Translational Medical Research Commons^™

Formulation And Characterization Of Biologics – From Sirna To Monoclonal Antibodies, Chinmay M. Jogdeo

Theses & Dissertations

Biologics are a rapidly growing class of therapeutics, encompassing a wide range of modalities, with gene therapy products and monoclonal antibodies (mAbs) constituting the majority. Proper formulation and characterization of these complex therapeutics is crucial to ensure their safety and therapeutic efficacy.

This dissertation focuses on two main areas: the development of a novel renal-targeted siRNA delivery system and the assessment of structural and conformational stability of mAbs in a simulated subcutaneous (SC) environment.

The first part of this dissertation presents the synthesis and characterization of a novel renal-targeted polymer for selective siRNA delivery to injured kidneys. Inulin was modified …

Sk609, A Novel Dopamine D3 Receptor Agonist And Norepinephrine Transporter Blocker With Putative Pro-Cognitive Actions, Does Not Induce Psychostimulant-Like Increases In Risky Choice During Probabilistic Discounting, Christopher P. Knapp, Brooke Fallon, Sandhya Kortagere, Barry D. Waterhouse, Stan B Floresco, Rachel L Navarra

Rowan-Virtua School of Osteopathic Medicine Departmental Research

RATIONALE: Psychostimulants, such as amphetamine (AMPH) and methylphenidate (MPH), non-selectively elevate extracellular concentrations of the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE), and are common pharmacological strategies used to improve prefrontal cortex (PFC)-dependent cognitive dysfunction. However, this approach can be problematic given AMPH has been shown to increase preference for risky choices in a rodent assay of risk/reward decision making. SK609 is a novel NE reuptake blocker that selectively activates DA D3 receptors without affinity for the DA transporter. SK609 has been shown to improve cognitive performance without increasing psychostimulant-like spontaneous locomotor activity, suggesting SK609 may benefit neurocognitive function without …

Defining The Peripheral Plasticity Of Nociceptive Afferents Following Spinal Cord Injury And Physical Therapy Intervention., Morgan Julianna Forston

Electronic Theses and Dissertations

The focus of this dissertation is to explore the peripheral plasticity of nociceptive afferents following spinal cord injury (SCI) and whether it is exacerbated or induced when physical therapy-based muscle stretching, a therapy we have shown to be detrimental to locomotor recovery in rodents, is implemented post-SCI. Chapter I provides a brief introduction on sensory afferents with particular emphasis on nociceptive afferents and their multifaceted role within the peripheral and central nervous systems. Chapter II describes SCI epidemiology and common sensory related complications that occur in patients as well and pharmaco- and physical therapies that are employed post-SCI. Chapter III …

Students Participating As Ambassadors For Research In Kentucky (Spark): A Health Equity Undergraduate Research Training Program, Ariel A. Arthur, Rebecca L. Delacerda Allen, Fidelis Y. Sesenu, Maxwell A. Groznik, Carrie B. Oser, Madeline Dunfee, Philip A. Kern, Nancy Schoenberg

UK CARES Faculty Publications

The Students Participating as Ambassadors for Research in Kentucky (SPARK) program provides novel health equity research training and targeted mentorship for undergraduates, particularly those from groups underrepresented in the biomedical and behavioral research and workforce. SPARK aims to address inadequate diversity in the medical and scientific research fields by providing comprehensive research mentorship and skill-building. Unlike most existing research training programs that are brief, focus on laboratory research, or are limited to graduate students and junior faculty, SPARK delivers a 16-month intensive behavioral and population health science training, equipping students with needed tools to conceptualize, plan, execute, and analyze their …

Metabolic Shifts In Ratio Of Ucocn To Cocn Toward Bone Resorption Contribute To Age-Dependent Bone Loss In Male Mice, Matthew Bernhard, Obinna Okorie, Wei-Ju Louis Tseng, Mengcun Chen, Julia Danon, Mingshu Cui, Elisabeth Lashbrooks, Yanmei Yang, Bin Wang

Center for Translational Medicine Faculty Papers

The study of the senile osteoporosis in men still lags significantly behind that in women. The changes of protein molecule levels and their relationships with bone loss remain poorly understood. In the present study, we used C57BL/6J male mice at ages from 3 to 24 mo to delineate the mechanisms of aging effects on bone loss. We used the microcomputed tomography, mechanical testing, histomorphometry assays, and detection of serum levels of undercarboxylated osteocalcin (ucOcn) and carboxylated osteocalcin (cOcn) to assess bone mass changes and their relationships with the ratios of ucOcn-to-cOcn in mice from different age groups. The results showed …

