Amino Acids, Peptides, and Proteins Commons^™

Concurrent Local Therapy Extends Clinical Benefit Of Tebentafusp In Metastatic Uveal Melanoma Patients, Tristan L. Lim, Kamaneh Montazeri, Eric Wehrenberg-Klee, Antoine Desilets, Rino S. Seedor, Marlana Orloff, Takami Sato, Michael Caplan, Mariam El-Ashmawy, Benjamin Izar, Shaheer Khan, Inderjit Mehmi, Aleigha Lawless, Theodore S. Hong, Omid Hamid, Richard D. Carvajal, Alexander Shoushtari, Ryan J. Sullivan

Kimmel Cancer Center Faculty Papers

BACKGROUND: Tebentafusp has significantly improved overall survival in HLA-A*02:01+ metastatic uveal melanoma (mUM) patients even in those with a best objective response of progressive disease. Thus, strategies to maintain tebentafusp therapy are critical. Here, we examine the efficacy and safety of adding concurrent local therapy (CLT) to tebentafusp upon radiological progression with tebentafusp alone.

PATIENTS AND METHODS: This multicenter retrospective study included mUM patients treated with tebentafusp and CLT, consisting of extrahepatic soft tissue irradiation and liver-directed therapies (LDTs). Efficacy of target and nontarget sites were assessed per RECIST version 1.1. PFS with tebentafusp alone (PFS1) was compared to that …

Predictive Gene Expression Signatures For Alzheimer's Disease Using Post-Mortem Brain Tissue, Ashley Duche, Oliver Tan, Andrius Baskys, Rachita K. Sumbria, Moom R. Roosan

Pharmacy Faculty Articles and Research

Background: Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and tau protein aggregates in the brain. These pathological features manifest in specific regions, but mechanisms rendering some areas more susceptible to early AD-related changes remain poorly understood. To address this, we developed predictive gene expression signatures to explore molecular mechanisms underlying regional vulnerability to AD pathology.

Methods: Post-mortem brain tissues from participants of the Religious Orders Study and Memory and Aging Project (ROSMAP), Mayo Clinic, and Mount Sinai Brain Bank (MSBB) were used to derive gene expression signatures from six brain regions affected at varying …

Uncovering The Pml::Rara Fusion In Cytogenetically Cryptic And Fish-Negative Acute Promyelocytic Leukemia-A Case Report And Comprehensive Literature Review, Busra Delikkaya, Jaime Eberle-Singh, Arianna Morton, Jerald Gong, Jinglan Liu

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The PML::RARA fusion resulting from t(15;17) is the genetic hallmark of acute promyelocytic leukemia (APL), typically detected by cytogenetics and/or fluorescence in situ hybridization (FISH) studies. Rarely, APL patients present with normal cytogenetics and FISH findings, complicating diagnosis and delaying life-saving therapy. We report a 23-year-old male with clinical, morphologic and immunophenotypic features consistent with APL but negative for FISH studies. Despite prompt initiation of all-trans retinoic acid (ATRA) based on clinical suspicion, the patient succumbed to intracranial hemorrhage. Quantitative reverse transcriptase PCR (qRT-PCR) confirmed a long isoform PML::RARA fusion. A review of 34 published cytogenetics- and FISH-negative cases since …

Non-Invasive Detection Of Choroidal Melanoma Via Tear-Derived Protein Corona On Gold Nanoparticles: A Machine Learning Approach, Hakimeh Rakhshandeh, Ahmad Nasiraei, Hamid Riazi-Esfahani, Babak Masoomian, Fariba Ghassemi, Mojtaba Arjmand, Saeed Heidari Keshel, Fatemeh Atyabi, Rassoul Dinarvand

Wills Eye Hospital Papers

This study investigates the feasibility of using tear sample analysis, based on protein corona formation on gold nanoparticles combined with electrospray ionization mass spectrometry (ESI-MS) and machine learning techniques, as a non-invasive approach for the detection of choroidal melanoma. The aim is to assess whether protein-nanoparticle interactions can support early and reliable identification of this ocular condition. Tear samples were collected using Schirmer strips from six healthy individuals and six patients diagnosed with choroidal melanoma, with subsequent augmentation to 18 samples per group. Gold nanoparticles (AuNPs, ~ 20 nm) were synthesized via citrate reduction and incubated with tear samples to …

Inflammation And Detection: Rethinking The Biomarker Landscape In Gastric Cancer, Keykavous Parang, Koosha Paydary

Pharmacy Faculty Articles and Research

Gastric carcinoma is a leading cause of cancer-related mortality worldwide, yet reliable noninvasive biomarkers for its early detection remain limited. As research continues to elucidate the inflammatory underpinnings of tumor initiation and progression, it has become increasingly clear that pro-inflammatory cytokines may hold promise as diagnostic adjuncts. Serum cytokines such as interleukin (IL)-1β, IL-6, IL-8, and interferon-gamma have been frequently reported as elevated in gastric cancer patients compared to healthy individuals. These molecules, known for their roles in modulating tumor-promoting inflammation, angiogenesis, and immune evasion, may serve as accessible indicators of disease presence or progression. Several studies have shown that …

