Medical Cell Biology Commons^™

Polymorphic Α-Glucans As Structural Scaffolds In Cryptococcus Cell Walls For Chitin, Capsule, And Melanin: Insights From 13c And 1h Solid-State Nmr, Ankur Ankur, Jayasubba Reddy Yarava, Isha Gautam, Faith J. Scott, Frederic Mentink-Vigier, Christine Chrissian, Li Xie, Dibakar Roy, Ruth E. Stark, Tamara L. Doering, Ping Wang, Tuo Wang

School of Graduate Studies Faculty Publications

Cryptococcus species are major fungal pathogens responsible for life-threatening infections in approximately a million individuals globally each year, with alarmingly high mortality rates. These fungi are distinguished by a distinctive cell wall architecture further reinforced by two virulence-associated layers, melanin and capsule, rendering them insensitive to antifungal agents targeting the cell wall, such as echinocandins. The molecular interplay between these three biomolecular layers remains poorly understood. Here we employ solid-state NMR spectroscopy to examine intact cells of both wild-type and capsule-deficient strains of C. neoformans, along with melanized cells. High-resolution 13C and 1H data revealed five distinct structural forms of …

Decoding Metastatic Microenvironments Through Single-Cell Omics Reveals New Insights Into Niche Dynamics And Tumor Evolution, Fengshuo Liu, Xiang H-F Zhang

Faculty, Staff and Students Publications

Metastasis is the predominant cause of cancer mortality, primarily driven by complex tumor-host interactions within specialized metastatic niches. Recent advances in single-cell technologies have provided unprecedented insights into metastatic niche formation, evolution and function, including how primary tumors precondition distant organs for metastases and how disseminated tumor cells dynamically interact with host cells to modulate their environments. Integrated single-cell studies across multiple cancer types have also revealed divergent and convergent metastatic adaptation strategies. These findings collectively highlight metastasis as a dynamic, cooperative process shaped by intricate tumor-host interactions, and provide a foundation for novel therapeutic strategies targeting components of the …

Association Of Statin Use On Survival Outcomes Of Patients With Early-Stage Her2-Positive Breast Cancer In The Aphinity Trial, Christian Maurer, Elisa Agostinetto, Lieveke Ameye, Matteo Lambertini, Samuel Martel, Noam Ponde, Mariana Brandão, Francesca Poggio, Arlindo Ferreira, Rachel Schiff, Carmine De Angelis, Richard D Gelber, Susan Dent, Christoph Thomssen, Martine Piccart, Evandro De Azambuja

Faculty, Staff and Students Publications

Purpose: There is evidence that statins might improve the outcome of patients with breast cancer. The role of statins in patients with early HER2-positive breast cancer is unknown. Therefore, we explored the association between statin use and survival outcomes in early HER2-positive breast cancer patients in the phase III APHINITY trial (adjuvant pertuzumab/trastuzumab).

Methods: All patients (intent-to-treat population, n = 4804) were included (6.2 years median follow-up database). The primary objective was to investigate the association of statin use on invasive disease-free survival (IDFS), distant relapse-free interval (DRFI), and overall survival (OS). Patients who received statins at baseline, or started …

Inhibition Of The Gsk3Β/Nav16 Complex Suppresses Early-Stage Alzheimer’S Hyperexcitability, Timothy John Baumgartner, Manuel Silva-Pérez, Zahra Haghighijoo, Nolan Michael Dvorak, Aditya Kumar Singh, Nana Aboadwe Goode, Jully Singh, Berenice Gutierrez Grebenkova, Mate Marosi, Jessica Di Re, Leandra Koff, Wissarut Wijitrmektong, Manu Bala, Hanyue Liao, Marijn Lijffijt, Adam Thomas Szafran, Michael James Bolt, Michael A Mancini, Gregory D Cuny, Diana Shu-Lian Chow, Agenor Limon, Jeannie Chin, Fernanda Laezza

Faculty, Staff and Students Publications

Introduction: Network hyperexcitability (NH) is observed in patients with early-stage Alzheimer's disease (AD), emerging decades before cognitive decline. A key molecular determinant of NH is voltage-gated Na+ channel 1.6 (Nav1.6), which mediates action potential firing in CA1 hippocampal neurons. Ameliorating NH through inhibition of the glycogen-synthase kinase 3β (GSK3β/Nav1.6 complex may provide immediate benefits to cognition and memory and slow AD progression.

