Chemicals and Drugs Commons^™

Epigenetic Profiling Of Cell-Free Dna In Cerebrospinal Fluid: A Novel Biomarker Approach For Metabolic Brain Diseases, Kyle Sporn, Rahul Kumar, Kiran Marla, Puja Ravi, Swapna Vaja, Phani Paladugu, Nasif Zaman, Alireza Tavakkoli

SKMC Student Presentations and Publications

Due to their clinical heterogeneity, nonspecific symptoms, and the limitations of existing biomarkers and imaging modalities, metabolic brain diseases (MBDs), such as mitochondrial encephalopathies, lysosomal storage disorders, and glucose metabolism syndromes, pose significant diagnostic challenges. This review examines the growing potential of cell-free DNA (cfDNA) derived from cerebrospinal fluid (CSF) epigenetic profiling as a dynamic, cell-type-specific, minimally invasive biomarker approach for MBD diagnosis and monitoring. We review important technological platforms and their use in identifying CNS-specific DNA methylation patterns indicative of neuronal injury, neuroinflammation, and metabolic reprogramming, including cfMeDIP-seq, enzymatic methyl sequencing (EM-seq), and targeted bisulfite sequencing. By synthesizing current …

Choline-An Essential Nutrient With Health Benefits And A Signaling Molecule, Brianne C. Burns, Jitendra D. Belani, Hailey N. Wittorf, Eugen Brailoiu, G. Cristina Brailoiu

College of Pharmacy Faculty Papers

Choline has been recognized as an essential nutrient involved in various physiological functions critical to human health. Adequate daily intake of choline has been established by the US National Academy of Medicine in 1998, considering choline requirements for different ages, sex differences and physiological states (e.g., pregnancy). By serving as a precursor for acetylcholine and phospholipids, choline is important for cholinergic transmission and the structural integrity of cell membranes. In addition, choline is involved in lipid and cholesterol transport and serves as a methyl donor after oxidation to betaine. Extracellular choline is transported across the cell membrane via various transport …

A Genetically-Engineered Thyroid Gland Built For Selective Triiodothyronine Secretion, Cintia E. Citterio, Berenice Morales-Rodriguez, Xiao-Hui Liao, Catherine Vu, Rachel Nguyen, Jessie Tsai, Jennifer Le, Ibrahim Metawea, Ming Liu, David P. Olson, Samuel Refetoff, Peter Arvan

Pharmacy Faculty Articles and Research

Thyroid hormones (thyroxine, T₄, and triiodothyronine, T₃) are indispensable for sustaining vertebrate life, and their deficiency gives rise to a wide range of symptoms characteristic of hypothyroidism, affecting 5–10% of the world’s population. The precursor for thyroid hormone synthesis is thyroglobulin (Tg), a large iodoglycoprotein consisting of upstream regions I-II-III (responsible for synthesis of most T₄) and the C-terminal CholinEsterase-Like (ChEL) domain (responsible for synthesis of most T₃, which can also be generated extrathyroidally by T₄ deiodination). Using CRISPR/Cas9-mediated mutagenesis, we engineered a knock-in of secretory ChEL into the endogenous TG …

Multiscale Modeling And Dynamic Mutational Profiling Of Binding Energetics And Immune Escape For Class I Antibodies With Sars-Cov-2 Spike Protein: Dissecting Mechanisms Of High Resistance To Viral Escape Against Emerging Variants, Mohammed Alshahrani, Vedant Parikh, Brandon Foley, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

The rapid evolution of SARS-CoV-2 has underscored the need for a detailed understanding of antibody binding mechanisms to combat immune evasion by emerging variants. In this study, we investigated the interactions between Class I neutralizing antibodies—BD55-1205, BD-604, OMI-42, P5S-1H1, and P5S-2B10—and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein using multiscale modeling, which combined molecular simulations with the ensemble-based mutational scanning of the binding interfaces and binding free energy computations. A central theme emerging from this work is that the unique binding strength and resilience to immune escape of the BD55-1205 antibody are determined by leveraging a broad epitope …

Templating Of Monomeric Alpha-Synuclein Results In Inflammation And Snpc Dopamine Neuron Death In A Genetic Mouse Model Of Induced Synucleinopathy, Matthew D. Byrne, Peyman Petramfar, Jae-Kyung Lee, Richard J. Smeyne

