart growth and function changes during development by ECHO and compare these to fetuses diagnosed with and without cardiomyopathy with diabetic mothers. There are existing mathematical models describing fetal heart development but they warrant revalidation and adjustment. 377 normal fetuses with healthy mothers, 98 normal fetuses with diabetic mothers, and 37 fetuses with cardiomyopathy and diabetic mothers had their cardiac structural dimensions, cardiothoracic ratio, valve flow velocities, and heart rates measured by fetal ECHO in a retrospective chart review. Cardiac features were fitted to linear functions, with respect to gestational age, femur length, head circumference, and biparietal diameter and z-scores were created to model normal fetal growth for all parameters. These z-scores were used to assess what metrics had no difference in means between the normal fetuses of both healthy and diabetic mothers but differed from those diagnosed with cardiomyopathy. It was found that functional metrics like mitral and tricuspid E wave and pulmonary velocity could be important predictors for cardiomyopathy when fitted by gestational age, femur length, head circumference, and biparietal diameter. Additionally, aortic and tricuspid annulus diameters when fitted to estimated gestational age showed potential to be predictors for fetal cardiomyopathy. While the metrics overlapped over their full range, combining them together may have the potential for predicting cardiomyopathy in utero. Future directions of this study will explore creating a classifier model that can predict cardiomyopathy using the metrics assessed in this study.
ContributorsMishra, Shambhavi (Co-author) / Numani, Asfia (Co-author) / Sweazea, Karen (Thesis director) / Plasencia, Jonathan (Committee member) / Economics Program in CLAS (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
This dissertation creates models of past potential vegetation in the Southern Levant during most of the Holocene, from the beginnings of farming through the rise of urbanized civilization (12 to 2.5 ka BP). The time scale encompasses the rise and collapse of the earliest agrarian civilizations in this region. The archaeological record suggests that increases in social complexity were linked to climatic episodes (e.g., favorable climatic conditions coincide with intervals of prosperity or marked social development such as the Neolithic Revolution ca. 11.5 ka BP, the Secondary Products Revolution ca. 6 ka BP, and the Middle Bronze Age ca. 4 ka BP). The opposite can be said about periods of climatic deterioration, when settled villages were abandoned as the inhabitants returned to nomadic or semi nomadic lifestyles (e.g., abandonment of the largest Neolithic farming towns after 8 ka BP and collapse of Bronze Age towns and cities after 3.5 ka BP during the Late Bronze Age). This study develops chronologically refined models of past vegetation from 12 to 2.5 ka BP, at 500 year intervals, using GIS, remote sensing and statistical modeling tools (MAXENT) that derive from species distribution modeling. Plants are sensitive to alterations in their environment and respond accordingly. Because of this, they are valuable indicators of landscape change. An extensive database of historical and field gathered observations was created. Using this database as well as environmental variables that include temperature and precipitation surfaces for the whole study period (also at 500 year intervals), the potential vegetation of the region was modeled. Through this means, a continuous chronology of potential vegetation of the Southern Levantwas built. The produced paleo-vegetation models generally agree with the proxy records. They indicate a gradual decline of forests and expansion of steppe and desert throughout the Holocene, interrupted briefly during the Mid Holocene (ca. 4 ka BP, Middle Bronze Age). They also suggest that during the Early Holocene, forest areas were extensive, spreading into the Northern Negev. The two remaining forested areas in the Northern and Southern Plateau Region in Jordan were also connected during this time. The models also show general agreement with the major cultural developments, with forested areas either expanding or remaining stable during prosperous periods (e.g., Pre Pottery Neolithic and Middle Bronze Age), and significantly contracting during moments of instability (e.g., Late Bronze Age).
ContributorsSoto-Berelov, Mariela (Author) / Fall, Patricia L. (Thesis advisor) / Myint, Soe (Committee member) / Turner, Billie L (Committee member) / Falconer, Steven (Committee member) / Arizona State University (Publisher)
Created2011
Description
Rabies disease remains enzootic among raccoons, skunks, foxes and bats in the United States. It is of primary concern for public-health agencies to control spatial spread of rabies in wildlife and its potential spillover infection of domestic animals and humans. Rabies is invariably fatal in wildlife if untreated, with a non-negligible incubation period. Understanding how this latency affects spatial spread of rabies in wildlife is the concern of chapter 2 and 3. Chapter 1 deals with the background of mathematical models for rabies and lists main objectives. In chapter 2, a reaction-diffusion susceptible-exposed-infected (SEI) model and a delayed diffusive susceptible-infected (SI) model are constructed to describe the same epidemic process -- rabies spread in foxes. For the delayed diffusive model a non-local infection term with delay is resulted from modeling the dispersal during incubation stage. Comparison is made regarding minimum traveling wave speeds of the two models, which are verified using numerical experiments. In chapter 3, starting with two Kermack and McKendrick's models where infectivity, death rate and diffusion rate of infected individuals can depend on the age of infection, the asymptotic speed of spread $c^\ast$ for the cumulated force of infection can be analyzed. For the special case of fixed incubation period, the asymptotic speed of spread is governed by the same integral equation for both models. Although explicit solutions for $c^\ast$ are difficult to obtain, assuming that diffusion coefficient of incubating animals is small, $c^\ast$ can be estimated in terms of model parameter values. Chapter 4 considers the implementation of realistic landscape in simulation of rabies spread in skunks and bats in northeast Texas. The Finite Element Method (FEM) is adopted because the irregular shapes of realistic landscape naturally lead to unstructured grids in the spatial domain. This implementation leads to a more accurate description of skunk rabies cases distributions.
