Medical Sciences Commons^™

Infiltrating Cd8+ T Cells Exacerbate Alzheimer’S Disease Pathology In A 3d Human Neuroimmune Axis Model, Jefin Jose, Devam Purohit

VCU's Medical Journal Club: The Work of Future Health Professionals

In this study, Jorfi et al. employed a neuroimmune axis model containing neurons, astrocytes, and microglia to examine the role of immune cells in Alzheimer's disease. Jorfi et al. found that T cells selectively infiltrated the BRAIN compartment of the neuroimmune axis model as compared to B cells and monocytes. Jorfi et al. further found that CD8+ T cells demonstrated heightened cytotoxicity in the Alzheimer's disease brain, illuminating the role of immune cells in neurodegeneration. Upon further examination, the CXCR3-CXCL10 signaling pathway was found to have an important role in inflammation.

A Genome-Wide In Vivo Crispr Screen Identifies Essential Regulators Of T Cell Migration To The Cns In A Multiple Sclerosis Model, Jefin Jose

VCU's Medical Journal Club: The Work of Future Health Professionals

Kendirli et al. (2023) used a CRISPR screen to determine the proteins involved in T cell migration into the CNS in multiple sclerosis. Overall, eighteen facilitators and five brakes to T cell infiltration into the CNS were identified. Kendirli et al. specifically identified ITGA4, FERMT3, and HSP90B1 to make up the adhesion module, CXCR3, GNAI2, and TBX21 to make up the chemotaxis module, and GRK2 and S1PR2 to make up the egress module. This study demonstrated the ability of a CRISPR screen to identify elements in a disease process and thus identify targets for future multiple sclerosis therapies.

Exploring Substance Use Initiation In Adolescent Twins: Unveiling Age-Specific Patterns And Sex Differences, Darren Farmer, Elizabeth Prom-Wormley Mph, Phd

IRBEH/Spit for Science Publications and Presentations

No abstract provided.

Observing Ceramide Pathway With Ferroptosis Via Mia Paca-2 Cell Treatment With Rsl3, Tazrin Rahman

AUCTUS: The Journal of Undergraduate Research and Creative Scholarship

Composed of sphingosine and a fatty acid, ceramides are lipid molecules that serve as key metabolic signaling molecules of a sphingolipid pathway. While it acts as a precursor of complex sphingolipids, inducing ceramide generation can cause cell stress leading to subsequent cell death via apoptosis, necrosis, and even mitophagy. With regards to cell death specifically, a novel form of regulated cell death, ferroptosis, has recently been recognized of necrotic nature. Its unique morphological features and distinct properties have been observed over the last several decades; however, the molecular features were not identifiable as pure evidence of cell death, until recently …

Contribution Of Metabolic Cell Swelling On Microcirculatory Perfusion In Septic Shock, Charles E. Payne

Theses and Dissertations

Sepsis, a systemic immunological response that leads to organ-dysfunction, the development of septic shock, and death has mortality rate of 15-25%. A subset of sepsis, septic shock, has an in-hospital mortality rate of 30-50%. Sepsis and its treatment are the most expensive healthcare problem in the United States with the US Agency for Healthcare Research and Quality estimating annual costs over $20 billion. Hypoxia experienced in septic shock induces metabolic cell and tissue swelling leading to further microcirculatory dysfunction and poor tissue perfusion. Reversing metabolic cell swelling corrects these perfusion defects. Two models were used in rats to induce septic …

Characterizing The Effects Of Antiandrogens And Senolytics To Enhance The Therapeutic Response To Castration-Resistant Prostate Cancer, Justin M. Silverman

Theses and Dissertations

Prostate cancer is the most frequently diagnosed cancer in males and the second most common cause of cancer deaths. Androgen deprivation therapy, whether through surgical or chemical castration, is the mainstay for treatment of advanced prostate cancer; however, despite an initial response, most patients eventually develop a progressive PSA rise, and castration- sensitive prostate cancer gives rise to castration-resistant prostate cancer. The standard of care therapy includes the antiandrogens such as enzalutamide and abiraterone acetate as well as the microtubule poison, docetaxel, and various immunotherapies; however, while prostate cancer research is progressing, there continues to be a compelling need for …

A Learning Health System For Radiation Oncology, Rishabh Kapoor

Theses and Dissertations

The proposed research aims to address the challenges faced by clinical data science researchers in radiation oncology accessing, integrating, and analyzing heterogeneous data from various sources. The research presents a scalable intelligent infrastructure, called the Health Information Gateway and Exchange (HINGE), which captures and structures data from multiple sources into a knowledge base with semantically interlinked entities. This infrastructure enables researchers to mine novel associations and gather relevant knowledge for personalized clinical outcomes.