Evaluation Of The Etiology Of Recurrent Pregnancy Loss (Rpl): An Explanatory Mixed Methods Study Exploring Obstetrician Gynecologist Clinical Provider Behaviors And Factors Contributing To Incomplete Evaluations, Emelia Grant

Doctor of Philosophy in Translational Health Sciences Dissertations

Background: More than 50% of patients with recurrent pregnancy loss (RPL) are left without explanations for their losses. However, current research suggests that up to 90% of these individuals could receive explanations through evidence-based laboratory testing. Professional guidelines vary in their recommendations for laboratory testing and RPL evaluation, which can contribute to delayed or fragmented care and untreated maternal disease. Inequities in access to genetic testing further complicate the diagnostic landscape of RPL since payor policies often determine which tests are covered, leaving many patients without access due to financial constraints.

Objective: This study aimed to evaluate current practices of …

Exploring Alternative Treatments For Acute Exacerbations Of Cannabis Hyperemesis Syndrome In Patients Who Plan To Continue Using Cannabis, Tabitha E H Moses

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Dean DJ, Sabagha N, Rose K, et al. A Pilot Trial of Topical Capsaicin Cream for Treatment of Cannabinoid Hyperemesis Syndrome. Acad Emerg Med. 2020;27(11):1166-1172. https://doi.org/10.1111/acem.14062

for a patient with cannabis hyperemesis syndrome.

Clinical Utility Of Abbreviated Eeg Monitoring In Patients Unable To Tolerate A Long-Term, Ambulatory Eeg, Jack T. Mcconnell

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Lee C, Lim S-N, Lien F, et al. Duration of electroencephalographic recordings in patients with epilepsy. Seizure. 2013;22(6):438-442. https://10.1016/j.seizure.2013.02.016

for a patient with an inability to tolerate a long-term, ambulatory EEG.

Breast Cancer Screening In Transgender Women With High-Risk Family History, John F. Lloyd

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

de Blok CJM, Wiepjes CM, Nota NM, et al. Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ. 2019;365:l1652. https://doi.org/10.1136/bmj.l1652

for a transgender woman with family history of breast cancer.

The Use Of Chewing Gum To Alleviate Thirst In Chf Patients Requiring Fluid Restrictions And Oral Diuretics, Madeline B. Simone

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Allida SM, Shehab S, Inglis SC, Davidson PM, Hayward CS, Newton PJ. A RandomisEd ControLled TrIal of ChEwing Gum to RelieVE Thirst in Chronic Heart Failure (RELIEVE-CHF). Heart Lung Circ. 2021;30(4):516-524. https://doi.org/10.1016/j.hlc.2020.09.004

for a woman with heart failure and under fluid restriction.

Exploring Alternative Treatment Options For A Patient With Acute Disseminated Encephalomyelitis (Adem) Suffering From Iatrogenic Cushing’S Symptoms, Alejandro Ponce Sepulveda

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Ravaglia, S,MD, P., Piccolo G, MD, Ceroni M, MD, et al. Severe steroid-resistant post-infectious encephalomyelitis: General features and effects of IVIg. J Neurol. 2007;254(11):1518-23. https://doi.org/10.1007/s00415-007-0561-4

for a patient with ADEM and iatrogenic Cushing’s secondary to long-term high dose corticosteroid therapy.

Etanercept, Methotrexate, Or Combined Therapy For Improving Rheumatoid Arthritis Symptoms, Ajith Dupati

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

van der Heijde D, Klareskog L, Rodriguez-Valverde V, et al. Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum. 2006;54(4):1063-1074. https://doi.org/10.1002/art.21655

for a patient with rheumatoid arthritis.

Use Of Empagliflozin As An Adjuvant Treatment For Obstructive Sleep Apnea For A Patient Who Has Not Seen A Physician In Over 40 Years, Andrew Demko

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Neeland IJ, Eliasson B, Kasai T, et al. The Impact of Empagliflozin on Obstructive Sleep Apnea and Cardiovascular and Renal Outcomes: An Exploratory Analysis of the EMPA-REG OUTCOME Trial. Diabetes Care. 2020;43(12):3007-3015. https://doi.org/10.2337/dc20-1096

for a patient with obstructive sleep apnea who has not seen a physician in over 40 years.

Mirabegron Does Not Adversely Impact Cognitive Function In Older Adults With Overactive Bladder Compared To Placebo, Sanjna Ghanshani, Abbie R. Bauer

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Griebling TL, Campbell NL, Mangel J, et al. Effect of mirabegron on cognitive function in elderly patients with overactive bladder: MoCA results from a phase 4, randomized, placebo-controlled study (PILLAR). BMC Geriatr. 2020;20(1):109. https://doi.org/10.1186/s12877-020-1474-7

for a patient with a history of lacunar infarctions who is experiencing urge incontinence.