ContributorsLiu, Hao (Author) / Kuang, Yang (Thesis advisor) / Jackiewicz, Zdzislaw (Committee member) / Lanchier, Nicolas (Committee member) / Smith, Hal (Committee member) / Thieme, Horst (Committee member) / Arizona State University (Publisher)
Created2013
Description
Vaccinia virus (VACV) is the current vaccine for the highly infectious smallpox disease. Since the eradication of smallpox, VACV has been developed extensively as a heterologous vaccine vector for several pathogens. However, due to the complications associated with this replication competent virus, the safety and efficacy of VACV vaccine vector has been reevaluated. To evaluate the safety and efficacy of VACV, we study the interactions between VACV and the host innate immune system, especially the type I interferon (IFN) signaling pathways. In this work, we evaluated the role of protein kinase R (PKR) and Adenosine Deaminase Acting on RNA 1(ADAR1), which are induced by IFN, in VACV infection. We found that PKR is necessary but is not sufficient to activate interferon regulatory factor 3 (IRF3) in the induction of type I IFN; and the activation of the stress-activated protein kinase/ c-Jun NH2-terminal kinase is required for the PKR-dependent activation of IRF3 during VACV infection. Even though PKR was found to have an antiviral effect in VACV, ADAR1 was found to have a pro-viral effect by destabilizing double stranded RNA (dsRNA), rescuing VACVΔE3L, VACV deleted of the virulence factor E3L, when provided in trans. With the lessons we learned from VACV and host cells interaction, we have developed and evaluated a safe replication-competent VACV vaccine vector for HIV. Our preliminary results indicate that our VACV vaccine vector can still induce the IFN pathway while maintaining the ability to replicate and to express the HIV antigen efficiently. This suggests that this VACV vector can be used as a safe and efficient vaccine vector for HIV.
ContributorsHuynh, Trung Phuoc (Author) / Jacobs, Bertram L (Thesis advisor) / Hogue, Brenda (Committee member) / Chang, Yung (Committee member) / Ugarova, Tatiana (Committee member) / Arizona State University (Publisher)
Created2013
Description
Two critical limitations for hyperspatial imagery are higher imagery variances and large data sizes. Although object-based analyses with a multi-scale framework for diverse object sizes are the solution, more data sources and large amounts of testing at high costs are required. In this study, I used tree density segmentation as the key element of a three-level hierarchical vegetation framework for reducing those costs, and a three-step procedure was used to evaluate its effects. A two-step procedure, which involved environmental stratifications and the random walker algorithm, was used for tree density segmentation. I determined whether variation in tone and texture could be reduced within environmental strata, and whether tree density segmentations could be labeled by species associations. At the final level, two tree density segmentations were partitioned into smaller subsets using eCognition in order to label individual species or tree stands in two test areas of two tree densities, and the Z values of Moran's I were used to evaluate whether imagery objects have different mean values from near segmentations as a measure of segmentation accuracy. The two-step procedure was able to delineating tree density segments and label species types robustly, compared to previous hierarchical frameworks. However, eCognition was not able to produce detailed, reasonable image objects with optimal scale parameters for species labeling. This hierarchical vegetation framework is applicable for fine-scale, time-series vegetation mapping to develop baseline data for evaluating climate change impacts on vegetation at low cost using widely available data and a personal laptop.