The dissertation discusses the design framework and implementation of HINGE, which abstracts structured data from treatment planning systems, treatment management systems, and electronic health records. It utilizes …

Evaluation Of Spliceai For Improved Genetic Variant Classification In Inherited Ophthalmic Disease Genes, Melissa Reeves

Theses and Dissertations

ABSTRACT

EVALUATION OF SPLICEAI FOR IMPROVED GENETIC VARIANT CLASSIFICATION IN INHERITED OPHTHALMIC DISEASE GENES

By Melissa Jean Reeves, Ph.D.

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University.

Virginia Commonwealth University, 2023

Major Director: Melissa Jamerson, PhD, MLS(ASCP)

Associate Professor, Department of Medical Laboratory Sciences

Inherited ophthalmic diseases impact individuals around the globe. Inherited retinal diseases (IRDs) are the leading cause of blindness in individuals aged 15 to 45. The personal, social, and economic impact of vision loss is profound. Due to individual differences, symptoms can be variable, and …

Role Of The Ormdls In Keratinocytes, Souad Hatmi

Theses and Dissertations

The epidermis, the outermost layer of the skin, serves as a vital barrier protecting the body from environmental stressors, pathogens, and dehydration. Keratinocytes, the predominant cell type in the epidermis, play a central role in maintaining skin integrity and barrier function. In normal human skin, keratinocytes move from the basal layer to the stratum corneum, the top layer of the epidermis. In their travel, keratinocytes undergo a process of terminal differentiation, loss their ability to proliferate, secrete sphingolipids into the extracellular space, and gradually loss their nucleus and organelles. Sphingolipids, particularly ceramides, are key components of the intercellular lipid lamellae …

Vulnerability And Adaptation Of Neocortical Neuron Subtypes In Models Of Concussive Traumatic Brain Injury And Multiple Sclerosis, Alan C. Harris Jr.

Theses and Dissertations

The pathognomonic sequela of traumatic brain injury is traumatic axonal injury, the

burden of which correlates with less favorable outcomes. Elucidation of

the intrinsic variables that endow delineated neuronal subgroups and microanatomical domains with outsized vulnerability to injury represents a critical domain of inquiry toward the successful translation of disease-modifying therapeutics. To this end, we studied mild traumatic brain injury (mTBI) within the central fluid percussion model to examine the consequences of mTBI on the morphology and functional integrity of the axon initial segment (AIS) and the relative contributions to network homeostasis mediated by distinct populations of inhibitory interneurons. One …

Molecular Target And Circuitry Underlying The Preclinical Effects Of Psychedelics In Models Of Opioid Use Disorder, Alaina M. Jaster

Theses and Dissertations

Opioid use disorder (OUD), like other substance use disorders (SUD), is characterized by maladaptive behavioral allocation away from other rewarding aspects of life following prolonged use, as well as large rates of relapse. While pharmacotherapies exist for OUD, they tend to only target the opioid receptors rather than the underlying mechanisms behind the maladaptive behaviors. Serotonin (5-hydroxytryptamine; 5-HT) is involved in modulation of cravings and regulation of motivational reward-related behaviors, thought to be due to a top-down processing method of external and internal stimuli. Serotonin 2A receptors (5-HT_2AR) are widespread throughout the brain and most densely populate layer …

Molecular Mechanisms Of Prdm16 As A Tumor Suppressor In Pancreatic Ductal Adenocarcinoma, Eric Hurwitz

Theses and Dissertations

The transcription factor Prdm16 functions as a potent suppressor of transforming growth factor-beta (TGF-b) signaling, whose inactivation is deemed essential to the progression of pancreatic ductal adenocarcinoma (PDAC). Using the Kras^G12D-based mouse model of human PDAC, we surprisingly found that ablating Prdm16 did not block but instead accelerated PDAC formation and progression, suggesting that Prdm16 might function as a tumor suppressor in this malignancy. Subsequent genetic experiments showed that ablating Prdm16 along with Smad4 resulted in a shift from a well-differentiated and confined neoplasm to a highly aggressive and metastatic disease, which was associated with a striking deviation …

Role Of Histone Deacetylase (Hdac) In Epithelial To Mesenchymal Transition (Emt) In A Human Cholangiocyte Model Of Ischemic Cholangiopathy, Priyanshi Pragnesh Parikh

