Digital Commons Network^™

Therapeutic Efficacy Of P53 Restoration In Mdm2-Overexpressing Tumors, Qin Li

Dissertations and Theses (Open Access)

The TP53 tumor suppressor is the most mutated gene in human cancers. Recent studies using genetically modified mouse models have shown that restoring the expression of wild-type p53 has led to tumor growth suppression in various types of tumors lacking p53. Other mechanisms, e.g. upregulation of Mdm2 levels, exist in tumors to inactivate the p53 pathway. Mdm2, an E3 ubiquitin-ligase that targets p53 for proteasomal degradation, is present at high levels in many tumors with wild-type p53. In this study, we probed the effects of restoring p53 activity in Mdm2-overexpressing tumors genetically using animal models. Here we demonstrated high levels …

Radiogenic Second Cancer Risk Differences In Female Hodgkin Lymphoma Patients Treated With Proton Versus Photon Radiotherapies, Kenneth L. Homann

Dissertations and Theses (Open Access)

Hodgkin Lymphoma (HL) is the most common cancer diagnosis of young adults in the United States. Advances in curative treatments for HL, including the use of photon radiation therapy (RT) techniques, have increased 10 year survival rates to approximately 90% among young patients. These RT treatments, however, contribute to an increased incidence of radiogenic second cancer (RSC) formation to the healthy tissue surrounding the tumor volume relative to the general population. These RSCs are the leading cause of death among long-term HL survivors. Proton therapy has been shown to reduce the therapeutic dose, and therefore, the risk of developing a …

Mtorc1 Signaling In Memory Formation And Dysfunction, Natalia S. Rozas De O'Laughlin

Dissertations and Theses (Open Access)

The mechanistic Target of Rapamycin Complex 1 (mTORC1) pathway integrates cellular availability of growth factors, energy and amino acids to regulate protein synthesis and autophagy. The mTORC1 pathway has also been shown to be required for memory consolidation, and its dysregulation is associated with many neurological disorders. MTORC1 is negatively regulated by the tuberous sclerosis complex (TSC1/2). When ATP and growth factors are available, TSC1/2 is inhibited and mTORC1 activity can be restored. In a complementary regulatory pathway, amino acids signal to mTORC1 through the Rag GTPases and Ragulator complex, which modulate the translocation of mTORC1 from the cytoplasm to …

Characterization Of The Role(S) Of Env Protein Of Human Endogenous Retrovirus-K In Multiple Human Cancers, Ming Li

Dissertations and Theses (Open Access)

Human endogenous retroviruses (HERVs) are remnants from ancient retroviral infections, and most of them are inactive in normal tissues. One family of HERV, HERV-K, is found to be associated with multiple human cancers including breast cancer, pancreatic cancer and melanoma, but the causal relationship between HERV-K and cancer is still unclear. Increased expression of HERV-K in melanoma cells correlates with malignant transformation, while a serological response to HERV-K in breast cancer or melanoma patients correlates with survival probability. However, the mechanism behind these observations remains obscure. Our laboratory reported that anti-HERV-K envelope (Env) protein antibodies show antitumor potential in targeting …

The Staphylococcus Pseudintermedius Adhesin Spsd Contains A Central Fibronectin-Binding Domain, Andrea S. Bordt

Dissertations and Theses (Open Access)

Staphylococcus pseudintermedius is a Gram-positive bacterium significant because of its ability to cause costly and difficult to treat veterinary infections worldwide. It exhibits several similarities to Staphylococcus aureus, however, very little is known about its surface adhesins. Surface adhesins in S. aureus are significant contributors to pathogenesis. S. pseudintermedius encodes the surface protein SpsD, which contains characteristics of the microbial surface components recognizing adhesive matrix molecules family and confers attachment of the heterologous host Lactococcus lactis to fibronectin. This work has identified a centrally-located fibronectin binding domain in SpsD which binds the 30 kDa N-terminal domain of fibronectin with …

Investigating Apoptosis Pathway In Chronic Lymphocytic Leukemia: Stromal Influence And Therapeutic Activation, Viralkumar M. Patel

Dissertations and Theses (Open Access)

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy. High levels of Bcl-2 and IAP family proteins are responsible for apoptotic-resistance and accumulation of mature CLL lymphocytes in bone-marrow, lymph nodes and peripheral blood. Besides pro-survival proteins, supporting stromal cells as well as soluble factors in the microenvironment of bone-marrow and lymph nodes provide survival advantage to CLL leukemic cells.