ContributorsLiau, Yan-ting (Author) / Franklin, Janet (Thesis advisor) / Turner, Billie (Committee member) / Myint, Soe (Committee member) / Arizona State University (Publisher)
Created2013
Description
DNA nanotechnology has been a rapidly growing research field in the recent decades, and there have been extensive efforts to construct various types of highly programmable and robust DNA nanostructures. Due to the advantage that DNA nanostructure can be used to organize biochemical molecules with precisely controlled spatial resolution, herein we used DNA nanostructure as a scaffold for biological applications. Targeted cell-cell interaction was reconstituted through a DNA scaffolded multivalent bispecific aptamer, which may lead to promising potentials in tumor therapeutics. In addition a synthetic vaccine was constructed using DNA nanostructure as a platform to assemble both model antigen and immunoadjuvant together, and strong antibody response was demonstrated in vivo, highlighting the potential of DNA nanostructures to serve as a new platform for vaccine construction, and therefore a DNA scaffolded hapten vaccine is further constructed and tested for its antibody response. Taken together, my research demonstrated the potential of DNA nanostructure to serve as a general platform for immunological applications.
ContributorsLiu, Xiaowei (Author) / Liu, Yan (Thesis advisor) / Chang, Yung (Thesis advisor) / Yan, Hao (Committee member) / Allen, James (Committee member) / Zhang, Peiming (Committee member) / Arizona State University (Publisher)
Created2012
Description
Land transformation under conditions of rapid urbanization has significantly altered the structure and functioning of Earth's systems. Land fragmentation, a characteristic of land transformation, is recognized as a primary driving force in the loss of biological diversity worldwide. However, little is known about its implications in complex urban settings where interaction with social dynamics is intense. This research asks: How do patterns of land cover and land fragmentation vary over time and space, and what are the socio-ecological drivers and consequences of land transformation in a rapidly growing city? Using Metropolitan Phoenix as a case study, the research links pattern and process relationships between land cover, land fragmentation, and socio-ecological systems in the region. It examines population growth, water provision and institutions as major drivers of land transformation, and the changes in bird biodiversity that result from land transformation. How to manage socio-ecological systems is one of the biggest challenges of moving towards sustainability. This research project provides a deeper understanding of how land transformation affects socio-ecological dynamics in an urban setting. It uses a series of indices to evaluate land cover and fragmentation patterns over the past twenty years, including land patch numbers, contagion, shapes, and diversities. It then generates empirical evidence on the linkages between land cover patterns and ecosystem properties by exploring the drivers and impacts of land cover change. An interdisciplinary approach that integrates social, ecological, and spatial analysis is applied in this research. Findings of the research provide a documented dataset that can help researchers study the relationship between human activities and biotic processes in an urban setting, and contribute to sustainable urban development.
ContributorsZhang, Sainan (Author) / Boone, Christopher G. (Thesis advisor) / York, Abigail M. (Committee member) / Myint, Soe (Committee member) / Arizona State University (Publisher)
Created2013
Description
Cancer is one of the most serious global diseases. We have focused on cancer immunoprevention. My thesis projects include developing a prophylactic primary and metastatic cancer vaccines, early cancer detection and investigation of genes involved in tumor development. These studies were focused on frame-shift (FS) antigens. The FS antigens are generated by genomic mutations or abnormal RNA processing, which cause a portion of a normal protein to be translated out of frame. The concept of the prophylactic cancer vaccine is to develop a general cancer vaccine that could prevent healthy people from developing different types of cancer. We have discovered a set of cancer specific FS antigens. One of the FS candidates, structural maintenance of chromosomes protein 1A (SMC1A) FS, could start to accumulate at early stages of tumor and be specifically exposed to the immune system by tumor cells. Prophylactic immunization with SMC1A-FS could significantly inhibit primary tumor development in different murine tumor models and also has the potential to inhibit tumor metastasis. The SMC1A-FS transcript was detected in the plasma of the 4T1/BALB/c mouse tumor model. The tumor size was correlated with the transcript ratio of the SMC1A-FS verses the WT in plasma, which could be measured by regular RT-PCR. This unique cancer biomarker has a practical potential for a large population cancer screen, as well as clinical tumor monitoring. With a set of mimotope peptides, antibodies against SMC1A-FS peptide were detected in different cancer patients, including breast cancer, pancreas cancer and lung cancer with a 53.8%, 56.5% and 12.5% positive rate respectively. This suggested that the FS antibody could be a biomarker for early cancer detection. The characterization of SMC1A suggested that: First, the deficiency of the SMC1A is common in different tumors and able to promote tumor initiation and development; second, the FS truncated protein may have nucleolus function in normal cells. Mis-control of this protein may promote tumor development. In summary, we developed a systematic general cancer prevention strategy through the variety immunological and molecular methods. The results gathered suggest the SMC1A-FS may be useful for the detection and prevention of cancer.
ContributorsShen, Luhui (Author) / Johnston, Stephen Albert (Thesis advisor) / Chang, Yung (Committee member) / Miller, Laurence (Committee member) / Sykes, Kathryn (Committee member) / Jacobs, Bertram (Committee member) / Arizona State University (Publisher)
Created2012