Medical Cell Biology Commons^™

Detection Of Heterogeneous Resistance Mechanisms To Tyrosine Kinase Inhibitors From Cell-Free Dna, Heather A Parsons, Conor Messer, Katheryn Santos, Jakob Weiss, David Merrell, Brian P Danysh, Melissa E Hughes, Gregory J Kirkner, Ashka Patel, Julian Hess, Kerry Sendrick, Chip Stewart, Elizabeth Grant, Kristy Schlueter-Kuck, Albert Grinshpun, Nikhil Wagle, Jamunarani Veeraraghavan, Jose Pablo Leone, Rachel A Freedman, Otto Metzger, Rachel Schiff, Eric P Winer, Sara M Tolaney, Mothaffar Rimawi, Ian E Krop, Gad Getz, Nancy U Lin

Faculty, Staff and Students Publications

Though there has been substantial progress in the development of anti-human epidermal growth factor receptor 2 (HER2) therapies to treat HER2-positive metastatic breast cancer (MBC) within the past two decades, most patients still experience disease progression and cancer-related death. HER2-directed tyrosine kinase inhibitors can be highly effective therapies for patients with HER2-positive MBC; however, an understanding of resistance mechanisms is needed to better inform treatment approaches. We performed whole-exome sequencing on 111 patients with 73 tumor biopsies and 120 cell-free DNA samples to assess mechanisms of resistance. In 11 of 26 patients with acquired resistance, we identified alterations in previously …

Identifying Novel Fibrotic Mechanisms Underlying Treatment-Resistant Lower Urinary Tract Dysfunction, Quentin Darcy

Graduate Doctoral Dissertations

ABSTRACT

IDENTIFYING NOVEL FIBROTIC MECHANISMS UNDERLYING TREATMENT-RESISTANT LOWER URINARY TRACT DYSFUNCTION

August 2025

Quentin D’Arcy, B.S., University of Massachusetts Amherst

Ph.D., University of Massachusetts Boston

Directed by Dr. Jill Macoska

Lower urinary tract dysfunction (LUTD) is a common, age-related disease that affects millions of men over the age of 50. Current treatment for this and other related prostate diseases concentrate on decreasing benign prostate growth and relaxing smooth muscle contractions to alleviate urinary voiding symptoms. However, up to 45% of patients with LUTD are treatment-resistant and require surgical intervention to resolve prostate issues. By focusing on the contribution of inflammation-derived …

Cathartocytosis: Jettisoning Of Cellular Material During Reprogramming Of Differentiated Cells, Jeffrey W Brown, Xiaobo Lin, Gabriel Anthony Nicolazzi, Xuemei Liu, Thanh Nguyen, Megan D Radyk, Joseph Burclaff, Jason C Mills

Faculty, Staff and Students Publications

Injury causes differentiated cells to undergo massive reprogramming to become proliferative and repair tissue via paligenosis. Gastric chief cells use paligenosis to reprogram into progenitor-like spasmolytic-polypeptide-expressing metaplasia (SPEM) cells. Stage 1 of paligenosis is the downscaling of mature cell architecture via a process involving lysosomes. Here, we notice that sulfated glycoproteins are not only digested during paligenosis but also excreted into the gland. Various genetic and pharmacological approaches show that endoplasmic reticulum membranes and secretory granule cargo are also excreted and that the process proceeds in parallel with but is mechanistically independent of autophagy. Three-dimensional light and electron microscopy demonstrated …

Placental Polycyclic Aromatic Hydrocarbon (Pah) Levels Are Associated With Spontaneous Preterm Birth, Gwendolynn Hummel, Sohini Banerjee, Vasanta Putluri, Inaara Malick, Grace Johnson, Abu Hena Mostafa Kamal, Chandra Shekar R Ambati, Nagireddy Putluri, Lori Showalter, Cynthia D Shope, Joseph Hagan, Kjersti M Aagaard, Bhagavatula Moorthy, Melissa A Suter

Faculty, Staff and Students Publications

While the cause of preterm birth (PTB) (i.e., delivery before 37 weeks of gestation) is likely multifactorial, ambient exposure to environmental chemicals has been postulated to play a role in its etiology. Our prior studies of exposure to polycyclic aromatic hydrocarbons (PAHs) in pregnancy have shown an increased level of placental PAH-induced bulky DNA adducts with increasing levels of PAH exposures. In this investigation, we hypothesized that higher levels of placental PAHs would be associated with an increased risk of PTB. Using gas chromatography and mass spectrometry (GC-MS/MS), we measured levels of benzo(a)pyrene (BaP), benzo(b)fluoranthene (BbF) and dibenz(a,h)anthracene (DBA) from …