Corticobasal Syndrome With Mixed Pathology In The Absence Of Grn Mutation: A Clinico-Pathological Case Of Ftld-Tdp With Coexisting Alzheimer’S And Lewy Body Pathology, Hugo Zamarron, David Irwin, Jeffery Phillips, Edward Lee, Matthew Tisdall, Corey Mcmillan

Research Colloquium

Background: Corticobasal syndrome (CBS) is a neurodegenerative disorder characterized by often asymmetric fronto-pariteal and extra-pyramidal features that is traditionally associated with tauopathy, but pathological findings are heterogenous, including other forms of frontotemporal lobar degeneration (FTLD) and mixed pathologies of aging. We present clinical, radiographic, and histopathologic features of asymmetry in a unique patient with CBS and underlying FTLD with TDP-43 pathology (FTLD-TDP), co-occurring with other age-related pathologies.

Case Presentation: A 76-year-old man presented with progressive cognitive and motor dysfunction including asymmetric parkinsonism, left-sided dystonia and rigidity, apraxia, visuospatial impairment, and a subtle social disorder including apathy and social withdrawal. The …

Editorial: Molecular Mechanisms Of Ion Channel Activation And Modulation, Meng Cui, Miao Zhang

Pharmacy Faculty Articles and Research

"Ion channels are integral membrane proteins that regulate the passage of ions across cell membranes, thereby shaping processes as diverse as neuronal signaling, muscle contraction, and hormone secretion. Channel activation is typically initiated by a stimulus such as voltage, ligand binding, or mechanical stress that induces conformational changes and opens the channel pore. Beyond activation, channels are subject to fine-tuned modulation by a wide range of endogenous and exogenous agents, from lipids and neurotransmitters to pharmacological drugs. Modulators can stabilize the open, closed, or inactivated states, shift ligand affinities, or alter gating kinetics. Dissecting the structural and dynamic basis of …

Allosteric Control Overcomes Steric Limitations For Neutralizing Antibodies Targeting Conserved Binding Epitopes Of The Sars-Cov-2 Spike Protein: Exploring The Intersection Of Binding, Allostery, And Immune Escape With A Multimodal Computational Approach, Mohammed Alshahrani, Vedant Parikh, Brandon Foley, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Understanding the atomistic basis of multi-layer mechanisms employed by broadly reactive neutralizing antibodies of the SARS-CoV-2 spike protein without directly blocking receptor engagement remains an important challenge in coronavirus immunology. Class 4 antibodies represent an intriguing case: they target a deeply conserved, cryptic epitope on the receptor-binding domain yet exhibit variable neutralization potency across subgroups F1 (CR3022, EY6A, COVA1-16), F2 (DH1047), and F3 (S2X259). The molecular basis for this variability is not fully understood. Here, we employed a multi-modal computational approach integrating atomistic and coarse-grained molecular dynamics simulations, binding free energy calculations, mutational scanning, and dynamic network analysis to elucidate …

Bard1: A Friend Or Foe In Pancreatic Ductal Adenocarcinoma?, Lily Zekavat, Aditi Jain

Department of Surgery Faculty Papers

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid malignancy with poor overall prognosis and limited response to standard treatments. Growing interest in the modulation of DNA repair mechanisms, including the homologous recombination (HR) repair pathway, has opened new avenues for therapeutic development. BARD1 (BRCA1-Associated RING Domain 1) plays a complex role in tumor biology, functioning either as a tumor suppressor or as an oncogenic driver, depending on isoform expression, cellular context, and regulatory environment. In this review, we examine the dual roles of BARD1, focusing on its regulation and paradoxical activities in PDAC. We summarize evidence that BARD1 and BARD1 …

Resolution Of Physics And Deep Learning-Based Protein Engineering Filters: A Case Study With A Lipase For Industrial Substrate Hydrolysis, Spencer Gardiner, Peter Dollinger, Filip Kovacic, Jörge Pietruszka, Daniel Ess, Karl-Erich Jaeger, Gunnar F. Schröder, Dennis Della Corte

Faculty Publications

Computational enzyme design remains a powerful yet imperfect tool for optimizing biocatalysts, especially when targeting non-natural substrates. Using design tools we investigated Pseudomonas aeruginosa LipA, a lipase with a flexible lid domain crucial for substrate binding and turnover, aiming to enhance its hydrolysis of the industrially relevant substrate Roche ester. We generated an initial set of single-point mutations based on structural proximity to the active site and evaluated their effects using a computational pipeline integrating molecular dynamics (MD) simulations, density functional theory (DFT) calculations, and ensemble-based energy scoring. While we identified several active variants, attempts to rank them by activity …

