Life Sciences Commons^™

Alzheimer's And Amyloid Beta: Amyloidogenicity And Tauopathy Via Dyshomeostatic Interactions Of Amyloid Beta, Jordan Tillinghast

Senior Honors Theses

This paper reviews functions of Amyloid-β (Aβ) in healthy individuals compared to the consequences of aberrant Aβ in Alzheimer’s disease (AD). As extraneuronal Aβ accumulation and plaque formation are characteristics of AD, it is reasonable to infer a pivotal role for Aβ in AD pathogenesis. Establishing progress of the disease as well as the mechanism of neurodegeneration from AD have proven difficult (Selkoe, 1994). This thesis provides evidence suggesting the pathogenesis of AD is due to dysfunctional neuronal processes involving Aβ’s synaptic malfunction, abnormal interaction with tau, and disruption of neuronal homeostasis. Significant evidence demonstrates that AD symptoms are partially …

Discovery Of Novel Mechanisms Regulating Cancer Extravasation In The Chorioallantoic Membrane Model, Yohan Kim

Electronic Thesis and Dissertation Repository

Cancer metastasis is a multistep process that begins with the invasion of tumour cells into the stroma and migration towards the blood vessels. Tumour cells that have entered the bloodstream must then survive and leave by a process known as extravasation. Finally, extravasated cells proliferate and establish the secondary site in the metastatic cascade. Although extravasation encompasses key events during cancer cell invasion to aid in the development of effective treatments, an in vivo model that rapidly, reproducibly and economically recapitulates cancer cell extravasation is needed. Therefore, the objectives of my research were to 1) establish and validate an in …

Activation Of Lxrβ Inhibits Tumor Respiration And Is Synthetically Lethal With Bcl-Xl Inhibition, Trang Thi Thu Nguyen, Chiaki Tsuge Ishida, Enyuan Shang, Chang Shu, Consuelo Torrini, Yiru Zhang, Elena Bianchetti, Maria J. Sanchez-Quintero, Giulio Kleiner, Catarina M. Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Peter Canoll, Markus D. Siegelin

Publications and Research

Liver-X-receptor (LXR) agonists are known to bear anti-tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance synergistically the anti-proliferative effect of BH3 mimetics in solid tumor malignancies, which is predominantly mediated by cell death with features of apoptosis and is rescued by exogenous cholesterol. Extracellular flux analysis and carbon tracing experiments (U-¹³C-glucose and U-¹³C-glutamine) reveal that within 5 h, activation of LXRβ results in reprogramming of tumor cell metabolism, leading …

Natural Autoantibodies: Origin, Function And Utility For Diagnosis Of Disease, Abhirup Sarkar

Graduate School of Biomedical Sciences Theses and Dissertations

Autoantibodies (aAbs) by the simplest definitions have been described as antibodies against self-antigens and were exclusively associated with autoimmune diseases. Eventually, studies demonstrated that they are abundant in the blood of all human sera, regardless of age, gender, or the presence or absence of disease, and were thus named as ‘natural autoantibodies’. The underlying reason for their ubiquity has remained elusive, but we have hypothesized that they are responsible for clearing blood-borne cell and tissue debris generated under conditions of health and disease. To test this, we chose to use two widely different disease model systems, namely neurodegenerative diseases and …

Cyclin C Regulated Oxidative Stress Responsive Transcriptome In Mus Musculus Embryonic Fibroblasts, David C Stieg, Kai-Ti Chang, Katrina F Cooper, Randy Strich

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

The transcriptional changes that occur in response to oxidative stress help direct the decision to maintain cell viability or enter a cell death pathway. Cyclin C-Cdk8 is a conserved kinase that associates with the RNA polymerase II Mediator complex that stimulates or represses transcription depending on the locus. In response to oxidative stress, cyclin C, but not Cdk8, displays partial translocation into the cytoplasm. These findings open the possibility that cyclin C relocalization is a regulatory mechanism governing oxidative stress-induced transcriptional changes. In the present study, the cyclin C-dependent transcriptome was determined and compared to transcriptional changes occurring in oxidatively …

Development Of A Sonically Powered Biodegradable Nanogenerator For Bone Regeneration, Avi Patel

Honors Scholar Theses

Background: Reconstruction of bone fractures and defects remains a big challenge in orthopedic surgery. While regenerative engineering has advanced the field greatly using a combination of biomaterial scaffolds and stem cells, one matter of difficulty is inducing osteogenesis in these cells. Recent works have shown electricity’s ability to promote osteogenesis in stem cell lines when seeded in bone scaffolds; however, typical electrical stimulators are either (a) externally housed and require overcomplex percutaneous wires be connected to the implanted scaffold or (b) implanted non-degradable devices which contain toxic batteries and require invasive removal surgeries.