Proteogenomic Characterization Unveils Biomarkers Associated With Chemoresistance In Muscle-Invasive Bladder Cancer, Matthew V Holt, Yongchao Dou, Meggie N Young, Alexander B Saltzman, Meenakshi Anurag, Jonathan T Lei, Antrix Jain, Mei Leng, Beom-Jun Kim, Lacey E Dobrolecki, Stefanie F Faucher, Sara Savage, Chenwei Wang, Zhiao Shi, Hugo Villanueva, Karoline Kremers, Kyle D Drinnon, Patricia D Castro, Michael M Ittmann, Mehak Mehboob Khatani, Sung Han Kim, Matthew J Ellis, Bing Zhang, Anna Malovannaya, Seth P Lerner

Faculty, Staff and Students Publications

To explore potential chemoresistance mechanisms and identify therapeutic opportunities in muscle-invasive bladder cancer (MIBC), we conduct comprehensive proteogenomic characterization of 46 pre- and 14 post-treatment MIBC tumors incorporating genomics, transcriptomics, proteomics, and phosphoproteomics. Multi-omics clustering not only recapitulated established molecular subtypes but also revealed subtypes associated with chemotherapy sensitivity. Protein isoform level analysis identifies protein abundance of a short isoform of ATAD1 and RAF family proteins as biomarkers of chemosensitivity. Integration of proteomic and phosphoproteomic data reveals Wnt signaling via GSK3B-S9 phosphorylation and the JAK/STAT pathway as potential targets to overcome chemoresistance. Correlations between PD-L1 and TROP-2/NECTIN-4 indicate an additive …

Sox2 Regulates Foregut Squamous Epithelial Homeostasis And Is Lost During Barrett’S Esophagus Development, Ramon U Jin, Yuanwei Xu, T Mamie Lih, Yang-Zhe Huang, Toni M Nittolo, Blake E Sells, Olivia M Dres, Jean S Wang, Qing K Li, Hui Zhang, Jason C Mills

Faculty, Staff and Students Publications

Esophageal adenocarcinoma is increasingly prevalent and is thought to arise from Barrett's esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE's molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between SOX2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2-KO (Krt5CreER/+ Sox2Δ/Δ ROSA26tdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at …

Restoring Translational Control With Novel Small Molecule Activators Of Pp2a In Cancer Cells, Kayla A. Jonas

Theses & Dissertations

Hyperactivation of eIF4E-dependent translation in tumor cells is required for robust expression of oncogenic proteins and maintenance of the transformed phenotype. eIF4E binds to the 7-methylguanylate structure at the 5’ end of cellular mRNAs and nucleates the formation of the translation initiation complex, eIF4F, which recruits the preinitiation complex and resolves secondary structure in the mRNA. The ability of eIF4E to promote eIF4F assembly is negatively regulated by the translational repressor, 4E-BP1, and tumorigenesis depends on functional inactivation of 4E-BP1. A major mechanism of 4E-BP1 inactivation involves inhibitory phosphorylation by mTOR which prevents eIF4E binding. Functional inactivation can also occur …

Co-Targeting Bcl-Xl With Mcl-1 Induces Lethal Mitochondrial Dysfunction In Diffuse Mesothelioma, Yuan Xu, Cristian G Medina, Deborah R Surman, Lacey E Dobrolecki, Monica Vilchis, Maheshwari Ramineni, Susan G Hilsenbeck, Yanming Li, Naren Li, Siqi Wu, Jaylon C Aggison, Xi Chen, Yi Zhu, Ying H Shen, R Taylor Ripley

Faculty, Staff and Students Publications

Diffuse mesothelioma (DM) is a rare but highly aggressive and treatment resistant neoplasm with low survival rates. Effective therapeutic strategies are limited, and resistance to treatment is a major obstacle. Myeloid Cell Leukemia (MCL)-1 and B-cell leukemia (BCL)-xL are anti-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins that block cell-intrinsic apoptosis through interactions on the mitochondrial outer membrane which contribute to therapeutic resistance.