Theses and Dissertations

Organ transplants are a vital intervention for many diseases that result in end stage organ failure. Currently, the donation pool is not meeting the demands of the transplant list. Expanding this pool to include donation after cardiac death (DCD) is highly sought-after. However, the use of DCD livers can lead to increased odds of graft failure and ischemic cholangiopathy. The loss of epithelialization and fibrosis that occurs during ischemic cholangiopathy is characteristic of these cells undergoing epithelial-to-mesenchymal transition (EMT). The biological changes the cell experiences enhance migratory capacity, invasiveness, and increased resistance to apoptosis. Our earlier studies have shown differential …

Formation Of Vasculogenic Mimicry: Role Of Melanoma Differentiation Associated Gene-9 In Human Melanoma, Jinkal Shah

Theses and Dissertations

Malignant melanoma (MM) is the most aggressive skin cancer and the most frequent skin disorder in Caucasians. MM is associated with aggressive and progressive disease states, leading to major cancer-related morbidity and mortality. Recent investigations identify an alternative pathway -vasculogenic mimicry (VM), which is considered a cancer hallmark that can independently facilitate tumor neovascularization by the formation of fluid-conducting and vascular endothelial cells. MM cells undergoing VM can dedifferentiate into numerous cellular phenotypes and acquire endothelial-like features, resulting in the formation of the de novo matrix-rich vascular-like networks, such as plasma and red blood cells. The co-generation of endothelial cells, …

Characterization And Investigation Of Cold Atmospheric Plasma And Its Effects On Cancer Cell Biology, Thomas M. Ritrosky

Theses and Dissertations

Modern cancer treatment uses radiation therapy in over 50% of patient cases. It is an e↵ective way of treating tumors because the mechanisms of cell killing are well known through the damage that ionizing radiation does to DNA. The amount of radiation can be tracked through measuring the dose of the clinical photon or electron beam used. However, there are limitations in the usage of radiation therapy, for example, a tumor can create hypoxic areas that become radioresistant leading to complete ine↵ectiveness of further radiation treatment. This project looks into the application of cold atmospheric plasma as an adjuvant therapy …

Proposing An Rna Interference (Rnai)-Based Treatment For Human Immunodeficiency Virus (Hiv) By Analyzing The Post-Transcriptional Gene Targeting Of Sars-Cov-2, Hepatitis C Virus, And A549 Lung Cancer Cells, Arjun Jagdeesh

Undergraduate Research Posters

Human Immunodeficiency Virus (HIV) is a retrovirus that infects CD4+ T cell lymphocytes in humans, leading to the development of Acquired Immunodeficiency Syndrome (AIDS) if left untreated. While current treatment methods, including antiretroviral combination treatments, effectively limit HIV replication, HIV can evade these treatments due to its high mutation rate. Long-term antiretroviral treatment can also be toxic to patients, meaning patients would benefit from a new mechanism of HIV treatment. RNA interference (RNAi) is an antiviral pathway found in mammals, plants, and insects that involves a small-interfering RNA that is incorporated into a protein complex called the RNA-induced Silencing Complex …

The Role Of The Nlrp3 Inflammasome In Alzheimer's Disease, Ethan S. Terman

Undergraduate Research Posters

This study examines the consequences of Alzheimer’s in rat and mice test subjects. The goal is to identify the effects of certain NLRP3 inhibiting drugs and to see if there are any noticeable effects in regards to impeding the pathological development of Alzheimer’s disease. The results are visualized by implementing the immunohistochemical process to identify neurodegeneration in the brain and to assess the expression levels of amyloid beta as an indicator of Alzheimer’s pathology. Other tests are also conducted on these transgenic mice to gauge cognitive functioning levels during the onset of their disease, those being behavior tests, but not …

Isoprenylation Inhibition Suppresses Fcεri-Mediated Mast Cell Function And Allergic Inflammation, Aditya Kotha, Jordan M. Dailey, Aslamuzzaman Kazi, Said Sebti, John J. Ryan

Undergraduate Research Posters

Allergic disease is driven by cell signaling cascades that activate immune cells. One key player is mast cells, which is activated by IgE antibodies signaling through the high affinity IgE receptor, FceRI. Therefore, targeting FceRI-mediated cascades can offer for novel treatments for allergic disease. Statins have been demonstrated to reduce the severity of asthma, a common allergic airway disease. Statins are an FDA approved class of drugs with the intended purpose of lowering blood cholesterol. We previously found that while statins inhibit mast cell function in allergic disease, these anti-inflammatory effects vary widely amongst differing mouse strains and human donors, …

Comparing The Microbiomes Of Dental Plaques In 19th Century Ancestral Remains, Ananya Udyaver

