A Novel Caspase 8 Selective Small Molecule Potentiates Trail-Induced Cell Death, Octavian Bucur, Gabriel Gaidos, Achani Yatawara, Bodvael Pennarun, Chamila Rupasinghe, Jérémie Roux, Stefan Andrei, Bingqian Guo, Alexandra Panaitiu, Maria Pellegrini, Dale Mierke, Roya Khosravi-Far

Dartmouth Scholarship

Recombinant soluble TRAIL and agonistic antibodies against TRAIL receptors (DR4 and DR5) are currently being created for clinical cancer therapy, due to their selective killing of cancer cells and high safety characteristics. However, resistance to TRAIL and other targeted therapies is an important issue facing current cancer research field. An attractive strategy to sensitize resistant malignancies to TRAIL-induced cell death is the design of small molecules that target and promote caspase 8 activation. For the first time, we describe the discovery and characterization of a small molecule that directly binds caspase 8 and enhances its activation when combined with TRAIL, …

Deciphering Signals From Huntington’S Disease Brains In The Search For Treatments, Kenneth P. Serbin

At Risk for Huntington's Disease

No abstract provided.

The Medical Response To The Black Death, Joseph A. Legan

Senior Honors Projects, 2010-2019

This paper discusses the medical response to the Black Death in both Europe and the Middle East. The Black Death was caused by a series of bacterial strands collectively known as Yersinia pestis. The Plague originated in the Mongolian Steppes. It was spread westward by the east-west trading system. Once it arrived in the Crimea in 1346, Italian merchants helped spread it throughout the Mediterranean. Medicine in Europe and the Middle East were centered on Galen’s theory of humors. There were many religious explanations for the Plague, but the main medical explanation was the spread of bad air, or …

Structural Studies Of The Ig58 Domain Of The Giant Muscle Protein Obscurin, Matthew C. Oehler

Senior Honors Projects, 2010-2019

Obscurin (720-900 kD) is a giant sarcomeric signaling protein that is the only known link

between the cytoskeleton and the surrounding membrane structure. Mutations to obscurin

and to obscurin binding partners have been linked to human muscle diseases such as

hypertrophic cardiomyopathies and muscular dystrophy. These diseases likely occur due

to the abrogation of specific molecular interactions necessary for suitable function. To

more fully understand how specific mutations lead to disease, here we solve the highresolution

structure of obscurin Ig58. The literature shows that an Arg8Gln mutation to

the Ig58 domain of obscurin is associated with hypertrophic cardiomyopathy (HCM).

Chemical …

Using Technology To Improve Diabetes Self-Management Within A Federally Qualified Community Health Center, Lisa Diane Morgan

Doctoral Projects

The Patient Centered Medical Home (PCMH) concept places the patient and family at the center of healthcare. The patient becomes actively involved in their own care. One aspect of PCMH is managing care and increasing chronic disease self-management. Diabetes, a chronic disease, is a leading diagnosis among the patients served by the federally qualified community health center (FQCHC). The prevalence of diabetes in Mississippi in 2012 was 12.3%. The purpose of this DNP Capstone project was to implement a pilot study to increase diabetes self-management knowledge. The program utilized the current technology of text messaging to send biweekly supportive and …

The Effect Of Run Sprint Interval Training On Diabetic Metabolic Markers In Prediabetic Adults, Kathryn L. Hilovsky

Masters Theses, 2010-2019

Abstract

Purpose: The primary purpose of this study was to compare the effects of an 8-week run-sprint interval training (R-SIT) and continuous moderate-intensity training (MIT) on fasting blood glucose, HbA1c, insulin sensitivity, and β-cell function in sedentary, prediabetic adults. Secondary outcomes of the study included anthropometric, body composition variables, and aerobic capacity.

Methods: Sedentary, physician diagnosed prediabetic individuals were randomized into R-SIT (n=7, BMI 36.76 ± 9.79) or MIT (n=8, BMI 40.59 ± 12.49) interventions. Subjects participated in supervised exercise three times a week and attended a Diabetes Prevention Program course, once weekly. R-SIT participants performed 4-6 x 30-second …

The Effect Of An Educational Intervention On Knowledge And Intent To Participate In Cervical Cancer Screening, Ann Marie Trapp

Evidence-Based Practice Project Reports

Globally, cervical cancer ranks third among cancers affecting women (Arbyn et al., 2013). In the United States, approximately 12,000 women are diagnosed with cervical cancer and approximately 4,000 women die yearly (Centers for Disease Control and Prevention, 2014). Papanicolaou (Pap) screening is an effective means of detecting precancerous cell changes of the cervix with early cervical cancer diagnosis carrying a 91% five-year survival rate (Gonzalez et al., 2012). The purpose of this evidence-based practice project was to identify interventions that increase adherence to cervical cancer screening and to implement best practices to reduce unnecessary deaths related to late diagnoses of …