Predictors And Diagnosis Of Adjustment Disorder In A Middle-Aged Patient With Cholangiocarcinoma, Zoya Gurm, Abbie R. Bauer

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Hund B, Reuter K, Härter M, et al. Stressors, Symptom Profile, and Predictors of Adjustment Disorder in Cancer Patients. Results from an Epidemiological Study with the Composite International Diagnostic Interview, Adaptation for Oncology (CIDI-O). Depression and Anxiety. 2016;33(2):153. https://doi.org/10.1002/da.22441

for a patient with recently diagnosed solid tumor malignancy.

Safety Of Ipsilateral Intravenous Access In Breast Cancer Surgery Patients, Austin J. Piontkowski, Abbie R. Bauer

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report appraising

Naranjo J, Portner ER, Jakub JW, Cheville AL, Nuttall GA. Ipsilateral Intravenous Catheter Placement in Breast Cancer Surgery Patients. Anesth Analg. 2021 Sep 1;133(3):707-712. https://doi.org/10.1213/ANE.0000000000005597

for a post-lumpectomy patient requiring ipsilateral peripherally inserted central catheter.

Cocaine-Induced Dna-Dependent Protein Kinase Relieves Rnap Ii Pausing By Promoting Trim28 Phosphorylation And Rnap Ii Hyperphosphorylation To Enhance Hiv Transcription, Adhikarimayum Lakhikumar Sharma, Priya Tyagi, Meenata Khumallambam, Mudit Tyagi

Center for Translational Medicine Faculty Papers

Drug abuse continues to pose a significant challenge in HIV control efforts. In our investigation, we discovered that cocaine not only upregulates the expression of the DNA-dependent protein kinase (DNA-PK) but also augments DNA-PK activation by enhancing its phosphorylation at S2056. Moreover, DNA-PK phosphorylation triggers the higher localization of the DNA-PK into the nucleus. The finding that cocaine increases the nuclear localization of the DNA-PK provides further support to our observation of enhanced DNA-PK recruitment at the HIV long terminal repeat (LTR) following cocaine exposure. By activating and facilitating the nuclear localization of the DNA-PK, cocaine effectively orchestrates multiple stages …

Avaren-Fc, A Novel Immunotherapeutic, Recruits Nk Cells In B16f10 Melanoma Tumor Tissue, Sreevatsa Vemuri, Katarina L Mayer, Nobuyuki Matoba

The Cardinal Edge

Melanoma is the fifth most common cancer in the US, with limited effective immunotherapeutic options available for patients. Avaren-Fc (AvFc) is a novel experimental immunotherapeutic agent with a unique “lectibody” property. It is capable of targeting cancer cells through the selective recognition of high mannose glycans, which are aberrantly overrepresented on the surface of malignant cells. Upon binding to cancer cells, AvFc can interact with circulating effector immune cells equipped with Fc receptors, such as natural killer (NK) cells to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and kill the cancer cells. Previous work has shown that AvFc effectively induces ADCC activity …

Ansa Cervicalis-To-Phrenic Nerve Transfer: Technical Note With Potential Application For Diaphragmatic Reanimation In Patients With High Cervical Spinal Cord Injury, Jonathan Melnick, Mohammadali M. Shoja, Gary B. Schwartz

HCA-NSU MD Research Day

Objective. This study was conducted to determine whether utilization of the superior root of ansa cervicalis (SRAC) as the donor for phrenic nerve (PN) transfer is technically feasible. Background. In patients with high cervical spinal cord injury resulting in diaphragmatic paralysis, another donor, the spinal accessory nerve, has been used successfully to reinnervate the PN and restore diaphragmatic function. Methods. Eight neck sides underwent cadaveric surgery. The sternocleidomastoid muscle was retracted posteriorly, the SRAC and PN were isolated, and the SRAC was cut near its distal end and transposed to the ipsilateral PN as it crossed the anterior scalene muscle. …

The Importance Of Including Maternal Immune Activation In Animal Models Of Hypoxic-Ischemic Encephalopathy, Bailey Collins, Elise A. Lemanski, Elizabeth Wright-Jin

Department of Medicine Faculty Papers

Hypoxic-ischemic encephalopathy (HIE) is a perinatal brain injury that is the leading cause of cerebral palsy, developmental delay, and poor cognitive outcomes in children born at term, occurring in about 1.5 out of 1000 births. The only proven therapy for HIE is therapeutic hypothermia. However, despite this treatment, many children ultimately suffer disability, brain injury, and even death. Barriers to implementation including late diagnosis and lack of resources also lead to poorer outcomes. This demonstrates a critical need for additional treatments for HIE, and to facilitate this, we need translational models that accurately reflect risk factors and interactions present in …

Summary Of: Reaching Structurally Vulnerable Populations Using Low-Barrier Covid-19 Testing Clinics Co-Created With Community Based Organizations, David Ngandu, Gloria Sclar, Ambia Ahmed, Sumayo A Awale, Caroline Fernandes, Joshua Goldstein, Hina Hashmi, Shruti Joshi, Et Al.