Methods: Hight-throughput virtual screening and multiple in vitro biological assays were utilized to identify compound 1063. Patch-clamp electrophysiology and electroencephalogram recordings were utilized to functionally assess 1063 in models of AD neuropathology.

Results: Building on previous studies identifying …

A Lysosomal Surveillance Response To Stress Extends Healthspan, Terytty Yang Li, Arwen W Gao, Rendan Yang, Yu Sun, Yuxuan Lei, Xiaoxu Li, Lin Chen, Yasmine J Liu, Rachel N Arey, Kimberly Morales, Raya B Liu, Wenzheng Wang, Ang Zhou, Tong-Jin Zhao, Weisha Li, Amélia Lalou, Qi Wang, Tanes Lima, Riekelt H Houtkooper, Johan Auwerx

Faculty, Staff and Students Publications

Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H+-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive transcriptional response typified by induction of a set of transcripts involved in lysosomal function and proteolysis, which we termed the lysosomal surveillance response (LySR). LySR activation is characterized by boosted lysosomal activity …

Carbon Monoxide Releasing Polymeric Micelles, Riya Joshi

Electronic Theses and Dissertations

Carbon monoxide (CO), traditionally known as a toxic gas, has emerged as a potential therapeutic agent due to its cytoprotective, anti-inflammatory, and vasodilatory properties. This study explores the development of CO-releasing polymeric micelles as a controlled delivery system for biomedical applications. Using ring-opening metathesis polymerization (ROMP), we synthesized diblock copolymers incorporating CO-releasing moiety diphenylcyclopropenone (DPCP) with hydrophilic polyethylene glycol (PEG) to enhance solubility and stability of the overall CO releasing system. Dynamic light scattering (DLS) and electron microscopy (EM) confirmed the formation of well-defined micelles, while fluorescence assays demonstrated efficient CO release with the use of Iridium photocatalyst under 470 …

Parp Inhibitor Response Is Enhanced In Prostate Cancer When Xrcc1 Expression Is Reduced, Kaveri Goel, Vani Venkatappa, Kimiko L Krieger, Dongquan Chen, Arun Sreekumar, Natalie R Gassman

Faculty, Staff and Students Publications

Prostate cancer (PCa) is the second most common cancer worldwide and the fifth leading cause of cancer-related deaths among men. The emergence of metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) exemplifies the complex disease management for PCa. PARP inhibitors (PARPis) are being tested to treat mCRPC in tumors with defective homologous recombination repair (HRR) to address this complexity. However, increasing resistance towards PARPi in HRR-deficient patients and the low percentage of HRR-defective mCRPC patients requires the identification of new genes whose deficiency can be exploited for PARPi treatment. XRCC1 is a DNA repair protein critical in the …

Stress, Employment Changes, And Psychological Distress Among Caregivers Of Patients With Head And Neck Cancer, Lama Abdurrahman, Vlad C Sandulache, Cielito Reyes-Gibby, Erich M Sturgis, Pavan Jhaveri, Hoda Badr

Faculty, Staff and Students Publications

Importance: Patients undergoing external beam radiation therapy (EBRT) for head and neck cancer (HNC) often experience adverse effects that require substantial caregiving. The burdens of caregiving can impact caregiver employment and mental health over time, yet this topic remains underexplored.

Objective: To examine the associations between caregiving for patients with HNC who undergo EBRT and caregiver stress, employment status, and psychological distress.