Though the stromal – leukemia cell interactions has been studied extensively, in-depth-knowledge on the regulation of apoptotic pathway proteins in the context of microenvironment is still limited. To address this, the first part of our study focused on comprehensive analysis of …

Characterizing The Effect Of Dasatinib On Anti-Tumor Immune Response And Exploring The Potential Of Combining Targeted Therapy And Immunotherapy In A C-Kit Mutant Mastocytoma Model, Yan Yang

Dissertations and Theses (Open Access)

Targeted therapy and immunotherapy eradicate malignant cells through different mechanisms, and the strengths and weaknesses of these two approaches are potentially complementary. Therefore, the combination of molecular targeted drugs with immune- based therapies is considered an attractive approach for improving the therapeutic efficacy of cancer treatment. The mutation and amplification of the c-KIT proto- oncogene are associated with multiple different cancer types, and multiple c-KIT inhibitors have been tested clinically. In spite of some encouraging results using these agents, most patients with c-KIT mutant cancers still relapse due to drug resistance. This also demonstrates the inherent limitation of molecular targeted …

Ventral Tegmental Area Neuronal Responses To Methylphenidate Correlated To Behavioral Responses Of Adolescent And Adult Rats, Zachary Jones

Dissertations and Theses (Open Access)

Methylphenidate (MPD) is a psychostimulant used in the treat treatment of attention deficit hyperactivity disorder and more recently is being used as a cognitive enhancement and recreational drug. Its therapeutic effects are not fully understood, nor are the long term effects of the drug on brain development. The ventral tegmental area (VTA) is a site of psychostimulant action thought to be involved in behavioral sensitization. The aim of the this study was to first determine if there are differences in neuronal responses between individuals, with respect to neuronal firing patterns in the ventral tegmental area (VTA), and whether these differences …

C-Jun N-Terminal Kinases Regulate Adenovirus-Mediated Autophagy And Antigen Presentation, Sarah R. Klein

Dissertations and Theses (Open Access)

Targeted immunotherapy with recombinant, oncolytic adenoviruses is under investigation for the treatment of cancer. Evidence indicates adenoviruses induce autophagy that is required for oncolysis, but the molecular regulation of autophagy in infected cells remains under investigation. Our data suggested the canonical pathway regulating starvation-induced autophagy was not implemented in adenovirus-induced autophagy; however, adenovirus infection triggered phosphorylation of c-Jun N-terminal kinases (JNK) that was essential for autophagy. Adenoviral replication within the host cell elicited JNK pathway activation leading to B cell lymphoma-2 (Bcl-2) phosphorylation. JNK-dependent Bcl-2 phosphorylation stimulated the dissociation of Bcl-2/beclin 1 heterodimers, enabling beclin 1 to initiate autophagy. Moreover, …

Basis For Targeting Met Activation Mediated Resistance To Pi3k Inhibition In Breast Cancer, Ana M. Gonzalez-Angulo

Dissertations and Theses (Open Access)

The identification of resistance mechanisms to emerging therapies, such as those targeting the PI3K pathway and the MET receptor, has the potential to benefit a significant number of patients with breast cancer. In this study we hypothesized that concurrent aberrations in PI3K and MET will render breast cancers resistant to therapies targeting each pathway, and that combination therapy targeting the PI3K and MET pathway will optimize therapy-effect by preventing the acquisition of resistance.

We analyzed cMET and phospho-cMET levels in 257 breast cancer samples and found that high levels of both the proteins were seen in all breast cancer subtypes, …

Characterization Of The Rna Binding And Rna Degrading Subunits Of The Eukaryotic Exosome, Borislava Tsanova

Dissertations and Theses (Open Access)

The exosome is an essential complex of ten proteins involved in the processing and degradation of many RNAs in the cell. These include various stable RNAs, mRNAs, and aberrant transcripts both in the nucleus and in the cytoplasm.

