Medicine and Health Sciences Commons^™

Discovery Of Dihydroartemisinin And Dasatinib Drug Combination To Cure Pooroutcome Bcr-Abl+ Acute Lymphoblastic Leukemia, Harpreet Singh

Theses and Dissertations (ETD)

Oncogenic signaling by the Philadelphia chromosome-encoded BCR-ABL fusion kinase initiates and drives both Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myelogenous leukemia (CML). Food and Drug Administration (FDA)- approved BCR-ABL-specific kinase inhibitors (BCR-ABL–KIs) imatinib, dasatinib and nilotinib induce prolonged remissions in CML but poor leukemia-reduction and relapse-control in Ph+ ALL. The relative primary BCR-ABL–KI-resistance in Ph+ ALL patients carrying predominantly BCR-ABLWT disease cannot be attributed to drug-resistant BCR-ABL mutations (BCR-ABLMUTANTS), and remains poorly understood.

We established a cell-based platform to evaluate the modulation of anti-Ph+ ALL activity of drugs by both tumor-extrinsic cytokines normally present in the leukemia …

Investigation Of Enhancement Of Furosemide Solubilization With Cyclodextrins And A Novel Octenyl Succinate Anhydride Starch, Rui Zhu

Theses and Dissertations (ETD)

Solubility behavior is one of the most challenging aspects for drug commercialization and often the main reason of drug that do not reach to its full potential. Now nearly 60% new chemical entities possess solubility problems, whereas practically no drug products with less than 10 µg/ml solubility in 70’s or 80’s. There is an ever increasing need to develop new formulation techniques and exicipients with novel mechanisms of action. Various techniques have been applied to enhance the drug solubility such as co-solvents, particle size reduction, lipid based drug delivery systems, nanosuspension, use of surfactants, salt formation, cyclodextrin complexes and solid …

Melanopsin Mediates Retrograde Visual Signaling In The Retina, Dao-Qi Zhang, Michael A. Belenky, Patricia J. Sollars, Gary E. Pickard, Douglas G. Mcmahon

School of Veterinary and Biomedical Sciences: Faculty Publications

The canonical flow of visual signals proceeds from outer to inner retina (photoreceptors→bipolar cells→ganglion cells). However, melanopsin-expressing ganglion cells are photosensitive and functional sustained light signaling to retinal dopaminergic interneurons persists in the absence of rods and cones. Here we show that the sustained-type light response of retinal dopamine neurons requires melanopsin and that the response is mediated by AMPA-type glutamate receptors, defining a retrograde retinal visual signaling pathway that fully reverses the usual flow of light signals in retinal circuits.

The Effect Of Exercise Training Modality On Serum Brain Derived Neurotrophic Factor Levels In Individuals With Type 2 Diabetes, Damon L. Swift, Neil M. Johannsen, Valerie H. Myers, Conrad P. Earnest, Jasper A. J. Smits, Steven N. Blair, Timothy S. Church

Faculty Publications

Introduction: Brain derived neurotrophic factor (BDNF) has been implicated in memory, learning, and neurodegenerative disease. However, the relationship of BDNF with cardiometabolic risk factors is unclear, and the effect of exercise training on BDNF has not been previously explored in individuals with type 2 diabetes.

Methods: Men and women (N=150) with type 2 diabetes were randomized to an aerobic exercise (aerobic), resistance exercise (resistance), or a combination of both (combination) for 9 months. Serum BDNF levels were evaluated at baseline and follow-up from archived blood samples.

