Translational Medical Research Commons^™

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.

Proteomic Profile Of The Icam1 Pk56m Hfpef Risk Variant, Pedro Giro, Mallory Filipp, Michael J Zhang, Ethan D Moser, Edward B Thorp, Prarthana J Dalal, Ravi V Shah, Patrick T Ellinor, Jonathan W Cunningham, Sean J Jurgens, Arjun Sinha, Laura Rasmussen-Torvik, Jorge Kizer, Kent D Taylor, Philip Greenland, Bruce M Psaty, Russell P Tracy, Lin Yee Chen, Amil M Shah, Bing Yu, Sanjiv J Shah, Ravi B Patel

Faculty, Staff and Student Publications

A common missense variant in ICAM1 among African American individuals (rs5491; pK56M) has been associated with risk of heart failure with preserved ejection fraction (HFpEF), but the pathways that lead to HFpEF among those with this variant are not clear. In this analysis of 92 circulating proteins and their associated networks, we identified 7 circulating inflammatory proteins associated with rs5491 among >600 African American individuals. Using weighted coexpression network analysis, 3 protein networks were identified, one of which was associated with rs5491. This protein network was most highly represented by members of the tumor necrosis receptor superfamily. The rs5491 variant …

Utilizing Thalamic Deep Brain Stimulation For An Electronic Seizure Diary In A Definite Sudden Unexpected Death In Epilepsy Case, Surya Suresh, Yash Vakilna, Vladimir Vashin, Samden Lhatoo, Sandipan Pati

Faculty, Staff and Student Publications

Objective: Sudden unexpected death in epilepsy (SUDEP) is a serious threat to individuals with intractable epilepsies, contributing to premature mortality. Understanding the elusive pathophysiological mechanisms of SUDEP, especially in cases without observable terminal events, remains a crucial area for investigation. This study aimed to shed light on the burden of epileptiform activity preceding SUDEP by utilizing an automated electronic seizure diary derived from a sensing-enabled thalamic deep brain stimulator (DBS).

Methods: Herein, we present the case of a 57-year-old man afflicted with intractable multifocal epilepsy secondary to cortical dysplasia and encephalomalacia resulting from severe traumatic brain injury. Despite an initial …

Exploit The Potential Clinical Benefit Of Using Proton Arc Therapy For Esophageal Cancer, Peilin Liu, Xiaoda Cong, Raymond Dalfsen, Martin Soukup, James E. Dolan, Shupeng Chen, Craig Stevens, Rohan Deroniyagala, Xiaoqiang Li, Xuanfeng Ding

Conference Presentation Abstracts

No abstract provided.

Quantitative Evaluation Of Gantry Rotation Perturbation Effects On Spot-Scanning Arc Therapy (Sparc), Peilin Liu, Lewei Zhao, Gang Liu, Xiaoda Cong, Xiaoqiang Li, Xuanfeng Ding

Conference Presentation Abstracts

Purpose: To quantitatively assess the impact of random gantry rotation perturbations on spot-scanning arc (SPArc) therapy.

Methods:

To simulate random gantry rotation perturbations, the initial gantry angle of SPArc treatment plans was modified using an in-house script. Four cases from different disease sites include brain, lung, liver and prostate were selected to evaluate. Original SPArc plans (SPArc_org) were developed through iterative processes, including control point re-sampling, redistribution of control points & energy layers, energy layer filtration, and re-sampling. Considering potential limitations, rotation perturbations of 1mm and 2mm were applied to al SPArc_org plans to generate perturbed SPArc …

Emerin Deficiency Drives Mcf7 Cells To An Invasive Phenotype, Emily Hansen, Christal Rolling, Matthew Wang, James M Holaska

Rowan-Virtua School of Osteopathic Medicine Departmental Research

During metastasis, cancer cells traverse the vasculature by squeezing through very small gaps in the endothelium. Thus, nuclei in metastatic cancer cells must become more malleable to move through these gaps. Our lab showed invasive breast cancer cells have 50% less emerin protein resulting in smaller, misshapen nuclei, and higher metastasis rates than non-cancerous controls. Thus, emerin deficiency was predicted to cause increased nuclear compliance, cell migration, and metastasis. We tested this hypothesis by downregulating emerin in noninvasive MCF7 cells and found emerin knockdown causes smaller, dysmorphic nuclei, resulting in increased impeded cell migration. Emerin reduction in invasive breast cancer …

Structural Basis For A Polθ Helicase Small-Molecule Inhibitor Revealed By Cryo-Em, Fumiaki Ito, Ziyuan Li, Leonid Minakhin, Gurushankar Chandramouly, Mrityunjay Tyagi, Robert Betsch, John J. Krais, Bernadette Taberi, Umeshkumar Vekariya, Marissa L Calbert, Tomasz Skorski, Neil Johnson, Xiaojiang S. Chen, Richard T. Pomerantz

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

DNA polymerase theta (Polθ) is a DNA helicase-polymerase protein that facilitates DNA repair and is synthetic lethal with homology-directed repair (HDR) factors. Thus, Polθ is a promising precision oncology drug-target in HDR-deficient cancers. Here, we characterize the binding and mechanism of action of a Polθ helicase (Polθ-hel) small-molecule inhibitor (AB25583) using cryo-EM. AB25583 exhibits 6 nM IC50 against Polθ-hel, selectively kills BRCA1/2-deficient cells, and acts synergistically with olaparib in cancer cells harboring pathogenic BRCA1/2 mutations. Cryo-EM uncovers predominantly dimeric Polθ-hel:AB25583 complex structures at 3.0-3.2 Å. The structures reveal a binding-pocket deep inside the helicase central-channel, which underscores the high specificity …