Design, setting, and participants: This was a secondary analysis of data from a longitudinal survey study that surveyed caregivers at baseline (ie, at initiation of EBRT) and at 4-month and 12-month follow-ups. The study was conducted at 2 …

The Aging Ovary Stands On The Shoulders Of Giant Multinucleated Cells, Avery A Ahmed, Stephanie A Pangas

Faculty, Staff and Students Publications

Reproductive aging is associated with declining fertility and increasing inflammation, though these events are not well understood. An exciting new study in PLOS Biology utilizes cutting-edge technologies to characterize the role of multinucleated giant cells in ovarian aging.

Human Endogenous Retroviruses (Hervs) Associated With Glioblastoma Risk And Prognosis, Harun Mazumder, Hui Yi Lin, Melody Baddoo, Wojciech Gałan, Diana Polania-Villanueva, Chindo Hicks, David Otohinoyi, Francesca Peruzzi, Zbigniew Madeja, Victoria P. Belancio, Erik K. Flemington, Krzysztof Reiss, Monika Rak

School of Medicine Faculty Publications

Emerging evidence suggests expression from human endogenous retrovirus (HERV) loci likely contributes to, or is a biomarker of, glioblastoma multiforme (GBM) disease progression. However, the relationship between HERV expression and GBM malignant phenotype is unclear. Applying several in silico analyses based on data from The Cancer Genome Atlas (TCGA), we derived a locus-specific HERV transcriptome for glioma that revealed 211 HERVs significantly dysregulated in the comparisons of GBM vs. normal brain (NB), GBM vs. low-grade glioma (LGG), and LGG vs. NB. Our analysis supported development of a unique HERV scoring algorithm that segregated GBM, LGG, and NB. Interestingly, lower HERV …

Theta Oscillons In Behaving Rats, M S Zobaer, Nastaran Lotfi, Carli M Domenico, Clarissa Hoffman, Luca Perotti, Daoyun Ji, Yuri Dabaghian

Faculty, Staff and Students Publications

Recently discovered constituents of the brain waves—the oscillons—provide a high-resolution representation of the extracellular field dynamics. Here, we study the most robust, highest-amplitude oscillons recorded in actively behaving male rats, which underlie the traditional θ-waves. The resemblances between θ-oscillons and the conventional θ-waves are manifested primarily at the ballpark level—mean frequencies, mean amplitudes, and bandwidths. In addition, both hippocampal and cortical oscillons exhibit a number of intricate, behavior-attuned, transient properties that suggest a new vantage point for understanding the θ-rhythms’ structure, origins and functions. In particular, we demonstrate that oscillons are frequency-modulated waves, with speed-controlled …

Ks151 Synergizes With Venetoclax And Abt-737 In Aml: Efficacy In Both Flt3-Wildtype And Flt3-Mutant Models, Sahil Jethi, Arnold Rojas, Omar S. Al-Odat, Krishne Gowda, Subash C. Jonnalagadda, Manoj Pandey

Rowan-Virtua Research Day

Acute myeloid leukemia (AML) is the most common leukemia in adult patients, with a 5-year survival rate of less than 30 percent. Therefore, more effective therapeutic strategies are required to prolong the survival of AML patients. Importantly, anti-apoptotic proteins, especially B-cell lymphoma 2 (Bcl-2), overexpression in AML is associated with uncontrolled growth as well as chemoresistance. Unsurprisingly, Bruton’s tyrosine kinase (BTK) overexpresses in AML and associated with poor prognosis and chemoresistance. The FDA-approved BTK inhibitor, ibrutinib, has been successful in treating other hematologic malignancies, but a proportion of patients relapse mainly because of acquired mutations at Cys481Ser (C481S) in the …

Exploring The Role Of Lysine Acetylation During Biofilm Formation In Bacillus Subtilis, Jennifer Nguyen, Briana Ericka Reid, Valerie Carabetta