Opposing Synovial Cannabinoid Receptor Type 2 And Transient Receptor Potential Vanilloid 1 Expression In Painful Osteoarthritis, Collin A. Toups, Lauren G. Guillot, Kaitlyn Redondo, Sydney Jensen, Jennifer Klein, Luis Marrero

School of Medicine Faculty Publications

Knee osteoarthritis (kOA) poses a major health challenge worldwide, but current non-surgical treatments have limited long-term success and do not address the underlying disease process. This study explores the complex relationship between the endocannabinoid system (ECS) and the endovanilloid system (EVS) in the synovial membrane of patients with kOA undergoing total knee replacement, focusing on how these systems relate to patient-reported pain and histological synovitis. Synovial tissues and fluid from patients grouped into high and low pain categories based on the Knee Injury and Osteoarthritis Outcome Score (KOOS) were examined for cannabinoid receptor type 2 (CB2R), transient receptor potential vanilloid …

Targeting Kinin B1r Attenuates Hypertension Through At1r-Dependent Mechanisms, Drew Theobald, Riley N. Bessetti, Yumei Feng Earley, Eric Lazartigues, Karen Litwa, Srinivas Sriramula

School of Medicine Faculty Publications

BACKGROUND: Neurogenic hypertension is chronically high blood pressure that is initiated and maintained through excessive sympathetic nervous system activity and has been associated with increased B1R (kinin B1 receptor) activation. We previously reported a central role for B1R in mediating inflammatory pathways in the development of deoxycorticosterone acetate salt hypertension. Additionally, we identified a causal relationship between B1R expression after Ang II (angiotensin II) stimulation, and that B1R can mediate the bidirectional interaction between neuroinflammation and oxidative stress. However, whether there are any interactions between AT1R (Ang II-type I receptor) and B1R, and if B1R can mediate the effects of …

Distinct Transcriptional Regulation Of The Wnt And Tgfβ Signaling Families Associated With Wound Healing And Fibrotic Outcomes To Lens Injury, Catherine Lalman, Kylie R. Stabler, Joshua Disatham, Lisa A. Brennan, Marc Kantorow, Janice L. Walker

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Posterior capsule opacification (PCO) is a fibrotic complication of cataract surgery caused by aberrant repair of residual lens cells. It remains unclear how the lens injury response shifts toward a pathological repair process. Here, we performed a transcriptional analysis of two major pro-fibrotic pathways, the TGF-β superfamily and Wnt signaling pathways to determine how they are differentially regulated during regenerative wound healing versus fibrosis in a lens injury model. For these studies, RNA sequencing was performed on an ex vivo lens explant system that models post-surgical healing within regenerative and fibrotic microenvironments, from 0 to 3 days post-injury. Fibrotic conditions …

Air Pollution And Diseases: Signaling, G Protein-Coupled And Toll Like Receptors, Isabella Cattani-Cavalieri, Katrina F. Ostrom, Jordyn Margolis, Rennolds S. Ostrom, Martina Schmidt

Pharmacy Faculty Articles and Research

Air pollution is a significant public health issue that impacts lung health, particularly in vulnerable populations such as children, the elderly, and individuals with pre-existing respiratory conditions. Both natural and anthropogenic sources of air pollution give rise to a variety of toxic compounds, including particulate matter (PM), ozone (O₃), sulfur dioxide (SO₂), nitrogen dioxide (NO₂), carbon monoxide (CO), and polycyclic aromatic hydrocarbons (PAHs). Exposure to these pollutants is strongly associated with the development and exacerbation of respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and idiopathic pulmonary fibrosis (IPF). Notably, early life exposure to pollutants such as …

Biofluid Biomarkers Aid In Diagnosing And Developing Improved Treatments For People With Alzheimer's Disease, Jonatan A. Lopez

University Honors Theses

Dementia is a disease in which daily life is disrupted by a loss of cognitive function. Late-onset Alzheimer's disease (AD) is the most common dementia that largely begins to affect individuals in their mid 60s or older. AD was selected as the focus of this paper because it is the most common form of dementia, accounting for 50-70% of dementia cases. A typical diagnostic approach used by physicians starts with a simple clinical test, the Mini-Mental State Examination (MMSE), when cognitive decline is suspected in a patient. Then if there is enough evidence to suggest AD, a physician would order …

Investigating Extracellualr Vesicles Role In The Pathogenesis Of Acute Lung Injury, Ruben Manuel Luciano Colunga Biancatelli, Pavel Solopov, Tierney Day, Anca Dobrian, John D. Catravas

Cardiovascular Research Symposium

Background: Extracellular vesicles (EVs) are small lipid-bound particles containing proteins and RNAs, whose role in intercellular communication and signaling is critical for homeostasis or inflammatory responses. Patients with acute lung injury display changes in EVs number, cargo content and signature compared to healthy individuals.