The Impact Of Minimally Processed High Fat Meals On Postprandial Glucose, Lipids And Metabolic Index In Pre-Diabetics, Oluwafemi Ayoola

Masters Theses, 2020-current

There is an increasing global prevalence of prediabetes, commonly diagnosed through increased fasting glucose (GLU). Elevated levels of GLU and triglycerides (TRG) have also been linked with more severe diabetes-related complications. Even a single high-fat meal (HFM) may result in adverse metabolic outcomes, in healthy individuals and prediabetics, which are a better predictor of disease risk than measuring fasting levels. Therefore, reducing these metabolic outcomes after a typical HFM often consumed in the Western diet is of critical importance to reduce chronic disease risk. The aim is to determine whether incorporating polyphenols and dietary fiber into an HFM would reduce …

Molecular Mechanism Of Bitter Taste Receptor Agonist-Mediated Relaxation Of Airway Smooth Muscle, Stanley Conaway, Weiliang Huang, Miguel A. Hernandez-Lara, Maureen A. Kane, Raymond B. Penn, Deepak A. Deshpande

Center for Translational Medicine Faculty Papers

G-protein-coupled receptors (GPCRs) belonging to the type 2 taste receptors (TAS2Rs) family are predominantly present in taste cells to allow the perception of bitter-tasting compounds. TAS2Rs have also been shown to be expressed in human airway smooth muscle (ASM), and TAS2R agonists relax ASM cells and bronchodilate airways despite elevating intracellular calcium. This calcium “paradox” (calcium mediates contraction by pro-contractile Gq-coupled GPCRs) and the mechanisms by which TAS2R agonists relax ASM remain poorly understood. To gain insight into pro-relaxant mechanisms effected by TAS2Rs, we employed an unbiased phosphoproteomic approach involving dual-mass spectrometry to determine differences in the phosphorylation of contractile-related …

In Search Of The Locus Coeruleus: Guidelines For Identifying Anatomical Boundaries And Electrophysiological Properties Of The Blue Spot In Mice, Fish, Finches, And Beyond, Amelien Vreven, Gary Aston-Jones, Anthony E Pickering, Gina R Poe, Barry Waterhouse, Nelson K Totah

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Our understanding of human brain function can be greatly aided by studying analogous brain structures in other organisms. One brain structure with neurochemical and anatomical homology throughout vertebrate species is the locus coeruleus (LC), a small collection of norepinephrine (NE)-containing neurons in the brainstem that project throughout the central nervous system. The LC is involved in nearly every aspect of brain function, including arousal and learning, which has been extensively examined in rats and nonhuman primates using single-unit recordings. Recent work has expanded into putative LC single-unit electrophysiological recordings in a nonmodel species, the zebra finch. Given the importance of …

Exploring Negotiated Autonomy In The Physician–Physician Assistant Collaborative Dyad, Stephen Robie

Doctor of Philosophy in Translational Health Sciences Dissertations

Physician Assistants (PAs) are integral members of multidisciplinary medical care teams who practice medicine legally under the supervision of physicians. During medical care, supervision is a dynamic process of collaboration wherein a PA who displays competence is granted increasing independence by the supervising physician. This process has been referred to as negotiated autonomy. Despite being noted in work-force literature, the mechanics of how negotiated autonomy operates in real-time have not been described. As organizations increasingly work to integrate PAs into practice, new-hire training programs called ‘on-boarding’ have been implemented to accelerate PA professional development with a goal of increased efficiency …

Exercise Is A Vital Sign, Megan Dannemiller, Anthony Shadiack, Marvin Sineath Jr, Andrew Baird, Marc Poirier, Kevin Thomas, Michael G. Flynn

HCA Healthcare Journal of Medicine

In this review, we argue that exercise (physical activity) be monitored as a vital sign since no other basic sign or symptom provides as much information about a patient's health status. The influence of regular exercise on patient health is indisputable, with strong evidence to show the power of exercise to mitigate chronic disease and improve overall health. Several simple tools, such as Physical Activity as a Vital Sign and Exercise as a Vital Sign are available to assess patient physical activity. When properly applied, there is evidence to support the efficacy of these tools, but there are barriers that …

Novel Adaptations In Iron Regulation Acquired During Chronic Fungal Cf Infections, Daniel R. Murante

Dartmouth College Ph.D Dissertations

Chronic fungal infections are highly recalcitrant to treatment; we postulated that as populations persist, increasing genetic diversity is reflected in phenotypic heterogeneity, contributing to treatment inefficacies. The study of evolutionary patterns is underrepresented in chronic fungal infections, and to supplement this body of knowledge, we leveraged isolates acquired from four individuals with chronic fungal-dominated cystic fibrosis infections. We evaluated in-host evolution through a whole-genome sequencing approach, comparing multiple isolates obtained from each subject's sputum and bronchoalveolar lavage fluid. Our analysis found non-synonymous mutations that arose in parallel across the independent infections in the gene MRS4, which encodes a mitochondrial …

Global Implications Of Covid-19 On Education And Research In Healthcare And Stem: Analysis Of Case Studies, Yumna Indorewala, Santanu De

FDLA Journal

The zoonotic novel coronavirus, SARS-CoV-2 posed major threats to the world’s economy, social development, and public health. Education and research in STEM and healthcare were no exceptions to the global implications of the Coronavirus Infectious Disease 2019 (COVID-19) pandemic. Social distancing guidelines were initially recommended to refrain from in-person operations for preventing the transmission of the virus. As academic organizations implemented multifarious methods to effectively transition to remote/online or hybrid educational formats, COVID-19 necessitated designing, adopting, as well as evaluating the efficacy of new instructional approaches, especially for disciplines that require active, experiential learning such as healthcare and STEM. These …