Effect Of Cmvil-10 On Exosome Production By Human Breast Cancer Cells, Susanna N. Basappa

Undergraduate Honors Theses

Human cytomegalovirus (HCMV) is a ubiquitous virus that infects 70-90% of the general population, primarily the immunocompromised, but has been implicated in several forms of cancer, including breast cancer. Breast cancer is the second leading cause of cancer related deaths in women in North America, usually from metastasis. Exosomes are 30-100nm vesicles produced by most cells which carry protein and RNA to cells in their microenvironment. The aim of this study is to investigate the impact of HCMV-infection of a secreted viral cytokine, cmvIL-10, on exosome production by highly metastatic breast cancer cells.

MDA-MB-231 cells were cultured in vitro, …

Structural And Functional Interactions Between Bro1 Domain Of Human Alix Protein And Nucleocapsid Packaging Rna Complex From Hiv, Scott Gross

Graduate School of Biomedical Sciences Theses and Dissertations

A virus is only as powerful as its ability to spread. Enveloped retroviruses, namely HIV-1, use exocytosis pathways that normal host cells use to release particles from the plasma membrane. The main pathways of interest in this study are the Endosomal Sorting Complex Required for Transport (ESCRT) and adjacent ALIX pathways. The ESCRT pathway is especially important for degradation of receptor/cargo complexes that form Multi-Vesicular Bodies (MVBs). Currently, there is no known therapy that targets this endosomal pathway, which would prevent the spread of the virus to other cells. The virus has adapted to jump from pathway to pathway when …

Age-Dependent Breakdown Of The Blood Brain Barrier And Associated Changes In S100b Ko Mice, Eric V. Brown

Graduate School of Biomedical Sciences Theses and Dissertations

Autoantibodies play an important role in many autoimmune diseases. Recent research has shown that breakdown of the blood brain barrier (BBB) occurs concomitant to generation of brain reactive autoantibodies in many neurodegenerative diseases, which serve as biomarkers and drivers of pathology. SI00B, a calcium binding protein found most highly expressed in astrocytes which ensheathe the BBB, has many functions in neural development and signaling. Currently literature indicates that S100B KO mice develop normally, with no phenotypic abnormalities. Here, it is demonstrated that S100B KO mice seem to develop a chronic BBB breakdown similar to that seen in human neurodegenerative diseases. …

Adapting The Standard Sir Disease Model In Order To Track And Predict The Spreading Of The Ebola Virus Using Twitter Data, Armin Smailhodzic

Masters Theses & Specialist Projects

A method has been developed to track infectious diseases by using data mining of active Twitter accounts and its efficacy was demonstrated during the West African Ebola outbreak of 2014. Using a meme based n-gram semantic usage model to search the Twitter database for indications of illness, flight and death from the spread of Ebola in Africa, principally from Guinea, Sierra Leone and Liberia. Memes of interest relate disease to location and severity and are coupled to the density of Tweets and re-Tweets. The meme spreads through the community of social users in a fashion similar to nonlinear wave propagation- …

Race And Ethnicity, Obesity, Metabolic Health, And Risk Of Cardiovascular Disease In Postmenopausal Women, Michelle D. Schmiegelow, Haley Hedlin, Rachel H. Mackey, Lisa W. Martin, Mara Z. Vitolins, Marcia L. Stefanick, Marco V. Perez, Matthew Allison, Mark A. Hlatky

Medicine Faculty Publications

Background It is unclear whether obesity unaccompanied by metabolic abnormalities is associated with increased cardiovascular disease risk across racial and ethnic subgroups.

Methods and Results We identified 14 364 postmenopausal women from the Women's Health Initiative who had data on fasting serum lipids and serum glucose and no history of cardiovascular disease or diabetes at baseline. We categorized women by body mass index (in kg/m²) as normal weight (body mass index 18.5 to P=0.05). Obese black women without metabolic syndrome had higher adjusted risk (HR 1.95) than obese white women (HR 1.07; interaction P=0.02). Among women with …

Effects Of Heat Stress On Arterial Compliance In Smokers: A Pilot Study, Erin Dougherty