In this work I characterize the three members of the exosome “cap”, the RNA binding proteins Rrp4, Rrp40, and Csl4. I determine that in spite of their structural similarity, they each have a unique essential role. Second, I determine that two of the cap proteins Rrp4 and Rrp40 have a role in bridging subunits of the PH ring of the exosome. The …

Neural Correlates Of Audiovisual Speech Perception In Aphasia And Healthy Aging, Sarah H. Baum

Dissertations and Theses (Open Access)

Understanding speech in face-to-face conversation utilizes the integration of multiple pieces of information, most importantly the auditory vocal sounds and visual lip movements. Prior studies of the neural underpinnings of audiovisual integration in the brain have provided converging evidence to suggest that neurons within the left superior temporal sulcus (STS) provide a critical neural hub for the integration of auditory and visual information in speech. While most studies of audiovisual processing focus on neural mechanisms within healthy, young adults, we currently know very little about how changes to the brain can affect audiovisual integration in speech. To examine this further, …

Less Acting, More Doing: How Surface Acting Relates To Perceived Meeting Effectiveness And Other Employee Outcomes, Linda R. Shanock, Joseph A. Allen, Alexandra M. Dunn, Benjamin E. Baran, Cliff W. Scott, Steven G. Rogelberg

Psychology Faculty Publications

This study adds to the growing body of research on work meetings and extends the emotional labour literature beyond a service context by examining the relationship between surface acting during meetings and perceived meeting effectiveness. Additionally, the relationships of surface acting during meetings and perceived meeting effectiveness with time-lagged reports of intention to quit and emotional exhaustion 3 months later were investigated. Structural equation modelling of data from 178 working adults revealed negative relationships between surface acting and perceptions of meeting effectiveness. Perceived meeting effectiveness partially mediated the relationship between surface acting and both intention to quit and emotional exhaustion …

Association Between In Utero Arsenic Exposure, Placental Gene Expression, And Infant Birth Weight: A Us Birth Cohort Study, Dennis Liang Fei, Devin C. Koestler, Zhigang Li, Camilla Giambelli, Avencia Sanchez-Mejias, Julie Gosse, Carmen J. Marsit, Margaret R. Karagas, David J. Robbins

Dartmouth Scholarship

Epidemiologic studies and animal models suggest that in utero arsenic exposure affects fetal health, with a negative association between maternal arsenic ingestion and infant birth weight often observed. However, the molecular mechanisms for this association remain elusive. In the present study, we aimed to increase our understanding of the impact of low-dose arsenic exposure on fetal health by identifying possible arsenic-associated fetal tissue biomarkers in a cohort of pregnant women exposed to arsenic at low levels.

Methods: Arsenic concentrations were determined from the urine samples of a cohort of 133 pregnant women from New Hampshire. Placental tissue samples collected from …

Securing Information Technology In Healthcare, Denise Anthony, Andrew T. Campbell, Thomas Candon, Andrew Gettinger, David Kotz, Lisa A. Marsch, Andrés Molina-Markham, Karen M. Page, Sean W. Smith, Carl A. Gunter, M. Eric Johnson

Dartmouth Scholarship

Information technology (IT) has great potential to improve healthcare quality while also improving efficiency, and thus has been a major focus of recent healthcare reform efforts. However, developing, deploying and using IT that is both secure and genuinely effective in the complex clinical, organizational and economic environment of healthcare is a significant challenge. Further, it is imperative that we better understand the privacy concerns of patients and providers, as well as the ability of current technologies, policies, and laws to adequately protect privacy. The Securing Information Technology in Healthcare (SITH) workshops were created to provide a forum to discuss security …

Macroscopic Investigation Of Ionic- And Nano-Silver Toxicity To Soil Nitrification Process, Abdurrahman Masrahi

All Theses

The worldwide production of engineered nanoparticles (ENPs) has grown rapidly in our era because of the popular applications in industrial and consumer markets. Especially silver (Ag) NP is one of mostly common ENPs in our consumer products due to its unique antimicrobial property. However, release of AgNPs into environment through wastewater treatment plants poses a question that what impact AgNPs have on microbially mediated processes in environment (e.g., nutrient and trace element cycles). In the last decades, numerous toxicological studies of AgNPs on bacteria have been conducted in pure culture systems, and several different antimicrobial mechanisms of AgNPs have been …

The Effect Of Cell Culture Environment On Expression Of Cd44+, Ki67, And Foxo3a And Its Implications On The Role Of Foxo3a In Triple Negative Breast Cancer, Erin Vegter