Department of Neuroscience Faculty Papers

While the etiology of most cases of Parkinson's disease (PD) are idiopathic, it has been estimated that 5-10% of PD arise from known genetic mutations. The first mutations described that leads to the development of an autosomal dominant form of PD are in the SNCA gene that codes for the protein alpha-synuclein (α-syn). α-syn is an abundant presynaptic protein that is natively disordered and whose function is still unclear. In PD, α-syn misfolds into multimeric b-pleated sheets that aggregate in neurons (Lewy Bodies/neurites) and spread throughout the neuraxis in a pattern that aligns with disease progression. Here, using IHC, HC, …

The Effect Of Tranexamic Acid On Blood Coagulation In Primary Total Hip Arthroplasty Using Rotational Thromboelastometry: A Randomized Controlled Trial, Uzung Yoon, David Beausang, Elia Elia, Marc Torjman, Jeffrey Mojica, James J. Purtill, David Nazarian, P. Maxwell Courtney, Yoogoo Kang

Department of Anesthesiology Faculty Papers

BACKGROUND: Tranexamic acid (TXA), is commonly administered prophylactically to reduce blood loss in patients undergoing total hip arthroplasty (THA). However, its effect has never been studied. We hypothesized that no difference exists in the degree of fibrinolysis and blood loss between patients receiving prophylactic TXA and placebo.

METHODS: This double-blinded randomized-controlled trial included 50 patients undergoing primary THA in 2021-2023. Clinicaltrials.gov (NCT03897621). Rotational-thromboelastometry (ROTEM) were performed to test blood coagulability using non citrated whole blood (NATEM) and blood treated with TXA (T-APTEM). The intervention group received TXA intravenously. The placebo group received 0.9% sodium chloride solution. The primary outcome measure …

Pembrolizumab And Lenvatinib In The Treatment Of Recurrent Ovarian Carcinoma: A Single Institution Experience, Helen Toma, Rebeca Kelly, Chelsea Katz, Hannah Hong, Hannah Diasti, David P Warshal, Lauren Krill

Kimmel Cancer Center Faculty Papers

BACKGROUND: Advanced stage ovarian carcinoma has a poor prognosis with recurrence rates of over 80%, 5-year survival of 36-45%, and limited response to standard therapy. Pembrolizumab and lenvatinib are FDA approved for treatment of microsatellite stable (MSS)/mismatch repair proficient (pMMR) endometrial and renal cell cancers. Early phase II studies have shown promising results in a variety of advanced solid tumors, including ovarian cancer. We report on the clinical outcome of recurrent MSS/pMMR ovarian cancer patients treated with this therapy.

METHODS: For this retrospective cohort study, patients with a diagnosis of ovarian cancer treated with pembrolizumab and lenvatinib from January 2020 …

Effect Of Margin Thickness And Cement Gap On The Fabrication And Fit Accuracy Of Additively Manufactured Crowns In Definitive Resins With Different Filler Content, Mustafa Borga Dönmez, Gülce Çakmak, Çiğdem Kahveci, Amir H. Nejat, Burak Yilmaz, Pinar Altinci

School of Dentistry Faculty Publications

PURPOSE: To evaluate how commercially available composite resins in varying filler content affect the fabrication and fit accuracy (trueness and precision) of additively manufactured (AM) definitive crowns with different margin thickness and cement gaps by comparing them to subtractively manufactured (SM) polymer-infiltrated ceramic crowns. MATERIALS AND METHODS: Two identical unprepared mandibular right first molars were prepared by an experienced prosthodontist for crowns with either 0.5 mm or 1.0 mm chamfer margins, verified using silicone indexes and a periodontal probe, and then digitized with an industrial-grade scanner. These scan files were used to design reference crowns with either 50-µm or 80-µm …

Nitric Oxide Does Not Improve Liver Mitochondrial Function 48 Hours After Cecal Ligation And Perforation In Experimental Sepsis, Pierre Eyenga, Shey-Shing Sheu

Center for Translational Medicine Faculty Papers

Nitric oxide (NO) has a dual effect on mitochondria. Incubating liver mitochondria with NO improves oxidative phosphorylation (OXPHOS) efficiency by decreasing state 4 respiration more than ATP synthesis and preventing mitochondrial permeability transition pore (mPTP) opening. We evaluated the effect of L-arginine (L-arg), an NO donor, on isolated liver mitochondrial respiration and mPTP in sepsis. Male mice were subjected to cecal ligation and perforation (CLP) with saline resuscitation or sham. After 8, 24, and 48 h, with and without L-arg, we measured isolated liver mitochondrial respiration and cytochrome c oxidase (COX) activity using polarographic methods and calcium retention capacity (CRC) …

Novel Piperidone And Bispidine Derivatives: A New Approach In Cancer Therapy, Lereen Khaled Youssry