Results: Baseline serum BDNF was not associated with fitness, body composition, anthropometry, glucose control, …

The Ventricular Volume Variability Study Of The Pediatric Heart Network: Study Design And Impact Of Beat Averaging And Variable Type On The Reproducibility Of Echocardiographic Measurements In Children With Chronic Dilated Cardiomyopathy., Steven D. Colan, Girish S. Shirali, Renee Margossian, Dianne Gallagher, Karen Altmann, Charles Canter, Shan Chen, Fraser Golding, Elizabeth Radojewski, Michael Camitta, Michael Carboni, Jack Rychik, Mario Stylianou, Lloyd Y. Tani, Elif Seda Selamet Tierney, Yanli Wang, Lynn A. Sleeper, Pediatric Heart Network Investigators

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Clinical trials often rely on echocardiographic measures of left ventricular size and function as surrogate end points. However, the quantitative impact of factors that affect the reproducibility of these measures is unknown. To address this issue, the National Heart, Lung, and Blood Institute-funded Pediatric Heart Network designed a longitudinal observational study of children with known or suspected dilated cardiomyopathy aged 0 to 22 years from eight pediatric clinical centers.

METHODS: Clinical data were collected together with 150 echocardiographic indices of left ventricular size and function. Separate observers performed duplicate echocardiographic imaging. Multiple observers performed measurements from three cardiac cycles …

Healing Hands Reviewing The Potential Applications Of Energy Therapies To Redirect Pain During Labor And Childbirth, Cecilia Dinh

HIM 1990-2015

The birth experience is a highly subjective phenomenon that leaves a lasting impression for mothers and their families and friends. Although the passage of a child from the mother's womb into the world is typically joyous, the experience is not always as positive. Negative physical and psychological factors may greatly impact a woman's impression of the childbirth experience. Among childbearing women, the two main concerns of childbirth are pain and safe management. Similarly among healthcare providers, management of labor pain is one of the main goals of maternity care. Pain is a highly subjective phenomenon that is expected during the …

Minimizing Incivility In The Workplace To Increase Retention Of New Graduate Nurses, Amanda D'Ambra

HIM 1990-2015

Efforts to maintain a sufficient nurse workforce are hampered by dissatisfaction with the work environment. Incivility in the work environment is a major source of dissatisfaction. A healthy work environment is associated with higher levels of job satisfaction and improved retention. New graduate transition programs have been recommended as a deterrent to high levels of turnover associated within the first two years of employment, some of which is related to incivility. The purpose of this thesis was to examine the influence of incivility in the nursing workplace on new graduate job satisfaction and determine if there is an association between …

Nursing Attitudes Toward The Use Of Reprocessed Single-Use Medical Devices, Laura Maben-Tenney

HIM 1990-2015

Background: Before the implementation of single-use devices (SUD) in health care, medical equipment was sterilized and reused. Now many medical devices are used once and then thrown away, contributing to the 5.9 million tons of medical waste produced yearly. This project explores nursing attitudes toward single-use medical devices, evaluates current recycling practices and examines whether student nurses would be likely to use reprocessed SUDs in their practice if given the option. Methodology: After obtaining IRB approval, students enrolled in nursing research courses were invited to participate in this exploratory study. 157 undergraduate nursing students completed the 46-question survey. Descriptive statistics …

Clinical Review Of Pediatric Pilocytic Astrocytomas Treated At A Tertiary Care Hospital In Pakistan, Muhib A. Khan, Saniya Siraj Godil, Halima Tabani, Sukaina A Panju, S. Ather Enam

Department of Surgery Docs

Abstract Background: Pilocytic Astrocytoma (PA) is a common type of brain tumor in the pediatric population. They have a fairly good prognosis. This study describes PAs in detail, with a focus on the demographic factors, presenting features, management and prognosis, and aims, to identify the negative outcome predictors in our population, which can affect the course of the disease. This article will add to the understanding of PAs from a third world perspective. Methods: The Aga Khan University medical records (1995 – 2007) were reviewed, to study the clinical features, management, and outcome of patients (0 – 15 years) with …

Effects Of Pristane On Growth Of Pink Salmon (Oncorhynchus Gorbuscha), Brielle D. Kemis, Bonita Nelson