Objective: Here, we establish a biodegradable, piezoelectric …

The Role Of Ros In The Progression And Treatment Of Castration-Resistant Prostate Cancer, Dannah R. Miller

Theses & Dissertations

Prostate cancer is the second leading cause of cancer-related deaths in U.S. men, primarily due to the development of castration-resistant (CR) prostate cancer (PCa), of which there are no effective treatment options. Reactive oxygen species (ROS) plays a critical role in prostate carcinogenesis, including the progression of the CR PCa phenotype. ROS regulates both cell proliferation and apoptosis; a moderate increase in ROS can promote proliferation; however, a substantial rise in ROS levels will result in apoptosis. Oxidase p66Shc is elevated in clinical PCa cells and has been associated with a metastatic phenotype of CR PCa cells, promoting PCa cell …

Yeast Mitochondrial Protein Pet111p Binds Directly To Two Distinct Targets In Cox2 Mrna, Suggesting A Mechanism Of Translational Activation, Julia L Jones, Katharina B Hofmann, Andrew T Cowan, Dmitry Temiakov, Patrick Cramer, Michael Anikin

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

The genes in mitochondrial DNA code for essential subunits of the respiratory chain complexes. In yeast, expression of mitochondrial genes is controlled by a group of gene-specific translational activators encoded in the nucleus. These factors appear to be part of a regulatory system that enables concerted expression of the necessary genes from both nuclear and mitochondrial genomes to produce functional respiratory complexes. Many of the translational activators are believed to act on the 5'-untranslated regions of target mRNAs, but the molecular mechanisms involved in this regulation remain obscure. In this study, we used a combination of in vivo and in …

Evaluating The Potential Of Repurposing Commercially Available Drugs For The Treatment Of Viral Infections, Brennan Connor Mcewan

Undergraduate Honors Capstone Projects

Viral infections that are often overlooked as common seasonal illnesses such as influenza can rapidly become a public threat. They threaten society as new, more dangerous strains of these common viruses emerge and as strains develop resistance to current vaccines and antiviral treatments (Kochanek, Murphy, Xu, & Tejada-Vera, 2014). To combat this, the development of antiviral treatments with novel mechanisms of action is essential. Repurposing drugs instead of developing new drugs can save years of development time and hundreds of millions of dollars (DiMasi, Hansen, & Grabowski, 2003). To support the effort to discover drugs with unique mechanisms of action, …

Translational Control Of Stress Induced Breast Cancer Plasticity, Michael Jewer

Electronic Thesis and Dissertation Repository

Cancer cell plasticity, whereby stem-cell-like properties are acquired in response to stress, represents a major challenge in cancer treatment. Using cell line and patient-derived xenograft (PDX) models, we demonstrate that translational reprogramming occurs in response to stresses such as hypoxia and chemotherapy which elicits stem cell properties in breast cancer. Other stresses like chemotherapy demonstrate the translational inhibition that has been well characterized as an integral hypoxic cellular response. The inhibition of translation is primarily regulated at initiation by mTOR/4E-BP1 and PERK/eIF2α signalling. We identify previously undescribed 5’ untranslated regions (5’UTRs) of plasticity-associated genes like NANOG, SNAIL and NODAL. …

Itch Nuclear Translocation And H1.2 Polyubiquitination Negatively Regulate The Dna Damage Response, Lufen Chang, Lei Shen, Hu Zhou, Jing Gao, Hangyi Pan, Li Zheng, Brian Armstrong, Yang Peng, Guang Peng, Binhua P. Zhou, Steven T. Rosen, Binghui Shen

Molecular and Cellular Biochemistry Faculty Publications

The downregulation of the DNA damage response (DDR) enables aggressive tumors to achieve uncontrolled proliferation against replication stress, but the mechanisms underlying this process in tumors are relatively complex. Here, we demonstrate a mechanism through which a distinct E3 ubiquitin ligase, ITCH, modulates DDR machinery in triple-negative breast cancer (TNBC). We found that expression of a nuclear form of ITCH was significantly increased in human TNBC cell lines and tumor specimens. Phosphorylation of ITCH at Ser257 by AKT led to the nuclear localization of ITCH and ubiquitination of H1.2. The ITCH-mediated polyubiquitination of H1.2 suppressed RNF8/RNF168-dependent formation of 53BP1 foci, …

Histology For Cytotechnologists I, Joanna Burkhardt

Library Impact Statements

No abstract provided.

Agent Based Model Of Cavitation In Spinal Cord Injury, Rahma Ahmed

Senior Projects Spring 2019

Annually, approximately 375,000 people suffer from spinal cord injury (SCI) worldwide and many SCI patients develop secondary health conditions such as respiratory, cardiovascular, and urinary/bowel complications which negatively impact their daily lives. SCI occurs when there is damage to the spinal cord resulting in decreased motor functions, decreased sensory functions, or paralysis. Days to weeks after initial impact, the lesion (area of injury) continues to increase in size in a process called progressive cavitation which demyelinates axons and inhibits effective axonal regeneration. In an in vitro model of progressive cavitation, Fitch et al. showed that activated macrophages cause cavities to …