Northern New England Clinical & Translational Research

The COVID-19 pandemic disproportionately affected people from structurally vulnerable communities. There was a need to improve COVID-19 testing in these communities to reduce viral spread and connect to treatment.

Study @ "Reaching Structurally Vulnerable Populations Using Low-Barrier COVID-1" by David Ngandu, Gloria D Sclar et al.

Metastatic Recurrence In Women Diagnosed With Non-Metastatic Breast Cancer: A Systematic Review And Meta-Analysis, Eileen Morgan, Colette O’Neill, Richa Shah, Oliver Langselius, Yaqi Su, Clara Frick, Hanna Fink, Aude Bardot, Miriam Mutebi, Paul Walsh

General Surgery, East Africa

Background: To assess proportions of metastatic recurrence in women initially diagnosed with non-metastatic breast cancer by stage at diagnosis, breast cancer subtype, calendar period and age.

Methods: A systematic search of MEDLINE and Web of Science databases (January 2010–12 May 2022) was conducted. Studies reporting the proportion of distant metastatic recurrence in women with non-metastatic breast cancer were identified and outcomes and characteristics were extracted. Risk of bias was assessed independently by two reviewers. Random-effects meta-analyses of proportions were used to calculate pooled estimates and 95% confidence intervals (CIs).

Results: 193 studies covering over 280,000 patients were included in the …

Recovery After Human Bone Marrow Mesenchymal Stem Cells (Hbm-Mcs)-Derived Extracellular Vesicles (Evs) Treatment In Post-Mcao Rats Requires Repeated Handling, Yolanda Gomez-Galvez, Malvika Gupta, Mandeep Kaur, Salvatore Fusco, Maria Vittoria Podda, Claudio Grassi, Amit K. Srivastava, Lorraine Iacovitti, Elena Blanco-Suarez

Farber Institute for Neuroscience Faculty Papers

Rehabilitation is the only current intervention that improves sensorimotor function in ischemic stroke patients, similar to task-specific intensive training in animal models of stroke. Bone marrow mesenchymal stem cells (BM-MSCs)-derived extracellular vesicles (EVs) are promising in restoring brain damage and function in stroke models. Additionally, the non-invasive intranasal route allows EVs to reach the brain and target specific ischemic regions. Yet unclear is how handling might enhance recovery or influence other therapies such as EVs after stroke. We used the transient middle cerebral artery occlusion (MCAO) model of stroke in rats to assess how intensive handling alone, in the form …

Genetic Knock-In Of Eif2ak3 Variants Reveals Differences In Perk Activity In Mouse Liver And Pancreas Under Endoplasmic Reticulum Stress, Shivesh Ghura, Noah R. Beratan, Xinglong Shi, Elena Alvarez-Periel, Sarah E. Bond Newton, Cagla Akay-Espinoza, Kelly L. Jordan-Sciutto

Farber Institute for Neuroscience Staff Papers and Presentations

Common single-nucleotide variants (SNVs) of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3) slightly increase the risk of disorders in the periphery and the central nervous system. EIF2AK3 encodes protein kinase RNA-like endoplasmic reticulum kinase (PERK), a key regulator of ER stress. Three exonic EIF2AK3 SNVs form the PERK-B haplotype, which is present in 28% of the global population. Importantly, the precise impact of these SNVs on PERK activity remains elusive. In this study, we demonstrate that PERK-B SNVs do not alter PERK expression or basal activity in vitro and in the novel triple knock-in mice expressing the exonic …

The Left Ventricle Under Stress: Exploring The Impact Of Gestational Stress On Postpartum Cardiovascular Health, Archana Ramesh

Senior Theses

A woman’s cardiovascular system undergoes several changes to equip it for the physiological demands of pregnancy. The left ventricle (LV) is most susceptible to changes such as increased cardiac output and workload because it is the primary chamber in the heart that pumps oxygenated blood to the entire body. Some mothers may be unable to cope with the physiological demands, and ventricular hypertrophy, along with other cardiac remodeling that takes place during pregnancy, may bring light to underlying cardiovascular disease (CVD). The peripartum period often comes with heightened stress, disproportionately for certain populations, and this stress has been linked with …

Evaluating The Impact Of Spot Position Errors On Dose Distribution: A Comparison Between Spot-Scanning Arc Therapy (Sparc) And Intensity-Modulated Proton Therapy (Impt), Peilin Liu, Lewei Zhao, Gang Liu, Xiaoda Cong, Xiaoqiang Li, Xuanfeng Ding

Conference Presentation Abstracts

Purpose: To quantitatively investigate the impact of spot position error (PE) on the dose distribution in (Spot-scanning arc therapy) SPArc plans versus Intensity-Modulated Proton Therapy (IMPT).