STAR Program Research Presentations

Pristane is a naturally occurring hydrocarbon that is generated by copepods in marine ecosystems. Organisms that eat copepods do not readily metabolize pristane, which causes it to accumulate throughout the marine food web. Understanding how pristane affects marine fish is essential because pristane is often used as a bioindicator in lab studies and may be influencing results in those studies. Also, this hydrocarbon may significantly reduce growth of marine fish in the wild. A previous study indicated that pristane is an appetite suppressant and growth retardant in fish. However, the study implemented a feeding regime with unnaturally high levels of …

Functional Story-Based Instruction About Hand Washing To Teach Emergent Literacy Skills And Hand Washing Skills To Three Elementary Students With Significant Intellectual Disabilities, Glenda Hyer

Doctoral Dissertations and Projects

This study used a multiple baseline across participants design to evaluate the effects of Functional Story-Based Instruction about hand washing on the independent and correct emergent literacy responses and independent and correct hand washing responses of three elementary students with significant intellectual disabilities in small inclusive reading groups. Data were collected during baseline, intervention, and generalization phases, and then analyzed using visual analyses. The result of the study indicated a functional relationship between the independent and dependent variables. Social validity indicated Functional Story-Based Instruction about hand washing was an effective approach for teaching both emergent literacy skills and hand washing …

Relationship Of A Nutrition Intervention Class For Middle School Students On Nutrition Knowledge And Attitudes, Kathy Hood

Doctoral Dissertations and Projects

A pre-test post-test nonequivalent group design was utilized to investigate the role nutrition education has on a student's choice to eat healthy foods. The Nutrition Essentials: Teaching Tools for Healthy Choices nutrition module was used to teach clinically based nutrition. The research used rural Georgia seventh and eighth grade students' to evaluate the effects of nutrition education on the students' nutrition knowledge and attitudes using the SPAN student questionnaire. MANOVA was used to determine if changes occurred between the control and experimental groups. Results of the study showed that the short term study did not improve student nutrition knowledge or …

Pastoral Care: A New Model For Assessing The Spiritual Needs Of Hospitalized Patients, Douglas Robinson

Doctoral Dissertations and Projects

Hospitalized patients are at an elevated risk of suffering from spiritual distress. Patients value and expect having spiritual and emotional needs met when hospitalized. A direct correlation exists between spiritual and physical health, making spiritual assessment and care a pastoral priority. Research indicates a lack of proper training for pastors making hospital visits. The purpose of this project is to provide pastors with resources and understanding of spiritual assessment of hospitalized patients. This project also provides pastors with a template for a new model of spiritual assessment to aid with establishing a spiritual assessment tool to meet their ministry needs, …

Genetic Predictors Of Clinical Outcomes In Non-Small Cell Lung Cancer Patients, Xia Pu

Dissertations and Theses (Open Access)

Lung cancer is the leading cause of cancer-related mortality in the US. Emerging evidence has shown that host genetic factors can interact with environmental exposures to influence patient susceptibility to the diseases as well as clinical outcomes, such as survival and recurrence. We aimed to identify genetic prognostic markers for non-small cell lung cancer (NSCLC), a major (85%) subtype of lung cancer, and also in other subgroups. With the fast evolution of genotyping technology, genetic association studies have went through candidate gene approach, to pathway-based approach, to the genome wide association study (GWAS). Even in the era of GWAS, pathway-based …

Characterization And Treatment Of A Novel Mouse Model Of Tsc-Associated Autism, Rachel Michelle Reith

Dissertations and Theses (Open Access)

Tuberous sclerosis complex (TSC) is a dominant tumor suppressor disorder caused by mutations in either TSC1 or TSC2. The proteins of these genes form a complex to inhibit the mammalian target of rapamycin complex 1 (mTORC1), which controls protein translation and cell growth. TSC causes substantial neuropathology, often leading to autism spectrum disorders (ASDs) in up to 60% of patients. The anatomic and neurophysiologic links between these two disorders are not well understood. However, both disorders share cerebellar abnormalities. Therefore, we have characterized a novel mouse model in which the Tsc2 gene was selectively deleted from cerebellar Purkinje cells (Tsc2f/-;Cre). …