Health, Human Performance and Recreation Undergraduate Honors Theses

Arterial compliance (i.e., arterial elasticity) is a major contributor to the pathophysiology of cardiovascular disease (CVD) and has been recognized as an independent risk factor for CVD. Smokers have poor arterial compliance compared to non-smokers. In non-smokers, passive heat stress has been shown to acutely improve arterial compliance. It is unknown how passive heat stress affects arterial compliance in smokers. The purpose of this pilot study was to test the hypothesis that passive heat stress improves arterial compliance in smokers to a greater extent than non-smokers. This pilot study involved 2 male smokers and 2 male non-smokers, ages 18-21. Smokers …

Plasminogen Activator Inhibitor-1 In Cigarette Smoke Exposure And Influenza A Virus Infection-Induced Lung Injury, Yashodhar P. Bhandary, Shwetha K. Shetty, Amarnath S. Marudamuthu, Krishna K. Midde, Hong-Long Ji, Homoyoun Shams, Renuka Subramaniam, Jian Fu, Steven Idell, Sreerama Shetty

Center for Research on Environmental Disease Faculty Publications

Parenchymal lung inflammation and airway and alveolar epithelial cell apoptosis are associated with cigarette smoke exposure (CSE), which contributes to chronic obstructive pulmonary disease (COPD). Epidemiological studies indicate that people exposed to chronic cigarette smoke with or without COPD are more susceptible to influenza A virus (IAV) infection. We found increased p53, PAI-1 and apoptosis in AECs, with accumulation of macrophages and neutrophils in the lungs of patients with COPD. In Wild-type (WT) mice with passive CSE (PCSE), p53 and PAI-1 expression and apoptosis were increased in AECs as was lung inflammation, while those lacking p53 or PAI-1 resisted AEC …

Efficient In Vitro Development Of Photoreceptors From Human Pluripotent Stem Cells, Joseph C. Reynolds

Dissertations, Masters Theses, Capstones, and Culminating Projects

Degeneration of the rod and cone photoreceptors in the human retina is among the most common causes of blindness. Replacing these damaged photoreceptors may help to restore vision. Repairing the damaged retina relies on the insertion of new, healthy cells. Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are two possible sources of photoreceptors to restore vision. Previous data shows that human ES cells and iPS cells can be differentiated into photoreceptors and transplanted into the eye to restore some vision. However, this process is inefficient, and costly. Here, we show a new method for inducing photoreceptor production …

The Incidence Of Chagas Coinfections Amongst Acute Dengue Patients In Machala, Ecuador, Elizabeth A. Mcmahon

Renée Crown University Honors Thesis Projects - All

Dengue fever is a febrile illness found throughout the tropics that, in severe cases, can be deadly. The most rapidly spreading of any mosquito-borne disease, dengue is re-emerging as an illness of great concern in Latin America and around the globe. The CDC estimates that as many as 400 million cases of dengue occur each year. The pathogenesis of dengue virus is complicated and acts through modulation of the host immune system. Dengue polarizes the immune system balance of T helper 1 (Th1) and T helper 2 (Th2) cells towards a Th1 inflammatory response. Parasitic infections have also been shown …

Maternal Obesity And Incidence Of Depression, Caroline A. Habjan

Renée Crown University Honors Thesis Projects - All

Obesity is a national epidemic in the United States, which both directly and indirectly affects the social productivity of individuals, the American macro economy and individuals’ personal health and well being. Depression often interferes with an individual’s ability to work, sleep, study, eat, and enjoy life. A maternal state of both obesity and depression may cause serious adverse medical conditions in the mother’s child. Taking steps to treat depression and obesity are critical in the construct of modern medicine. This project yields results that have the potential to make treatment options better tailored, more efficient, effective and economically-sound for the …

Alzheimer's Disease: From Clinical Tragedy To Reason For Hope, Kenneth Adams

Bridgewater Review

No abstract provided.

Phenytoin-Induced Purple Glove Syndrome: A Case Report And Review Of The Literature, John Okogbaa, Ifeanyi Onor, Oluwatoyin Arije, Martha Harris, Rebecca Lillis

Faculty and Staff Publications

OBJECTIVE:To present a case report and literature review of phenytoin-induced purple glove syndrome (PGS).CASE SUMMARY:A 54-year-old African American male presented to our hospital's emergency department (ED) following a seizure episode, cardiac arrest, and loss of consciousness. On arrival to the ED, the patient's total phenytoin level was subtherapeutic at 4.1 mcg/mL and his corrected total phenytoin level was subtherapeutic at 5.1 mcg/mL. In the ED, the patient received a loading dose of intravenous (IV) phenytoin 1,000 mg once via the left cephalic vein, at a rate of 50 mg/min, and was admitted to the medicine service. A day following IV …

Evaluation Of Bde-47 And -99 Lipid Modulating Effects In Hepg2 Human Carcinoma Cells, Eileen A. Holovac