Methods:

Four representative disease sites, including brain, lung, liver, and prostate cancers, were retrospectively selected. Spot position errors were simulated during dynamic SPArc treatment delivery. Two types of errors were generated, including randomized error and systematic error. For each random error scenario, they were further examined across four sub-scenarios (25%, 50%, 75%, and 100% of spots affected) at 1 mm and 2 mm deviations.The randomized errors used two categories with and without Gaussian distribution …

Fair Compensation For Patient Partners In Clinical Research: Perspectives And Practices, Michelle Culp

Doctor of Philosophy in Translational Health Sciences Dissertations

Engaging patient partners in clinical trial design is a valuable process for making trials more patient-centric, resulting in greater patient participation in clinical trials, better generalizability of results and more outcomes of relevance to patients and providers. Patient partners are people with a disease or condition who are involved in clinical trial planning, conduct, and dissemination with clinical trial researchers. Patient engagement is the meaningful and collaborative interaction between patient partners and clinical trial researchers across the clinical trial lifecycle where research decision-making is guided by patient partners’ input about their lived experiences. Patient partners, clinical trial researchers, funders, and …

Downregulation Of Piezo2 In The Detrusor Of Men With Bladder Outlet Obstruction And Its Association With Urinary Retention And Decreased Bladder Compliance, Carlos Henrique Suzuki Bellucci, Thiago Souto Hemerly, Luisa Resende Tenório De Albuquerque, Ruan Pimenta, Vanessa Guimaraes Schreiter, Sabrina Thalita Dos Reis, Jose De Bessa Jr, Katia Ramos Moreira Leite, Alberto Antunes, Boopathi Ettickan, William C. Nahas, Cristiano Mendes Gomes

Center for Translational Medicine Faculty Papers

PURPOSE: Recent research has highlighted the mechanotransducer PIEZO2 as a crucial factor in lower urinary tract function, demonstrating associations with bladder compliance (BC), bladder wall thickening, and elevated bladder pressure. We explored the hypothesis that PIEZO2 expression may be associated with lower urinary tract dysfunction in men with bladder outlet obstruction (BOO) due to benign prostatic hyperplasia (BPH).

METHODS: The study included a consecutive series of patients undergoing open prostatectomy for BPH at our hospital between September 2014 and January 2016. All participants underwent comprehensive preoperative evaluations, including urodynamic assessments. During prostatectomy, a full-thickness fragment of the bladder wall was …

Inhibiting Endothelial Cell Mst1 Attenuates Acute Lung Injury In Mice, Zhi-Fu Guo, Nopprarat Tongmuang, Chao Li, Chen Zhang, Louis Hu, Daniel Capreri, Mei-Xing Zuo, Ross Summer, Jianxin Sun

Center for Translational Medicine Faculty Papers

Lung endothelium plays a pivotal role in the orchestration of inflammatory responses to acute pulmonary insults. Mammalian sterile 20-like kinase 1 (Mst1) is a serine/threonine kinase that has been shown to play an important role in the regulation of apoptosis, stress responses, and organ growth. This study investigated the role of Mst1 in lung endothelial activation and acute lung injury (ALI). We found that Mst1 was significantly activated in inflamed lung endothelial cells (ECs) and mouse lung tissues. Overexpression of Mst1 promoted nuclear factor κ-B (NF-κB) activation through promoting JNK and p38 activation in lung ECs. Inhibition of Mst1 by …

Developing Coexpression Systems To Introduce Hydroxyproline Into Protein Engineered Collagen Peptides Utilizing Hydroxylase From Acanthamoeba Polyphaga Mimivirus, Jennifer Soldatich

Theses and Dissertations

A major challenge of developing collagen mimetic peptides (CMPs) by bacterial expression is to include hydroxyproline for biomedical applications. Coexpression of Prolyl-4-hydroxylase from A.mimivirus with CMPs was investigated. Additionally, four expression designs were created for potential applications in mammalian cells to utilize their natural ability of proline-hydroxylation by post-translational modification.