Evaluation Of The Effectiveness Of Anisotropic Analytical Algorithm In Flattened And Flattening-Filter-Free Beams For High Energy Lung Dose Delivery Using The Radiological Physics Center Lung Phantom, Roman Repchak, David Scott Followill

Dissertations and Theses (Open Access)

The effectiveness of the Anisotropic Analytical Algorithm (AAA) implemented in the Eclipse treatment planning system (TPS) was evaluated using theRadiologicalPhysicsCenteranthropomorphic lung phantom using both flattened and flattening-filter-free high energy beams. Radiation treatment plans were developed following the Radiation Therapy Oncology Group and theRadiologicalPhysicsCenterguidelines for lung treatment using Stereotactic Radiation Body Therapy. The tumor was covered such that at least 95% of Planning Target Volume (PTV) received 100% of the prescribed dose while ensuring that normal tissue constraints were followed as well. Calculated doses were exported from the Eclipse TPS and compared with the experimental data as measured using thermoluminescence detectors …

Understanding The Influence Of Photon Energy On 6mv Non Reference Dosimetry And Ct Dosimetry Using Tld And Osld, Sarah B. Scarboro

Dissertations and Theses (Open Access)

Measurement of the absorbed dose from ionizing radiation in medical applications is an essential component to providing safe and reproducible patient care. There are a wide variety of tools available for measuring radiation dose; this work focuses on the characterization of two common, solid-state dosimeters in medical applications: thermoluminescent dosimeters (TLD) and optically stimulated luminescent dosimeters (OSLD).

There were two main objectives to this work. The first objective was to evaluate the energy dependence of TLD and OSLD for non-reference measurement conditions in a radiotherapy environment. The second objective was to fully characterize the OSLD nanoDot in a CT environment, …

The New Role Of Proprotein Convertase Subtilisin/Kexin Type 9: A Connection Of Proprotein Convertase Subtilisin/Kexin Type 9, Apolipoprotein B, And Autophagy, Hua Sun

Dissertations and Theses (Open Access)

Plasma low-density lipoprotein (LDL) levels are positively correlated with the incidence of coronary artery disease. In the circulation, the plasma LDL clearance is mainly achieved by the uptake via LDL receptor (LDLR). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a newly discovered gene, playing an important role in LDL metabolism. Gain-of-function mutations of PCSK9 lead to hypercholesterolemia and loss-of-function mutations of PCSK9 are associated with decrease of LDL cholesterol. The effects of PCSK9 on cholesterol levels are the consequence of a strong interaction between the catalytic domain of PCSK9 and epidermal growth factor-like repeat A (EGF-A) domain of …

Development And Implementation Of The Use Of Optically Stimulated Luminescent Detectors In The Radiological Physics Center Anthropomorphic Quality Assurance Phantoms, Jennelle Bergene

Dissertations and Theses (Open Access)

The Radiological Physics Center (RPC) uses both on-site and remote reviews to credential institutions for participation in clinical trials. Anthropomorphic quality assurance (QA) phantoms are one tool the RPC uses to remotely audit institutions, which include thermoluminescent dosimeters (TLDs) and radiochromic film. The RPC desires to switch from TLD as the absolute dosimeter in the phantoms, to optically stimulated luminescent dosimeters (OSLDs), but a problem lies in the angular dependence exhibited by the OSLD. The purpose of this study was to characterize the angular dependence of OSLD and establish a correction factor if necessary, to provide accurate dosimetric measurements as …

The Regulation Of Mtorc2 Kinase Activity And Complex Integrity, Chien-Hung Chen

Dissertations and Theses (Open Access)

Growth factor signaling promotes anabolic processes via activation of the

PI3K-Akt kinase cascade. Deregulation of the growth factor-dependent PI3K-Akt

pathway was implicated in tumorigenesis. Akt is an essential serine/threonine

protein kinase that controls multiple physiological functions such as cell growth,

proliferation, and survival to maintain cellular homeostasis. Recently, the

mammalian Target of Rapamycin Complex 2 (mTORC2) was identified as the

main Akt Ser-473 kinase, and Ser-473 phosphorylation is required for Akt

hyperactivation. However, the detailed mechanism of mTORC2 regulation in

response to growth factor stimulation or cellular stresses is not well understood.