Theses and Dissertations

Cancer remains the second leading cause of death worldwide. As a result, scientists have been trying to find novel therapeutic approaches that target specific metabolic pathways selective to tumor cells. In this study, two novel piperidone and bispidine derivatives, organic molecules that target polyamine metabolism, were synthesized, and their potential cytotoxic, antioxidant and anti-inflammatory effects were investigated. Polyamines are naturally occurring metabolites that were reported to be in excess at cancer cells and were accounted for tumor proliferation, invasion and metastasis. Accordingly, the novel piperidone and bispidine derivatives were expected to disrupt tumor growth and progression via up-regulation of key …

Identification Of Serum Exosome Proteins In Systemic Sclerosis With Interstitial Lung Disease By Aptamer Proteomics, Sonsoles Piera-Velazquez, Simon T. Dillon, Xuesong Gu, Towia A. Libermann, Sergio A. Jimenez

Jefferson Institute of Molecular Medicine Papers and Presentations

OBJECTIVE: A major unmet need for Systemic Sclerosis (SSc) clinical management is the absence of well validated biomarkers for early diagnosis of SSc-associated interstitial lung disease (SSc-ILD). The objective of this study was to identify proteins contained within serum exosomes that may serve as potential biomarkers to differentiate patients with Diffuse SSc without SSc-ILD from patients with Diffuse SSc with SSc-ILD employing aptamer-based proteomics.

METHODS: Serum exosomes were isolated from two cohorts of patients. The first cohort included 15 patients with Diffuse SSc without SSc-ILD and 14 patients with Diffuse SSc with SSc-ILD and the second cohort included 12 patients …

Prognostic Value Of Lipoprotein(A) For Cardiovascular Events After Lower Limb Revascularization In Diabetic Patients With Chronic Limb-Threatening Ischemia, Federico Biscetti, Maria Margherita Rando, Maria Anna Nicolazzi, Flavia Angelini, Roberto Iezzi, Luis H. Eraso, Paul J. Dimuzio, Dario Pitocco, Massimo Massetti, Antonio Gasbarrini, Andrea Flex

Department of Surgery Faculty Papers

BACKGROUND: Chronic limb-threatening ischemia (CLTI) presents a major clinical challenge in patients with Type 2 Diabetes Mellitus (T2DM), requiring lower extremity revascularization (LER) to mitigate adverse cardiovascular and limb outcomes. Lipoprotein(a) (Lp(a)) has been implicated in cardiovascular risk, but its role in patients with T2DM and CLTI undergoing revascularization remains unclear. Thus, this study aimed to investigate the prognostic value of Lp(a) levels in diabetic CLTI patients for major adverse cardiovascular events (MACE), major adverse limb events (MALE), or both after LER.

METHODS: In this prospective cohort study of 158 individuals with T2DM and CLTI undergoing LER, baseline clinical data …

First-In-Human Phase I Open-Label Study Of The Anti-Tim-3 Monoclonal Antibody Incagn02390 In Patients With Select Advanced Or Metastatic Solid Tumors, Martin E. Gutierrez, Shou Ching Tang, John D. Powderly, Ani S. Balmanoukian, Paul E. Hoyle, Zhiwan Dong, Lulu Cheng, Xiaohua Gong, John E. Janik, Nawel Bourayou, Omid Hamid

School of Medicine Faculty Publications

Background T-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) is an immune checkpoint receptor upregulated during anti-programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy for cancer. TIM-3 blockade may improve the antitumor activity of PD-1/PD-L1inhibition. This phase 1 study evaluated INCAGN02390, a novel, fully human Fc-engineered antibody against TIM-3. Methods INCAGN02390 was evaluated by dose escalation at 10-1600 mg infused in 14-day cycles (every 2 weeks [Q2W]) in pretreated patients with select advanced/metastatic immunogenic solid tumors. Objectives included evaluation of safety/tolerability and maximum tolerated dose (MTD) (primary), pharmacokinetics, preliminary antitumor activity, pharmacodynamics, and immunogenicity (secondary). Results Forty patients were enrolled and …

Systemic Carbonic Anhydrase Inhibitors In Common Ophthalmic Diseases: A Scoping Review From A Clinical Standpoint, Shahin Hallaj, Wesam S. Shalaby, Sapna Sinha, Jonathan S. Myers, Reza Razeghinejad

Wills Eye Hospital Papers

PURPOSE OF REVIEW: This paper provides a detailed overview of systemic carbonic anhydrase inhibitors (CAIs) and their application in managing ophthalmic conditions, including glaucoma, cystoid macular edema, and idiopathic intracranial hypertension. Despite their recognized clinical benefits, the potential for severe systemic adverse effects often discourages clinicians from prescribing these agents. By examining the pharmacology, pharmacokinetics, safety profile, and clinical indications of systemic CAIs, this review highlights strategies to mitigate treatment challenges, particularly in patients with comorbidities and complex medical backgrounds.