All Theses

Triple negative breast cancer (TNBC) is a highly aggressive cancer, which is known for a high rate of metastasis and poor prognosis. TNBC cells are hypothesized to undergo the cellular processes epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET). The known prognostic markers CD44+ and Ki67 as well as the transcription factor and proposed tumor suppressor FoxO3a are thought to be indicators of EMT and MET activity in cancer cells. In order to better understand these processes an effective cell culture technique to mimic the tumor environment needs to be established. The purpose of this study was to determine if changing …

Bite Detection And Differentiation Using Templates Of Wrist Motion, Soheila Eskandari

All Theses

We introduce a new algorithm of bite detection during an eating activity based on template matching. The algorithm uses a template to model the motion of the wrist over a 6-second window centered on the time when a person takes a bite. We also determine if different types of bites (for example food vs. drink, or using different types of utensils) have different wrist motion templates. This method is implemented on 22,383 bites and 5 different types of templates are built. We then describe a method to recognize different types of bites using the set of templates. The obtained accuracy …

An Exploratory Study On The Effects Of Goal Alignment, Interventions, And Motivational Factors On Innovative Engineering Design Projects, Blake Linnerud

All Theses

Innovation has become an important facet of engineering design, both in industry and the academy. Many senior-level engineering design courses encourage students to develop innovative solutions to open design projects from industry sponsors. Like industry, these academic problems are tackled by teams of students. Student teams that function at the highest level are more likely to reach the innovative solutions for which they are searching. The research presented in this work focuses on two main areas: (1) understanding what motivates engineers when working on innovative design projects and (2) determining the effects of goal alignment interventions on design teams working …

Differences Between For-Profit, Non-Profit, And Public Hospitals In Medical And Non-Medical Categories: Costs And Outsourcing Decisions, Justin Knutter

All Theses

The purpose of this study is to measure and compare several potential differences between for-profit, non-profit, and public hospitals in medical and non-medical cost categories. To do this, costs associated with two medical and two non-medical categories for California short-term general care hospitals were broken down into several subsets in order to better understand exactly how and why each category behaves as it does. The results show significant differences for total costs between for-profits and the other hospital types across the board and a difference for outsourcing decisions between for-profits and the other hospital types for the medical categories but …

Methane Prediction By Nutrient Profiles In Ruminal Continuous Cultures Fed An All Forage Diet Of Bermudagrass Or Annual Ryegrass, Kaylin Young

All Theses

Extensive research has been done on the effect of diet on rumen methane (CH4) production, and on developing equations to accurately predict CH4 in cattle. However, the majority of this research has been gathered from feedlot cattle or cattle fed a total mixed ration (TMR). To date, no studies have examined nutrient correlations with CH4 when feeding an all pasture diet of warm season or cool season grasses. This study included two in vitro experiments, one with a warm season forage and one with a cool season forage to see which nutrient characteristics of each forage best correlated with CH4 …

Studies Of Molecular Mechanisms Of Cranberry Mediated Healthspan Promotion In Caenorhabditis Elegans, Sujay Guha

All Dissertations

Extensive studies have demonstrated the potent ability of many nutraceuticals to alleviate the symptoms of aging and stress. We found that cranberry extract (CBE) supplementation at an optimum concentration could prolong Caenorhabditis elegans (C. elegans) lifespan in a manner of daf-16 and osr-1 dependence. Considering that aging is a progressive degeneration of physiological functions, it is intriguing to know whether CBE consumption may delay the age-related degenerative changes in animals. Thus, we examined the effect of CBE consumption on healthspan in C. elegans populations with different ages and age-related disorders. Our results suggest that long-term CBE supplementation leads to a …

Vascular Nanomedicine: Site Specific Delivery Of Elastin Stabilizing Therapeutics To Damaged Arteries, Aditi Sinha

All Dissertations

Elastin, a structural protein in the extra-cellular matrix, plays a critical role in the normal functioning of blood vessels. Apart from performing its primary function of providing resilience to arteries, it also plays major role in regulating cell-cell and cell-matrix interactions, response to injury, and morphogenesis. Medial arterial calcification (MAC) and abdominal aortic aneurysm (AAA) are two diseases where the structural and functional integrity of elastin is severely compromised. Although the clinical presentation of MAC and AAA differ, they have one common underlying causative mechanism--pathological degradation of elastin. Hence prevention of elastin degradation in the early stages of MAC and …

Arachidonic Acid Reverses The Pyriproxyfen And Ibuprofen Induced Toxicity In Daphnia Magna, Gautam Kumar Ginjupalli