In the first project, we studied the regulation …

Low Reactive Oxygen Species And High Glycolysis In Glioblastoma Stem Cells:Mechanisms And Therapeutic Implications, Feng Wang

Dissertations and Theses (Open Access)

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with poor prognosis due in part to drug resistance and high incidence of tumor recurrence. The drug resistant and cancer recurrence phenotype may be ascribed to the presence of glioblastoma stem cells (GSCs), which seem to reside in special stem-cell niches in vivo and require special culture conditions including certain growth factors and serum-free medium to maintain their stemness in vitro. Exposure of GSCs to fetal bovine serum (FBS) can cause their differentiation, the underlying mechanism of which remains unknown. Reactive oxygen species (ROS) play an important role …

Role Of Stat3 In Keratinocyte Stem Cells During Skin Tumorigenesis, Dharanija Rao

Dissertations and Theses (Open Access)

STATs play crucial roles in a wide variety of biological functions, including development, proliferation, differentiation, migration and in cancer development. In the present study, we examined the impact of Stat3 deletion or activation on behavior of keratinocytes, including keratinocyte stem cells (KSCs). Deletion of Stat3 specifically in the bulge region of the hair follicle using K15.CrePR1 X Stat3^fl/fl mice led to decreased tumor development by altering survival of bulge region KSCs. To further understand the role of KSCs in skin tumorigenesis, K5.Stat3C transgenic (Tg) mice which express a constitutively active/dimerized form of Stat3 called Stat3C via the bovine keratin …

Transcriptional And Post-Translational Mechanisms Contribute To Maintenance Of Rest In Neural Tumors, Akanksha Singh

Dissertations and Theses (Open Access)

The RE-1 silencing transcription factor (REST) is an important regulator of normal nervous system development. It negatively regulates neuronal lineage specification in neural progenitors by binding to its consensus RE-1 element(s) located in the regulatory region of its target neuronal differentiation genes. The developmentally coordinated down-regulation of REST mRNA and protein in neural progenitors triggers terminal neurogenesis.

REST is overexpressed in pediatric neural tumors such as medulloblastoma and neuroblastoma and is associated with poor neuronal differentiation. High REST protein correlate with poor prognosis for patients with medulloblastoma, however similar studies have not been done with neuroblastoma patients. Mechanism(s) underlying elevated …

The Functional Organization Of Synaptic Vesicle Pools In A Retinal Bipolar Neuron, Proleta Datta

Dissertations and Theses (Open Access)

Ribbon synapses are found in sensory systems and are characterized by ‘ribbon-like’ organelles that tether synaptic vesicles. The synaptic ribbons co-localize with sites of calcium entry and vesicle fusion, forming ribbon-style active zones. The ability of ribbon synapses to maintain rapid and sustained neurotransmission is critical for vision, hearing and balance. At retinal ribbon synapses, three vesicle pools have been proposed. A rapid pool of vesicles that are docked at the plasma membrane, and whose fusion is limited only by calcium entry, a releasable pool of ATP-primed vesicles whose size also correlates with the number of ribbon-tethered vesicles, and a …

Targeting Traf6 For Cancer Therapeutical Development, John K. Morrow

Dissertations and Theses (Open Access)

Tumor necrosis factor (TNF)-Receptor Associated Factors (TRAFs) are a family of signal transducer proteins. TRAF6 is a unique member of this family in that it is involved in not only the TNF superfamily, but the toll-like receptor (TLR)/IL-1R (TIR) superfamily. The formation of the complex consisting of Receptor Activator of Nuclear Factor κ B (RANK), with its ligand (RANKL) results in the recruitment of TRAF6, which activates NF-κB, JNK and MAP kinase pathways. TRAF6 is critical in signaling with leading to release of various growth factors in bone, and promotes osteoclastogenesis. TRAF6 has also been implicated as an oncogene in …