Senior Honors Projects

Non-alcoholic fatty liver disease (NAFLD) is becoming a significantly more common problem in today’s society, affecting up to 25% of people in the United States as reported by the American Liver Foundation. According to the American Association of the Study of Liver Diseases, NAFLD is the buildup of fat in the liver that is not caused by secondary factors such as alcohol consumption, hereditary disorders, or the use of steatogenic medication such as amioderone. A liver is considered fatty when 5-10% of the liver’s weight is fat. The progression of NAFLD can lead to cirrhosis, liver cancer, or liver failure. …

Periodontal Disease: Molecular Visualization Through Computer Modeling And 3d Printing, Catherine Chatowsky

Senior Honors Projects

Periodontal disease is a common infection that damages gingival tissue and creates jawbone destruction that can lead to the loosening or loss of teeth. Hundreds of diverse bacterial species reside in the harsh environment of the oral cavity. The creation of plaque and biofilms serve to allow the bacteria to avoid immune-mediated destruction. This project analyzed periodontal disease pathogens using molecular printing 3D visualization. Two bacterial species (T. denticola and P. gingivalis) were chosen from the public resource: Research Collaboratory for Structural Bioinformatics: Protein Data Bank. T. denticola was a bacteria found to have a binding protein (FhbB) …

Identification Of Transcription Factors Gzf3, Rfx1, Orf19.3928 As Being Implicated In Candida-Bacterial Interactions., Joni Watson

Undergraduate Honors Theses

Candida albicans is an opportunistic pathogen that is present in the normal flora in a majority of individuals. One key factor in C. albicans virulence is the ability to change its morphology from yeast to an elongated or hyphal form. The regulation of this morphogenesis relies in part upon quorum sensing (QS) molecules. C. albicans often exists as part of a mixed culture alongside other microbes and is influenced by their presence as well as the presence of QS molecules that they produce. In this study, a library of diploid homozygous transcriptional regulator knockout (TRKO) mutants were screened to identify …

Inverse Changes In Ghrelin And A2a Receptor Gene Expression Levels In The Hippocampus Of Heart Failure Canines Following Spinal Cord Stimulation, Benjamin E. Jewett

Undergraduate Honors Theses

Myocardial infarction (MI), often referred to as a heart attack, is a serious health issue in the United States. There is a well-documented link between MI and major depressive disorder (MDD), with a high incidence of MDD occurring after an MI. Overlapping pathologies have been observed within the hippocampus of the brain in animal models of MI and depression. These observations suggest that pathobiological cross-talk between the heart and brain could have a role in the etiology of MDD that occurs after an MI. Spinal cord stimulation (SCS) has previously been shown to have both cardioprotective and neuroprotective effects post-MI, …

Serum Omentin As A Potential Biomarker For Complex Atypical Hyperplasia And Endometrioid Endometrial Adenocarcinoma, Laura L. Holman Md

Dissertations and Theses (Open Access)

Obesity is a significant risk factor for endometrial cancer, the most common gynecologic malignancy in the United States, but much remains unclear about the relationship between obesity-related factors and the development of endometrial cancer. Omentin, a recently discovered adipokine, has been shown to be present in lower levels in patients who are obese and/or insulin resistant. A case-control study was conducted using the serum of 140 women with endometrial cancer and 75 women with endometrial hyperplasia who were matched 1:1 based on body mass index (BMI) and menopausal status to women with no history of endometrial cancer (controls). The concentration …

Immune Reconstitution But Persistent Activation After 48 Weeks Of Antiretroviral Therapy In Youth With Pre-Therapy Cd4 >350 In Atn 061., Bret J. Rudy, Bill G. Kapogiannis, Carol Worrell, Kathleen E. Squires, James Bethel, Su Li, Craig M. Wilson, Allison Agwu, Patricia Emmanuel, Georgine Price, Stephanie Hudey, Maureen M. Goodenow, John W. Sleasman

Department of Medicine Faculty Papers

BACKGROUND: Measures of immune outcomes in youth who initiate combination antiretroviral therapy (cART) early in HIV infection are limited.

DESIGN: Adolescent Trials Network 061 examined changes over 48 weeks of cART in T-cell subsets and markers of T-cell and macrophage activation in subjects with pre-therapy CD4 > 350 cells/mm. All subjects had optimal viral suppression from weeks 24 through 48.

METHODS: Subjects (n = 48) initiated cART with tenofovir/emtricitabine plus ritonavir-boosted atazanavir. Data were collected at baseline and weeks 12, 24, and 48. Trends were compared to uninfected controls.