RECENT FINDINGS: New insights into the diverse roles and distribution of carbonic anhydrase (CA) isozymes have expanded our understanding of …

Modulation Of Redox-Sensitive Cardiac Ion Channels, Rawan S. Orfali, Al Hassan Gamal El-Din, Varnika Karthik, Elisanjer Lamis, Vanna Xiao, Alena Ramanishka, Abdullah Alwatban, Osama Alkhamees, Ali Alaseem, Young-Woo Nam, Miao Zhang

Pharmacy Faculty Articles and Research

Redox regulation is crucial for the cardiac action potential, coordinating the sodium-driven depolarization, calcium-mediated plateau formation, and potassium-dependent repolarization processes required for proper heart function. Under physiological conditions, low-level reactive oxygen species (ROS), generated by mitochondria and membrane oxidases, adjust ion channel function and support excitation–contraction coupling. However, when ROS accumulate, they modify a variety of important channel proteins in cardiomyocytes, which commonly results in reducing potassium currents, enhancing sodium and calcium influx, and enhancing intracellular calcium release. These redox-driven alterations disrupt the cardiac rhythm, promote after-depolarizations, impair contractile force, and accelerate the development of heart diseases. Experimental models demonstrate …

Kshv Vil6 Inhibits Functional B Cell Maturation During De Novo Infection, Wajd Zakir, Jessica M. Osborn, Jennifer Totonchy

Pharmacy Faculty Articles and Research

Despite causative links to lymphoproliferative disorders, little is known about early events governing KSHV infection in B lymphocytes. IL-6 signaling plays a critical role in KSHV-mediated disease, with human IL-6 (hIL6) levels correlating with viral load and disease progression. This dynamic is even more complex due to the coexistence of hIL6 and KSHV-encoded viral IL-6 (vIL6) in these diseases. We hypothesize that hIL6 and vIL6 play critical, separable and collective roles in the early stages of KSHV infection in B cells. In this study, we use our ex vivo model of KSHV infection in human tonsil lymphocytes to investigate the …

An Integrative Genomics Approach For The Discovery Of Potential Clinically Actionable Diagnostic And Prognostic Biomarkers In Colorectal Cancer, Mark Fertel, Duaa Mohammad Alawad, Chindo Hicks

School of Graduate Studies Faculty Publications

Background: Despite remarkable progress in clinical management of patients and intensified screening, colorectal cancer remains the second most common cause of cancer-related death in the United States. The recent surge of next generation sequencing has enabled genomic analysis of colorectal cancer genomes. However, to date, there is little information about leveraging gene expression data and integrating it with somatic mutation information to discover potential biomarkers and therapeutic targets. Here, we integrated gene expression data with somatic mutation information to discover potential diagnostic and prognostic biomarkers and molecular drivers of colorectal cancer. Methods: We used publicly available gene expression and somatic …

Pharmacological Considerations For Healthcare Providers When Caring For Muslim Patients: A Practical Guide, Layla Abubshait, Nissa Tasnim, Taha Cangoz

Einstein Health Papers

Healthcare providers increasingly encounter Muslim patients with unique pharmacological considerations influenced by religious beliefs and practices. Islam, as the world's second-largest religion, includes specific guidelines affecting medication permissibility, particularly regarding alcohol and pork-derived ingredients. This educational guide examines the intersection of Islamic teachings with pharmacotherapy, providing examples of commonly prescribed medications containing alcohol or porcine-derived gelatin from our academic medical center's inpatient and outpatient formulary. We document alcohol content percentages in various medications and suggest possible alternatives as illustrative examples. Most importantly, we present a step-by-step practical framework for using National Drug Code (NDC) numbers and the DailyMed database, enabling …

New Onset Diabetic Retinopathy With Glucagon-Like Peptide-1 Receptor Agonists: A Case Report, Jennifer Ko, Yaseman Jahromi

Pharmacy Faculty Articles and Research

Background

Alfred Russel Wallace Notes 37. What About Wallace On Vaccination . . . ?, Charles H. Smith

Faculty/Staff Personal Papers

Best known for his natural history studies on evolution and biogeography, Alfred Russel Wallace (1823−1913) had a significant second career as a social critic. One of his most controversial stances was his position on (smallpox) vaccination. Anti-vaxxers of the present frequently bring up his name as a resource for their side, but the situation is not so easily reducible to that.