All Dissertations

Healthy reproduction and neonatal sex ratios of Daphnia are crucial to the health of the aquatic ecosystems in which Daphnia play principal roles in trophic transfer of nutrients. Combinations of environmental factors such as availability and quality of diet, overcrowding, hypoxia, reduced photoperiods and fall in ambient temperatures perturb normal parthenogeneic reproduction and induce sexual reproduction through male production. Male production provides a mechanism for overcoming specific stressors such as overcrowding and overwinter pond desiccation. However, it also induces a decrease in the Daphnia population that could have adverse implications on the pond ecosystem that depend on Daphnia . Interestingly, …

Biological Scaffolds For Peripheral Vascular Surgery, George Fercana

All Dissertations

The gold standards for small diameter peripheral vascular graft replacement are autologous arteries or veins; however, one-third of patients lack such vessels due to previous vessel harvesting or advanced vascular disease. A promising approach for patients in this category is tissue engineering with off-the-shelf biological vascular grafts. Three small diameter acellular scaffolds were developed and evaluated as vascular grafts. Porcine renal arteries (2-3 mm diameter, 20 mm length) were decellularized by immersion and stabilized with penta-galloyl glucose (PGG) with and without subsequent heparinization via carbodiimide chemistry. Bovine mammary (4-6 mm ID, 250 mm length) and femoral arteries (6-8 mm ID, …

Assessment Of The Human Factors Analysis And Classification System (Hfacs): Intra-Rater And Inter-Rater Reliability, Awatef Ergai

All Dissertations

Human error has been identified as the primary contributing cause for up to 80% of the accidents in complex, high risk systems such as aviation, oil and gas, mining and healthcare. Many models have been proposed to analyze these incidents and identify their causes, focusing on the human factor. One such safety model is the Human Factors Analysis and Classification System (HFACS), a comprehensive accident investigation and analysis tool which focuses not only on the act of the individual preceding the accident but on other contributing factors in the system as well. Since its development, HFACS has received substantial research …

The Effects Of Yoga Participation On Symptoms Associated With Menopause: A Mixed Methods Study, Brandi Crowe

All Dissertations

During midlife, it is expected that women will progress towards the biological state of menopause; the permanent condition of infertility due to alterations or diminution of reproductive hormones. Typically lasting 5-10 years, the menopausal transition is associated with symptoms including hot flashes, night sweats, interrupted sleep, anxiety, forgetfulness, and inconsistent mood. As these symptoms often hinder a women's successful functioning in everyday life, hormone therapy is commonly prescribed as a means for diminishing symptoms. However, many women are seeking alternative/complementary treatments that can assist in managing menopausal symptoms due to the detrimental health-risks associated with the use of conventional therapies. …

The Roles Of Phenotypic Plasticity And Genotypic Specialization In High Altitude Adaptation, Danielle M. Tufts

School of Biological Sciences: Dissertations, Theses, and Student Research

In vertebrates living at high altitude, arterial hypoxemia may be ameliorated by reversible changes in the oxygen-carrying capacity of the blood (regulated by erythropoiesis) and/or changes in blood–oxygen affinity (regulated by allosteric effectors of hemoglobin function). These hematological traits often differ between taxa that are native to different elevational zones, but it is often unknown whether the observed physiological differences reflect fixed, genetically based differences or environmentally induced acclimatization responses (phenotypic plasticity). Here, we report measurements of hematological traits related to blood–O₂ transport in populations of deer mice (Peromyscus maniculatus) that are native to high- and low-altitude …

An Efficient Two Sample Capture-Recapture Model With High Recaptures, Danjuma Jibasen, Yusuf J. Adams

CBN Journal of Applied Statistics (JAS)

This paper proposed an efficient two sample capture-recapture model (Ma) with high recaptures and compared it with the existing models like the model of no factor effect (Mo), behavioral response model (Mb) and the Petersen model (Ms), using simulated data. We found that the Petersen model provides a better estimate of the population size when the observations follow a hypergeometric distribution and the population is overestimated when recapture is high. It was also found that the proposed model provides a better estimator of the population size than the existing ones when the recapture is high. This model is particularly useful …

Recent Developments In Slovak Competition Law - Legislation And Case Law Review, Zuzana Šabová, Katarína Fodorová, Daniela Lukáčová

Yearbook of Antitrust and Regulatory Studies

No abstract provided.