We investigated whether B-cell homology domain (BH)-3 profiles were consistent between intra-patient fresh tumor sample, patient-derived cells (PDC), and patient-derived xenografts (PDX) by BH3 profiling; we observed striking consistency which enabled cross model comparisons. Next, we co-targeted BCL-xl …

Impact Of S-Phase Kinase Protien 2 Blockades On Hematopoetic Stem Cell Metabolism, Nicole Elmaraghy

Electronic Theses, Projects, and Dissertations

Hematopoietic stem and progenitor cells (HSPCs) quiescence is vital for the success of bone marrow transplantation, as it preserves long term self- renewal and prevents premature exhaustion (Takubo et al., 2013; Wilson et al., 2008). However, bone marrow transplant (BMT) failure remains a clinical challenge, often due to lack of long-term engraftment and insufficient stress reliance. Both of these characteristics are tightly linked to disrupted stem cell quiescence and metabolic imbalance (Anso et al., 2017; Vannini et al., 2016). One key player is S-phase kinase protein (SKP2), an E3 ubiquitin ligase that targets cell cycle inhibitors, like p27, for proteosome …

Low-Dose Metformin Requires Brain Rap1 For Its Antidiabetic Action, Hsiao-Yun Lin, Weisheng Lu, Yanlin He, Yukiko Fu, Kentaro Kaneko, Peimeng Huang, Ana B De La Puente-Gomez, Chunmei Wang, Yongjie Yang, Feng Li, Yong Xu, Makoto Fukuda

Faculty, Staff and Students Publications

Metformin is the most commonly prescribed antidiabetes drug, yet its precise mechanism of action remains controversial. Previous studies have suggested that metformin acts peripherally by reducing hepatic glucose output and altering gut functions. Here, we report a neural mechanism via the small guanosine triphosphatase Ras-related protein 1 (Rap1). Mice with forebrain-specific Rap1 knockout exhibited resistance to the antidiabetic effects of low-dose metformin while remaining sensitive to other antidiabetic agents. Centrally administered metformin inhibited brain Rap1 and reduced hyperglycemia. Conversely, forced activation of brain Rap1 increased glycemia and abolished the glycemic effect of metformin. Metformin activated a specific subset of neurons …

Nerve-To-Cancer Transfer Of Mitochondria During Cancer Metastasis, Gregory Hoover, Shila Gilbert, Olivia Curley, Clémence Obellianne, Mike T Lin, William Hixson, Terry W Pierce, Joel F Andrews, Mikhail F Alexeyev, Yi Ding, Ping Bu, Fariba Behbod, Daniel Medina, Jeffrey T Chang, Gustavo Ayala, Simon Grelet

Faculty, Staff and Students Publications

The nervous system has a pivotal role in cancer biology, and pathological investigations have linked intratumoural nerve density to metastasis1. However, the precise impact of cancer-associated neurons and the communication channels at the nerve–cancer interface remain poorly understood. Previous cancer denervation models in rodents and humans have highlighted robust cancer dependency on nerves, but the underlying mechanisms that drive nerve-mediated cancer aggressivity remain unknown2,3. Here we show that cancer-associated neurons enhance cancer metabolic plasticity by transferring mitochondria to cancer cells. Breast cancer denervation and nerve–cancer coculture models confirmed that neurons significantly improve tumour energetics. …

Single-Cell Transcriptomics Reveals Biomarker Heterogeneity Linked To Cdk4/6 Inhibitor Resistance In Breast Cancer Cell Lines, Ilenia Migliaccio, Martina Bonechi, Dario Romagnoli, Giulia Boccalini, Francesca Galardi, Cristina Guarducci, Agostina Nardone, Rachel Schiff, Laura Biganzoli, Luca Malorni, Matteo Benelli

Faculty, Staff and Students Publications

Cyclin dependent kinases 4 and 6 inhibitors have brought great improvements in the treatment of luminal breast cancer, but resistance is a major clinical hurdle. Multiple biomarkers of resistance have been proposed, but none is currently utilized in clinical practice. By performing single-cell RNA sequencing of seven palbociclib-naïve luminal breast cancer cell lines and palbociclib-resistant derivatives, we show that established biomarkers and pathways related to CDK4/6i resistance present marked intra- and inter- cell-line heterogeneity. Transcriptional features of resistance could be already observed in naïve cells correlating with levels of sensitivity (IC50) to palbociclib. Resistant derivatives showed transcriptional clusters that significantly …

