Chemicals and Drugs Commons^™

Effectiveness And Safety Of Abobotulinumtoxina In Pediatric Lower Limb Spasticity: A Phase Iv, Prospective, Observational, Multicenter Study, Mark E. Gormley, Edward Dabrowski, Mauricio R. Delgado, Ann Tilton, Asare Christian, Sarah Helen Evans, Anne-Sophie Grandoulier, Jumaah Goldberg

School of Medicine Faculty Publications

Aim: To assess the longitudinal attainment of patient-centered, function-related Goal Attainment Scaling Total (GAS T)-score after repeated abobotulinumtoxinA (AboBoNT-A) injections over a period of up to 30 months and up to 10 cycles. Method: In this prospective observational study, the investigators' clinical practices recruited patients aged 2 to 17 years with pediatric lower limb spasticity (PLLS). GAS T-scores were assessed for each injection, and goals could be redefined at each visit; scores of 50 reflected goal achievement. Adverse events were recorded. Results: Of 210 patients in the effectiveness population, 171 had cerebral palsy and 163 were previously treated with a …

Sex-Dependent Differences In Cardiac Function And Strain In Doxorubicin-Induced Cardiomyopathy, Anna J. A. Webb, Bea O. Cabot, Aasish Chowdary, Wilhelm S. Smith, Benjamin Zeidler, Cortland H. Johns, Craig J. Goergen

Discovery Undergraduate Interdisciplinary Research Internship

Doxorubicin is a chemotherapeutic agent used to treat many types of cancer. While effective, doxorubicin can cause cardiomyopathy, a disease affecting the heart muscle. Although the effects of doxorubicin on the heart are well studied, the mechanisms leading to cardiomyopathy are not well understood. Previous studies have used murine models to study the cardiotoxicity of doxorubicin. These reports showed that cardiac dysfunction is more pronounced in male compared to female mice. The goal of this study is to further evaluate sex differences in doxorubicin induced cardiomyopathy using 4-dimensional strain mapping techniques. In this study, both female and male C57Bl/6J mice …

Ctnna3 Deficiency Promotes Heart Regeneration By Enhancing Cardiomyocyte Proliferation In Neonatal Mice, Sha Zou, Wuhou Dai, Wufan Tao, Jifen Li, Zeyi Cheng, Hongyan Wang

Department of Medicine Faculty Papers

Background: Heart regeneration requires renewal of lost cardiomyocytes. However, the mammalian heart loses its proliferative capacity soon after birth, and the molecular signaling underlying the loss of cardiac proliferation postnatally is not fully understood.

Purpose: This study aimed to investigate the role of Catenin alpha 3 (Ctnna3), coding for alpha T catenin (αT-catenin) protein in regulating cardiomyocyte proliferation and heart regeneration during the neonatal period.

Methods: Here we report that ablation of Ctnna3 and highly expressed in hearts, accelerated heart regeneration following heart apex resection in neonatal mice.

Results: Our results show that Ctnna3 deficiency enhances cardiomyocyte proliferation …

Effects Of Liver Surgery On Drug Transporters In The Liver And Remote Organs, Reza Mehvar

Pharmacy Faculty Articles and Research

Alterations in drug transporters in acute liver failure and chronic liver diseases, such as cirrhosis, have been reviewed before. However, there is a lack of comprehensive reviews on how liver surgery, including transplantation and partial hepatectomy, affects drug transporters. Because ischemia–reperfusion (IR) injury is a hallmark of liver transplantation and most other surgical procedures of the liver, this review focuses on the effects of IR injury, in addition to liver resection, on the expression and function of transporters in the liver and remote organs. Most of the reported studies in this area are carried out in animal models of liver …

A Mutational Analysis Of Thatisin: How Single Point Mutations Impact The Biosynthetic Process Of A Group 16 Graspetide, John F. Boynton Jr

Chemistry and Chemical Biology ETDs

Abstract:

Graspetides are a family of Ribosomally synthesized and Post-translationally modified Peptide (RiPP) natural products named for their ATP Grasp Macrocyclases. We identified several Graspetide Biosynthetic Gene Clusters containing common double glycine cleavage motifs and attempted characterization of the mature Graspetides. One of the resulting peptides, Thatisin, has a topology with two interlocking macrolactones installed by a single ATP Grasp Ligase named ThtC. Here we use single and double point mutations to observe the impact or variation on the installation of these macrocycles. Alanine scan mutagenesis is used to assess leader peptide residues in the precursor peptide ThtA to determine …

Effects Of Neoadjuvant Immunotherapy On Hearing In Patients With Head And Neck Squamous Cell Carcinoma, Bryce Hambach, Anhelina Bilokon, John Lee, L. Noelle Allemang, Jennifer Chisholm, Chris K. Zalewski, Julie Christensen, Carmen C. Brewer, James L. Gulley, Clint T. Allen, Lisa L. Cunningham, Katharine A. Fernandez

SKMC Student Presentations and Publications

Immune checkpoint blockade (ICB) is a commonly used treatment modality for cancer with a growing list of oncologic indications. Ototoxicity is a potential immune-related adverse event of ICB treatment, but the risk of hearing loss after ICB remains unknown. This retrospective chart review sought to identify individuals who received ICB and had available audiometric data before and after treatment in order to identify clinically meaningful changes in hearing. This single center, institutional chart review examined hearing function data in patients who underwent audiometry before and after ICB treatment. Measures included pure tone thresholds, distortion product otoacoustic emissions (DPOAEs), tympanometry, and …

Engineered Bifidobacterium Strains Colonization At Tumor Sites: A Novel Approach To The Delivery Of Cancer Treatments, Rhea Amonkar, Ashley Ann Uy, Pablo Ramirez, Harina Patel, Jae Jin Jeong, Nicole Oyinade Shoyele, Vidhi Vaghela, Ashakumary Lakshmikuttyamma

College of Pharmacy Faculty Papers

Bacteria-mediated cancer therapy represents a novel and promising strategy for targeted drug delivery to solid tumors. Multiple studies have demonstrated that various Bifidobacterium species can selectively colonize the hypoxic microenvironments characteristic of solid tumors. Leveraging this property, Bifidobacterium has been explored as a delivery vector for a range of anti-cancer approaches such as immunotherapy, nanoformulated chemothera- peutics, and gene therapy. Notably, anti-angiogenic genes such as endostatin and tumstatin have been successfully delivered to colorectal tumors using Bifidobacterium infantis and Bifidobacterium longum, respectively. Additionally, Bifidobacterium bifidum has been employed to transport doxorubicin and paclitaxel nanoparticles to breast and lung tumor …

Rna Sequencing Reveals Inflammatory And Metabolic Changes In The Lung And Brain After Carbon Black And Naphthalene Whole Body Inhalation Exposure In A Rodent Model Of Military Burn Pit Exposures, Allison M. Haaning, Brian J. Sandri, Henry L. Wyneken, William T. Goldsmith, Joshua P. Nixon, Timothy R. Nurkiewicz, Chris H. Wendt, Paul Barach, Janeen H. Trembley, Tammy A. Butterick

College of Population Health Faculty Papers

Military personnel deployed to Iraq and Afghanistan were exposed to emissions from open-air burn pits, where plastics, metals, and medical waste were incinerated. These exposures have been linked to deployment-related respiratory diseases (DRRD) and may also impact neurological health via the lung-brain axis. To investigate molecular mechanisms, adult male rats were exposed to filtered air, naphthalene (a representative volatile organic compound), or a combination of naphthalene and carbon black (surrogate for particulate matter; CBN) via whole-body inhalation (six hours/day, three consecutive days). Lung, brain, and plasma samples were collected 24 h after the final exposure. Pro-inflammatory biomarkers were assessed using …

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 …

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 …

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 …

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 …