Phenothiazines Induce Abortive Autophagy Leading To Cancer Cell Death, Catherine T. Charles

Dissertations and Theses (Open Access)

Autophagy is an evolutionarily conserved process that functions to maintain homeostasis and provides energy during nutrient deprivation and environmental stresses for the survival of cells by delivering cytoplasmic contents to the lysosomes for recycling and energy generation. Dysregulation of this process has been linked to human diseases including immune disorders, neurodegenerative muscular diseases and cancer.

Autophagy is a double edged sword in that it has both pro-survival and pro-death roles in cancer cells. Its cancer suppressive roles include the clearance of damaged organelles, which could otherwise lead to inflammation and therefore promote tumorigenesis. In its pro-survival role, autophagy allows cancer …

Transcriptional Regulation Of Profilin Is Required For Drosophila Larval Wound Closure, Amanda Brock

Dissertations and Theses (Open Access)

Injury is an inevitable part of life, making wound healing essential for survival. In postembryonic skin, wound closure requires that epidermal cells recognize the presence of a gap and change their behavior to migrate across it. In Drosophila larvae, wound closure requires two signaling pathways (the Jun N-terminal kinase (JNK) pathway and the Pvr receptor tyrosine kinase signaling pathway) and regulation of the actin cytoskeleton. In this and other systems, it remains unclear how the signaling pathways that initiate wound closure connect to the actin regulators that help execute wound- induced cell migrations. Here we show that chickadee, which encodes …

Platelets And Anti-Angiogenic Resistance In Ovarian Carcinoma, Justin N. Bottsford-Miller

Dissertations and Theses (Open Access)

Background: Resistance to targeted anti-angiogenic therapy is a growing clinical concern given the disappointing clinical impact of anti-angiogenic. Platelets represent a component of the tumor microenvironment that are implicated in metastasis and represent a significant reservoir of angiogenic regulators. Thrombocytosis has been shown to be caused by malignancy and associated with adverse clinical outcomes, however the causal connections between these associations remain to be identified.

Materials and Methods: Following IRB approval, patient data were collected on patients from four U.S. centers and platelet levels through and after therapy were considered as indicators of recurrence of disease. In vitro effects of …

Development And Implementation Of A Remote Audit To Ol For High Dose Rate (Hdr) 192ir Brachytherapy Using Optically Stimulated Luminescence Dosimetry, Kevin Casey

Dissertations and Theses (Open Access)

This work aimed to create a mailable and OSLD-based phantom with accuracy suitable for RPC audits of HDR brachytherapy sources at institutions participating in NCI-funded cooperative clinical trials. An 8 × 8 × 10 cm³ prototype with two slots capable of holding nanoDot Al₂O₃:C OSL dosimeters (Landauer, Glenwood, IL) was designed and built. The phantom has a single channel capable of accepting all ¹⁹²Ir HDR brachytherapy sources in current clinical use in the United States. Irradiations were performed with an ¹⁹²Ir HDR source to determine correction factors for linearity with dose, dose rate, …

Regulation Of To Xin Synthesis By Clostridium Difficile, Charles Darkoh

Dissertations and Theses (Open Access)

Clostridium difficile is the leading definable cause of nosocomial diarrhea worldwide due to its virulence, multi-drug resistance, spore-forming ability, and environmental persistence. The incidence of C. difficile infection (CDI) has been increasing exponentially in the last decade. Virulent strains of C. difficile produce either toxin A and/or toxin B, which are essential for the pathogenesis of this bacterium. Current methods for diagnosing CDI are mostly qualitative tests that detect the bacterium, the toxins, or the toxin genes. These methods do not differentiate virulent C. difficile strains that produce active toxins from non-virulent strains that do not produce toxins or produce …