Phosphoglycerate Mutase Regulates Treg Differentiation Through Control Of Serine Synthesis And One-Carbon Metabolism, Wesley H Godfrey, Judy J Lee, Shruthi Shanmukha, Kaho Cho, Xiaojing Deng, Chandra Shekar R Ambati, Vasanta Putluri, Abu Hena Mostafa Kamal, Paul M Kim, Nagireddy Putluri, Michael D Kornberg

Faculty, Staff and Students Publications

The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array of metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the regulatory role of glycolytic enzymes in Tregs and identified phosphoglycerate mutase (PGAM) as being differentially overexpressed in Tregs and associated with a highly suppressive phenotype. Pharmacologic or genetic inhibition of PGAM reduced Treg differentiation and suppressive function while reciprocally inducing markers of a pro-inflammatory, T helper 17 (Th17)-like state. The regulatory role of PGAM was dependent on the contribution of 3-phosphoglycerate (3 PG), the PGAM substrate, …

The Influence Of Myocardin Effector Genes On The Tgf-Beta Smad3 Signaling Pathway In Human Pleural Mesothelial Cells, Hema Chandra Hrushi Dusharla

Biotechnology Theses

Pleural Fibrosis (PF) involves excessive extracellular matrix (ECM) deposition, mainly by myofibroblasts, leading to pleural thickening and impaired lung function. Pleural mesothelial cells (PMCs) contribute via mesothelial and mesenchymal transition (MesoMT), triggered by cytokines like TGF-β. Our lab identified Myocardin (MyoCD), a transcriptional co-activator of cardiac and smooth muscle, is a master regulator of pleural fibrosis through interactions with serum response factor (SRF) and Smad2/3 transcription factors which initiate fibrosis signaling. RNA sequencing and qPCR analysis revealed that silencing MyoCD decreased the expression of CTNNB1, MDFI, and Tspan2. MDFI emerged as a potent candidate, as this gene affecting the expression …

Effects Of Maackia Amurensis Seed Lectin (Masl) On Oscc Cell Morphology, Pdpn Expression, Growth, And Motility In A Phase 1 Clinical Trial, Ariel C Yin, Cayla J Holdcraft, Tyler J Hellmig, Eamonn J Brace, David I Suster, Alan J Shienbaum, Dylan Roden, Evelyne Kalyoussef, Ghayoour Mir, Eugenio Capitle, Soly Baredes, Rabie M Shanti, Mika K Kaneko, Yukinari Kato, Hisataka Kobayashi, Aki Furusawa, Mahnaz Fatahzadeh, Gary S Goldberg

Rowan-Virtua School of Osteopathic Medicine Departmental Research

BACKGROUND: Podoplanin (PDPN) has emerged as a functionally relevant biomarker and chemotherapeutic target expressed by OSCC cells. PDPN signaling can directly increase tumor cell invasion and metastasis, and also inhibit host lymphocyte activation and immune response. Accordingly, antibodies and Maackia amurensis seed lectin (MASL) can target the PDPN receptor to inhibit OSCC cell migration and viability. However, the effects of MASL on OSCC cells in oral cancer patients has not yet been reported.

METHODS: We conducted a Phase 1 human clinical trial to examine the effects of a single 100 mg oral dose of MASL on OSCC cell morphology, PDPN …

Mouse Metastable Epialleles Are Extremely Rare, Chathura J Gunasekara, Uditha Maduranga, Taylor Zhang, Jonathan N Wells, Maria S Baker, Eleonora Laritsky, Yumei Li, Cristian Coarfa, Yi Zhu, Robert A Waterland

Faculty, Staff and Students Publications

Metastable epialleles (MEs) are genomic loci at which epigenetic marks are established stochastically during early embryonic development and maintained during subsequent differentiation and throughout life, leading to stable epigenetic and phenotypic variation among genetically identical individuals. Although MEs were first described in mice over 20 years ago, the extent of epigenetic metastability in the mouse genome remains unknown. We present the first unbiased genome-wide screen for MEs in mice. Using deep whole-genome bisulfite sequencing across tissues derived from the three embryonic germ layers in isogenic C57BL/6J mice, we identified only 29 MEs, precisely localizing them and documenting their rarity. Consistent …