Undergraduate Research Posters

During the construction of VCU’s Hermes A. Kontos Medical Sciences Building in April 1994, nineteenth century ancestral remains were found in an abandoned well on the Medical College of Virginia (MCV) campus. This well, now known as the East Marshall Street Well (EMSW), is thought to have been used as a disposal location for cadaver dissection for surgical and other medical waste in the past. VCU is now seeking to use DNA sequencing technology to match and assemble bones from each individual for a proper burial, uncover the cultural and historical context in which these people lived, and bring a …

Investigation Of The Dyrk1a Regulation By Lzts2-Sipa1l1 Complex, Rebecca Gunnin, Austin Witt B.S., Larisa Litovchick M.D.,Ph.D.

Undergraduate Research Posters

A region on chromosome 21, the Down Syndrome critical region (DSCR), is associated with major defects found in Down Syndrome, such as craniofacial malformations. DYRK1A is a gene found on chromosome 21 within the DSCR that encodes an enzyme, dual specificity tyrosine-phosphorylation-regulated kinase 1A. DYRK1A is known to phosphorylate many substrate proteins and is thought to be involved in tumor suppression, neurological development, cell cycle regulation, and aging. Recently, the Litovchick lab and others reported that DYRK1A also plays a role in the double-strand break repair of DNA, which could lead to mutations and tumorigenesis, if deregulated.

The Litovchick lab …

A Within-Host Modeling Framework For Sars-Cov-2 Infection To Support Vaccine Strategies, Morgan Rose, Rachel Jennings, Jeffry Schroeter

Biology and Medicine Through Mathematics Conference

No abstract provided.

Study Of Cardiovascular Dynamics During Graded Head-Up Tilt Test In The Young With Syncope Tendency, Martin A. Miranda Sr

Biology and Medicine Through Mathematics Conference

No abstract provided.

Viridiflorol Induces Anti-Neoplastic Effects On Breast, Lung, And Brain Cancer Cells Through Apoptosis, Maaged A. Akiel, Ohoud Y. Alshehri, Shokran A. Aljihani, Amani Almuaysib, Ammar Bader, Ahmed I. Al‐Asmari, Hassan S. Alamri, Bahauddeen M. Alrfaei, Majed A. Halwani

Human and Molecular Genetics Publications

All active natural molecules are not fully exploited as therapeutic agents, causing delays in the advancement of anticancer drug discovery. Viridiflorol is a natural volatile element that may work as anti-cancer compound. We tested the anticancer properties of viridiflorol at different concentrations ranging from 0.03 to 300 μM in vitro on three cancer cells including breast (MCF-7), lung (A549) and brain (Daoy). The cancer cells responses were documented after treatment using MTT and Annexin V assays. Viridiflorol showed cytotoxic effects against all tested cell lines, reducing cell viability in a concentration-dependent manner with variable IC50 values. Daoy and A549 cell …

Repeated Exposure To Chlorpyrifos Is Associated With A Dose-Dependent Chronic Neurobehavioral Deficit In Adult Rats, Ana C. R. Ribeiro, Elisa Hawkins, Fay M. Jahr, Joseph L. Mcclay, Laxmikant Deshpande

Neurology Publications

Organophosphate (OP) chemicals include commonly used pesticides and chemical warfare agents, and mechanistically they are potent inhibitors of the cholinesterase (ChE) enzyme. Epidemiological studies report long-term neuropsychiatric issues, including depression and cognitive impairments in OP-exposed individuals. Chlorpyrifos (CPF) is one of the most widely used pesticides worldwide. Multiple laboratory studies have reported on either the long-term behavioral effect of an acute high-dose CPF (30-250 mg/kg) or studied sub-chronic behavioral effects, particularly the motor and cognitive effects of repeated low-dose CPF. However, studies are lacking on chronic mood and depression-related morbidities following repeated CPF doses that would mimic occupationally relevant OP …

Sorafenib, Rapamycin, And Venetoclax Attenuate Doxorubicin-Induced Senescence And Promote Apoptosis In Hct116 Cells, Homood M. As Sobeai, Munirah Alohaydib, Ali R. Alhoshani, Khalid Alhazzani, Mashal M. Almutairi, Tareq Saleh, David A. Gewirtz, Moureq R. Alotiabi