Rowan-Virtua Research Day

Biofilms are structured communities of bacterial cells encased in a self-produced extracellular matrix, composed of polysaccharides, extracellular DNA, and proteins. Bacteria in a biofilm pose significant challenges in healthcare due to their resistance to disinfectants and tolerance to antibiotics. In some species, histone-like proteins were found to be important structural components of the biofilm. Nε-Lysine acetylation is a widespread post-translational modification (PTM) in bacteria, which can alter a protein’s function. The histone-like protein HBsu in Bacillus subtilis is acetylated at seven sites in vivo. We hypothesized that the acetylation state of HBsu may alter biofilm structure or the genetic programming, …

Exploring Intracellular Signaling Responses To Ks18, A Potent Mcl-1 Inhibitor, In Multiple Myeloma, Emily Nelson, Omar S Al-Odat, Dhruti A. Brahmbhatt, Tulin Budak-Alpdogan, Subash Jonnalagadda, Manoj Kumar Pandey

Rowan-Virtua Research Day

Multiple myeloma (MM), a cancer of plasma B cells, is a hematological malignancy in which patients inevitably relapse and develop drug resistance. Mcl-1, a member of the anti-apoptotic subgroup of Bcl-2 family proteins, plays a critical role in the progression of multiple myeloma and contributes significantly to drug resistance. Elevated Mcl-1 expression is observed in approximately 52% of MM patients at diagnosis, increasing to 81% at relapse. Given its driving role in disease progression and therapy resistance, Mcl-1 inhibition has emerged as a promising therapeutic target, prompting ongoing research into the development and clinical evaluation of Mcl-1 inhibitors, particularly for …

Modulation Of Opioid Receptor Expression In The Ventral Tegmental Area Following Stress Exposure In Rats, Maya Patel, John Tkaczynski, Jordan Riser, Nicole Shellenbarger, Jin Park, Daniel Manvich, Daniel J. Chandler

Rowan-Virtua Research Day

Background: The ventral tegmental area (VTA) contains dopamine-producing neurons projecting to various brain regions. VTA dysfunction is linked to addiction and depression. Delta opioid receptor upregulation relates to chronic pain, inflammation, cancer, and early adversity. Kappa receptors in the VTA influence stress, drug-seeking, mood, and reward. Notably, chronic substance abuse upregulates the κ-receptor/dynorphin system, and the opioid system regulates social interaction needs.

Hypothesis: Stress will upregulate opioid receptors.

Methods: We compared group-housed and individually-housed rats using stress tests, analyzing behavior and quantifying VTA opioid receptor expression.

Results: Social isolation upregulated delta and kappa opioid receptors in …

Pseudomonas Aeruginosa Exoenzyme Y Enzymatic Activity Inhibits Exoenzyme S-Induced Caspase Activation But Not Cytotoxicity In Pulmonary Microvascular Endothelial Cells, Connor Holm

Honors Theses

Pseudomonas aeruginosa (P. aeruginosa) is the most common cause of ventilator-associated pneumonia in intensive care unit patients. P. aeruginosa utilizes a type III secretion system that injects exoenzymes U, S, T, and/or Y into the host cell cytosol. A majority of clinically isolated P. aeruginosa strains express ExoY often in combination with ExoU and ExoT, or ExoS and ExoT. Host signaling mechanisms in response to intoxication with individual exoenzymes have been extensively studied, yet little is known about host cell response to co-intoxication. In this study, pulmonary microvascular endothelial cells (PMVECs) were infected with P. aeruginosa strains expressing different combinations …

Developing A Small Molecule To Inhibit Hsf1 Expression In Cancer And Evaluating Natural Genetic Variation In Small Molecule Toxicity., Michaela Kendal Foley

Theses and Dissertations

Each year cancer affects nearly 20 million people worldwide and genetic differences across populations can impact cancer onset and progression. Specifically, tumors with high levels of HSF1, the master regulator of the cytoprotective heat shock response (HSR), are correlated with poor patient outcomes in multiple cancers such as prostate, breast, and melanoma. Subsequently, the development of pharmacological inhibitors of HSF1 represents a promising strategy for anticancer therapeutics. Using a luciferase-based transcriptional reporter, two small molecule libraries were screened for inhibitors of HSF1 expression in human embryonic kidney cells, yielding ten compounds that decrease HSF1 expression. To identify if cancer lines …