RESULTS: Significant increases over 48 weeks were noted in all CD4 populations, …

Sexual Relationships Outside Primary Partnerships And Abstinence Are Associated With Lower Adherence And Adherence Gaps: Data From The Partners Prep Ancillary Adherence Study, Alexander Kintu, Susan E. Hankinson, Raji Balasubramanian, Karen Ertel, Elioda Tumwesigye, David Bangsberg, Jessica E. Haberer

OHSU-PSU School of Public Health Faculty Publications and Presentations

Objective—To assess the role of sexual relationships on levels and patterns of adherence to medication for pre-exposure prophylaxis (PrEP) against HIV.

Methods—We enrolled 1,147 HIV-negative individuals in long-term serodiscordant relationships at three sites in Uganda from the Partners PrEP Study- a randomized placebo-controlled trial of daily oral tenofovir and emtricitabine/tenofovir. We used generalized estimation equations to assess the effects of sexual relationships on low adherence (

Results—Fifty-three percent were male, 51% were 18-34 years and 24% were polygamous. Participants who reported sex in the past month with someone other than their primary partner and with

Conclusions—Risk of low overall adherence …

Super Learner Analysis Of Electronic Adherence Data Improves Viral Prediction And May Provide Strategies For Selective Hiv Rna Monitoring, Maya L. Petersen, Erin Ledell, Joshua Schwab, Varada Sarovar, Robert Gross, Nancy Reynolds, Jessica E. Haberer, Kathy Goggin, Carol E. Golin, Julia Arnsten, Marc Rosen, Robert H. Remien, David Etoori, Ira B. Wilson, Jane M. Simoni, Judith A. Erlen, Mark J. Van Der Laan, Honghu Liu, David Bangsberg

OHSU-PSU School of Public Health Faculty Publications and Presentations

Objective—Regular HIV RNA testing for all HIV positive patients on antiretroviral therapy (ART) is expensive and has low yield since most tests are undetectable. Selective testing of those at higher risk of failure may improve efficiency. We investigated whether a novel analysis of adherence data could correctly classify virological failure and potentially inform a selective testing strategy.

Design—Multisite prospective cohort consortium.

Methods—We evaluated longitudinal data on 1478 adult patients treated with ART and monitored using the Medication Event Monitoring System (MEMS) in 16 United States cohorts contributing to the MACH14 consortium. Since the relationship between adherence and virological failure is …

Pathological Effects Of Repeated Concussive Tbi In Mouse Models: Periventricular Damage And Ventriculomegaly, Richard H. Wolferz Jr.

Honors Scholar Theses

Repeated concussive traumatic brain injury (rcTBI) is the most prominent form of head injury affecting the brain, with an estimated 1.7 million Americans affected each year (Kuhn 2012). Neurologists have been concerned about the danger of repeated head impacts since the 1920’s, but researchers have only begun to understand the long-term effects of rcTBI (McKee 2009). Although symptoms can be as mild as dizziness, current research suggests that multiple concussions can lead to a progressive degenerative brain disease known as chronic traumatic encephalopathy (CTE) (Luo 2008, McKee 2009, Kane 2013). Research on the brain is just beginning to scratch the …

Evaluating The Effectiveness Of Cranial Molding For Treatment Of Positional Plagiocephaly Using Finite Element Analysis, Maziyar Keshtgar

Master's Theses

Since the advent of recommendations for placing infants in the supine position during sleep to reduce the incidence of sudden infant death syndrome, clinicians have noted an increase in the frequency of cranial asymmetry due to deformation of suture sections of the infants’ skulls as a result of constant concentrated stress in one area at the back of their head. This specific form of cranial deformation is known as positional plagiocephaly and its rate of occurrence has increased from 0.3% in 8.2% within the past 30 years.

Current treatments and methodologies for preventing and correcting positional plagiocephaly such as stretching …

Src Homology 2 Domain-Containing 5’-Inositol Phosphatase-2 (Ship2) Is An Effector Of Lymphatic Dysfunction, Germaine D. Agollah

Dissertations and Theses (Open Access)

The lymphatic system is essential for the transport of excess fluid, protein, and foreign materials from interstitial tissues to lymph nodes; for immune surveillance, and to maintain fluid homeostasis. Dysregulated lymphatics can be attributed to pathological conditions including tumor metastasis, inflammation, chronic wounds, obesity, blood vascular disorders, and lymphedema. Of these, lymphedema is the most extreme of lymphatic disorders and is represented by a spectrum of symptoms ranging from mild, subtle presentation to severe, disfiguring, overt presentation. Lymphedema is more manageable in the early stages of disease but severely reduces quality of life with progression. Due to lack of molecular …