Pharmacology and Toxicology Publications

Emerging evidence has shown that the therapy-induced senescent growth arrest in cancer cells is of durable nature whereby a subset of cells can reinstate proliferative capacity. Promising new drugs named senolytics selectively target senescent cells and commit them into apoptosis. Accordingly, senolytics have been proposed as adjuvant cancer treatment to cull senescent tumor cells, and thus, screening for agents that exhibit senolytic properties is highly warranted. Our study aimed to investigate three agents, sorafenib, rapamycin, and venetoclax for their senolytic potential in doxorubicin-induced senescence in HCT116 cells. HCT116 cells were treated with one of the three agents, sorafenib …

Therapeutic Approaches For Respiratory Distress Syndrome, Franck J. Kamga Gninzeko

Theses and Dissertations

Respiratory distress syndrome (RDS) is characterized by shortness of breath and low oxygen levels. RDS affects the neonatal and adult populations. In the neonatal population, RDS can be classified as NRDS (Neonatal respiratory distress syndrome), while in adults, it is known as ARDS (acute respiratory distress syndrome). This dissertation examines a therapeutic approach to NRDS and a mechanistic approach to ARDS with in vivo and in vitro models of lung injury. NRDS is characterized by a deficiency or lack of surfactant. Surfactant is an essential compound composed of phospholipids and proteins to prevent the lungs from collapsing. There are several …

Modeling Of Patient-Specific Periaortic Mechanics And Pulmonary Artery Hemodynamics Based On Phase-Contrast Magnetic Resonance Imaging Sequences., Johane H. Bracamonte

Theses and Dissertations

Inverse modeling in cardiovascular medicine is a collection of methodologies that can provide non-invasive patient-specific estimations of clinical risk factors using medical imaging as inputs. Its incorporation into clinical practice has the potential to improve diagnosis and treatment planning with low associated risks and costs.

Herein, three different phase contrast magnetic resonance imaging (MRI) modalities were implemented as input data, displacement encoding with stimulated echoes (DENSE MRI) applied, and time-resolved velocity encoding phase-contrast MRI, in 1D and 3D, applied to pulmonary artery (PA) hemodynamics.

A model to account for the effect of periaortic interactions due to static and dynamic structures …

Investigating The Role Of Nlrp3 Inflammasome In Chemotherapy-Induced Peripheral Neuropathy, Urszula O. Warncke

Theses and Dissertations

Paclitaxel and oxaliplatin are commonly used antineoplastic drugs that cause chemotherapy-induce peripheral neuropathy (CIPN) in up to 90% of patients. The sensory symptoms of CIPN include numbness, loss of proprioception, tingling, spontaneous burning, shooting or electric shock-like pain, mechanical and thermal allodynia, and cold hypersensitivity among others. Affected patients struggle with daily activities, have a low quality of life, and might stop cancer treatment. Unfortunately, there are no effective prophylactic or therapeutic treatments for these side effects. Many studies point to the involvement of inflammation as a major contributor of CIPN pathology. We investigated the effects of genetic (NLRP3 …

Crosstalk Between Hippo And Rb Tumour Suppressor Pathways In Ovarian Cancer, Fatmata Sesay

Theses and Dissertations

The cell cycle is a highly regulated process that ensures the timely and accurate division of cells. Events of the normal cell cycle fall under two categories - positive and negative regulatory mechanisms. The first category, positive regulatory machinery, includes active protein complexes of cyclins in association with their partnering cyclin-dependent kinases (cyclin/CDK), which mediate series of phosphorylation events that relay a cell cycle progression from one stage to the next. The second category, the negative regulatory mechanisms, include the checkpoint controls consisting of the retinoblastoma (RB) family of proteins, some of which can form a transcriptional repressor complex DREAM. …

Effects Of The Selective Gsk3b Inhibitor, Tideglusib, On Ethanol Consumption, Anxiety-Like Behavior, Taste Preference, And Downstream Proteins, Sam Gottlieb, Douglas Bledsoe, Jessica L. Maltman, Alanna Morgan, Jennifer T. Wolstenholme, Michael F. Miles

Graduate Research Posters

Background: We have shown modulations in glycogen synthase kinase 3 beta (GSK3B) abundance or activity regulate ethanol consumption, suggesting potential as a therapeutic target for alcohol use disorder (AUD). Here we report the GSK3B inhibitor tideglusib’s actions on ethanol consumption, basal behaviors, and modulation of GSK3B targets.

Methods: C57BL/6J males and females received i.g. 200mg/kg tideglusib, except drinking-in-the-dark (males;100mg/kg i.p.). Drinking-in-the-dark (DID): Mice given 20% ethanol 4-hours, 4-days/week x 3 weeks and then i.p. tideglusib or vehicle x 4 days in a Latin Square design with ethanol consumption measured daily. Light/Dark Box: Mice gavaged with tideglusib or vehicle …