Myb And Hif1Α Crosstalk Drives Hypoxia-Induced Transcriptional Reprogramming And Adaptive Signaling Alterations In Pancreatic Cancer, Shashi Anand, Kunwar Somesh Vikramdeo, Mohammad Aslam Khan, Ajay Pratap Singh

Cell and Molecular Biology Publications

Pancreatic cancer is an aggressive malignancy, characterized by extensive desmoplasia and a hypoxic tumor microenvironment that contributes to therapy resistance. MYB, a proto-oncogene encoding a transcription factor, plays a crucial role in pancreatic tumor growth and metastasis. Recently, we also revealed a role of MYB in hypoxic survival of pancreatic cancer cells by promoting metabolic reprogramming through interaction with HIF1α, modulating its expression and binding to glycolytic gene promoters. In this study, we investigated how hypoxia influences the genome-wide occupancy of MYB using chromatin immunoprecipitation sequencing (ChIP-seq), and whether this effect is modulated by its interaction with HIF1α. In addition, …

Altered Patterning Of Neural Activity In A Neuropathology, Clarissa Hoffman, Jingheng Cheng, Rodrigo Morales, Daoyun Ji, Yuri Dabaghian

Faculty, Staff and Students Publications

The dynamics of neural circuits and their role in mediating cellular and organismal phenomena remain poorly understood, despite numerous efforts to dissect these processes through precise instantaneous measurements or longer-time averages and approximations. We use an alternative approach: we investigate these dynamics at the system's mesoscale by analyzing spike trains and waveforms. These extended activity patterns carry robust, tractable information, are highly responsive to physiological specifics, and enable detailed tracking of circuit behavior. In particular, this methodology allows for characterizing the functionality of tau-pathology-afflicted hippocampal circuits and identifying circuit-level abnormalities that are missed by through traditional analyses. In healthy mice, …

Exogenous Arginine Differentially Regulates Inflammatory Cytokine And Inducible Nitric Oxide Synthase Expression In Macrophages, Kelsey Stayer, Saliha Pathan, Aalekhya Biswas, Huiqiao Li, Yi Zhu, Fong Wilson Lam, Juan Marini, Sundararajah Thevananther

Faculty, Staff and Students Publications

Immune dysfunction and late mortality from multiorgan failure are hallmarks of severe sepsis. Arginine, a semi-essential amino acid important for protein synthesis, immune response, and circulatory regulation, is deficient in sepsis. However, arginine supplementation in sepsis remains controversial due to the potential to upregulate inducible nitric oxide synthase (iNOS)-mediated excessive nitric oxide (NO) generation in macrophages, leading to vasodilation and hemodynamic catastrophe. Citrulline supplementation has been considered an alternative to replenishing arginine via de novo synthesis, orchestrated by argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL). However, the functional relevance of the ASS1-ASL pathway in macrophages after endotoxin stimulation is …

Single-Cell Profiling Of Bone Metastasis Ecosystems From Multiple Cancer Types Reveals Convergent And Divergent Mechanisms Of Bone Colonization, Fengshuo Liu, Yunfeng Ding, Zhan Xu, Xiaoxin Hao, Tianhong Pan, George Miles, Siyue Wang, Yi-Hsuan Wu, Jun Liu, Igor L Bado, Weijie Zhang, Ling Wu, Yang Gao, Liqun Yu, David G Edwards, Hilda L Chan, Sergio Aguirre, Michael Warren Dieffenbach, Elina Chen, Yichao Shen, Dane Hoffman, Luis Becerra Dominguez, Charlotte Helena Rivas, Xiang Chen, Hai Wang, Zbigniew Gugala, Robert L Satcher, Xiang H-F Zhang

Faculty, Staff and Students Publications

Bone is a common site for metastasis of solid cancers. The diversity of histological and molecular characteristics of bone metastases (BMs) remains poorly studied. Here, we performed single-cell RNA sequencing on 42 BMs from eight cancer types, identifying three distinct ecosystem archetypes, each characterized by an enrichment of specific immune cells: macrophages/osteoclasts, regulatory/exhausted T cells, or monocytes. We validated these archetypes by immunostaining on tissue sections and bioinformatic analysis of bulk RNA sequencing/microarray data from 158 BMs across more than 10 cancer types. Interestingly, we found only a modest correlation between the BM archetypes and the tissues of origin; BMs …

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 …