Ascl2 Positive Tumor Cells Modulate The Response Of Metastatic Colorectal Cancer To Mapk-Targeting Therapy, Oscar Eduardo Villarreal

Dissertations and Theses (Open Access)

Colorectal cancer (CRC) is the second leading cause of cancer related deaths with nearly a quarter of patients presenting with metastatic disease at the time of their diagnosis. Therapeutic management of metastatic CRC continues to be a major challenge due to therapy resistance and disease heterogeneity. Due to its central role in tumorigenesis, CRC is commonly treated with MAPK pathway inhibitors (MAPKi). However, clinical trials repeatedly demonstrates that durability of benefit is short-lived in many patients. While genomic mechanisms of acquired resistance have been described, they explain a minority of patients, and further research is needed to determine the underlying …

Relationship Between Processing Body Formation, Epithelial-To-Mesenchymal Transition, And Invasion In Lung Adenocarcinoma, Amanda Warner

Dissertations and Theses (Open Access)

Lung cancer is the leading cause of cancer-related deaths in the United States, largely due to its ability to metastasize. Epithelial-to-mesenchymal transition (EMT) is a process that enhances the ability of cells to lose their cell-cell contacts, invade, and enter the blood stream which are essential during metastasis. Many transcriptional gene programs are altered during EMT such as activation of mesenchymal transcription factors, like ZEB1, and enhanced response to the TGFβ1 cytokine. In oncogenic contexts, TGFβ1 enhances the formation of processing-bodies (P-bodies) where P-body proteins are required for invasion in multiple cancerous cell lines. P-bodies are a type of ribonucleoprotein …

The Contribution Of De Novo Coding Mutations To Meningomyelocele, Yoo-Jin Jiny Ha, Ashna Nisal, Isaac Tang, Chanjae Lee, Ishani Jhamb, Cassidy Wallace, Robyn Howarth, Sarah Schroeder, Keng Ioi Vong, Naomi Meave, Fiza Jiwani, Chelsea Barrows, Sangmoon Lee, Nan Jiang, Arzoo Patel, Krisha Bagga, Niyati Banka, Liana Friedman, Francisco A Blanco, Seyoung Yu, Soeun Rhee, Hui Su Jeong, Isaac Plutzer, Michael B Major, Béatrice Benoit, Christian Poüs, Caleb Heffner, Zoha Kibar, Gyang Markus Bot, Hope Northrup, Kit Sing Au, Madison Strain, Allison E Ashley-Koch, Richard H Finnell, Joan T Le, Hal S Meltzer, Camila Araujo, Helio R Machado, Roger E Stevenson, Anna Yurrita, Sara Mumtaz, Awais Ahmed, Mulazim Hussain Khara, Osvaldo M Mutchinick, José Ramón Medina-Bereciartu, Friedhelm Hildebrandt, Gia Melikishvili, Ahmed I Marwan, Valeria Capra, Mahmoud M Noureldeen, Aida M S Salem, Mahmoud Y Issa, Maha S Zaki, Libin Xu, Ji Eun Lee, Donghyuk Shin, Anna Alkelai, Alan R Shuldiner, Stephen F Kingsmore, Stephen A Murray, Heon Yung Gee, W Todd Miller, Kimberley F Tolias, John B Wallingford, Spina Bifida Sequencing Consortium, Sangwoo Kim, Joseph G Gleeson

Faculty, Staff and Students Publications

Meningomyelocele (also known as spina bifida) is considered to be a genetically complex disease resulting from a failure of the neural tube to close. Individuals with meningomyelocele display neuromotor disability and frequent hydrocephalus, requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but beyond that it remains unexplained1. We postulated that de novo mutations under purifying selection contribute to the risk of developing meningomyelocele2. Here we recruited a cohort of 851 meningomyelocele trios who required shunting at birth and 732 control trios, and found that de novo likely gene disruption or …