Hypothesis: We have hypothesized that EVs may play a role in the pathogenesis of acute lung, by transferring harmful mediators of inflammation and disrupting recipient cells homeostasis.

Methods: C57BL/6j mice (8-10 weeks old, 25g BW) were intratracheally instilled with 50µL of 5*1010- 11 EVs isolated from Human Lung Microvascular Endothelial cells (HLMVEC) exposed to 1 µg …

Peptide-Based Inorganic Nanoparticles As Efficient Intracellular Delivery Systems, Amir Nasrolahi Shirazi, Rajesh Vadlapatla, Ajoy Koomer, Anthony Nguyen, Vian Khoury, Keykavous Parang

Pharmacy Faculty Articles and Research

Background/Objectives: Peptide-based inorganic nanoparticles (PINPs) have emerged as promising candidates for intracellular delivery due to their unique structural and functional attributes. These hybrid nanostructures combine the high surface area and tunable optical/magnetic properties of metal cores (e.g., Au, Ag, Fe3O4) with the biocompatibility, targeting specificity, and responsive behavior of peptides. In particular, peptides with amphipathic or cell-penetrating features could facilitate efficient transport of molecular cargos across cellular membranes while enabling stimulus-responsive drug release in target tissues. Methods: We review key synthesis methods (especially green, peptide-mediated one-pot approaches), functionalization strategies (e.g., thiol-gold bonds, click chemistries), and characterization techniques (TEM, …

Interleukin-22 And Interleukin-22 Binding Protein Signaling Axis Influences Intubation Status In Trauma, Augustus E. Anderson, Jacob Broome, Aaron L. Albuck, Megan Shenk, Valeria Noguera, Wid Covey, Alison Smith, Juan Duchesne, Danielle Tatum, Christine M. Bojanowski, Derek Pociask, Jay K. Kolls, Olan Jackson-Weaver, Sharven Taghavi

School of Medicine Faculty Publications

Background: Interleukin-22 is a cytokine involved in mucosal immunity, whereas interleukin-22 binding protein is a soluble receptor that can potently block interleukin-22. The role of interleukin-22 and interleukin-22 binding protein in trauma remains unclear. This study investigates whether IL-22 levels are associated with intubation in patients with trauma. We hypothesized interleukin-22 levels would be lower in intubated patients. Methods: Plasma samples were prospectively obtained in the trauma bay at consecutive Level 1 activations from November 2021 to November 2022. Patients were categorized as having respiratory failure (intubated) or as controls (nonintubated). Two-to-one case-control matching was conducted based on age, sex, …

Silvestrol Inhibits Nasopharyngeal Carcinoma Cells And Synergizes With Cx‑5461: Insights From A Proteomics Study, Maelinda Daker, Munirah Ahmad, Alan Khoo, Lu Ping Tan, Siok-Fong Chin, Siaw San Hwang, Paul Neilsen

Department of Medical Oncology Faculty Papers

Nasopharyngeal carcinoma (NPC) is a cancer arising from the epithelial cells of the nasopharynx, which is rare in Western countries but extremely prevalent in Borneo and the Southern China region. Present-day hurdles in NPC treatment that lead to poor quality of life and poor survival include distant metastasis and resistance to chemoradiotherapy. Silvestrol and its 5'''-epimer, episilvestrol, are compounds isolated from the plant Aglaia stellatopilosa, which is endemic to Borneo. Silvestrol, a protein synthesis inhibitor, preferentially inhibits the translation of cancer-associated mRNAs. CX-5461 is an inhibitor of RNA polymerase I that catalyzes rRNA synthesis. The present study sought to …

Dietary Protein’S Effect On The Gut Microbiome And Its Metabolites: Protocol Description And Virtual Recruitment Efforts For A Remote Randomized Controlled Trial, Karyn M. Gallivan, Kristin S. Ondrak, Denise M. Danos, Meng Luo, Christopher M. Taylor, Lauren E. Meyer, Ann M. Byerley, Alexander W. Nguyen, Sabyasachi Chatterjee, Jiri Adamec, Lauri O. Byerley

School of Medicine Faculty Publications

Fiber’s effect on our gut microbes has been studied extensively, while knowledge of the effect of protein is sparse. Colonic putrefaction of dietary protein is known to produce several potentially detrimental compounds. This randomized controlled trial (RCT) uses a pre- and post-study design to investigate the effect of consuming higher levels of dietary protein on the gut microbiota and the metabolites it produces. Here, we describe our virtual recruitment efforts and RCT protocol. Potential participants lived throughout the contiguous US. Several recruitment methods were employed, of which email reached the largest group of people (approximately 9,100) and generated a 0.3% …