Digital Commons Network^™

Enpp1 Enzyme Replacement Therapy Improves Ectopic Calcification But Does Not Rescue Skeletal Phenotype In A Mouse Model For Craniometaphyseal Dysplasia, Ernst Reichenberger, Kevin O'Brien, Ayano Hatori, Thomas Carpenter, Koen Van De Wetering, Lisa Flaman, Jennifer Howe, Daniel Ortiz, Yves Sabbagh, I-Ping Chen

Jefferson Institute of Molecular Medicine Papers and Presentations

Craniometaphyseal dysplasia (CMD) is a rare genetic bone disorder, characterized by progressive thickening of craniofacial bones and flared metaphyses of long bones. Craniofacial hyperostosis leads to the obstruction of neural foramina and neurological symptoms such as facial palsy, blindness, deafness, or severe headache. Mutations in ANKH (mouse ortholog ANK), a transporter of small molecules such as citrate and ATP, are responsible for autosomal dominant CMD. Knock-in (KI) mice carrying an ANK_F377del mutation (Ank^KI/KI) replicate many features of human CMD. Pyrophosphate (PPi) levels in plasma are significantly reduced in Ank^KI/KI mice. PPi is a potent inhibitor of …

Lysineless Hibit And Nanoluc Tagging Systems As Alternative Tools For Monitoring Targeted Protein Degradation, Hanfeng Lin, Kristin Riching, May Poh Lai, Dong Lu, Ran Cheng, Xiaoli Qi, Jin Wang

Faculty, Staff and Students Publications

Target protein degradation (TPD) has emerged as a revolutionary approach in drug discovery, leveraging the cell’s intrinsic machinery to selectively degrade disease-associated proteins. Nanoluciferase (nLuc) fusion proteins and the NanoBiT technology offer two robust and sensitive screening platforms to monitor the subtle changes in protein abundance induced by TPD molecules. Despite these advantages, concerns have arisen regarding potential degradation artifacts introduced by tagging systems due to the presence of lysine residues on them, prompting the development of alternative tools. In this study, we introduce HiBiT-RR and nLucK0, variants devoid of lysine residues, to mitigate such artifacts. Our findings demonstrate that …

The Dna Methylome Of Pediatric Brain Tumors Appears Shaped By Structural Variation And Predicts Survival, Fengju Chen, Yiqun Zhang, Lanlan Shen, Chad J Creighton

Faculty, Staff and Students Publications

Structural variation heavily influences the molecular landscape of cancer, in part by impacting DNA methylation-mediated transcriptional regulation. Here, using multi-omic datasets involving >2400 pediatric brain and central nervous system tumors of diverse histologies from the Children's Brain Tumor Network, we report hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of somatic structural variant (SV) breakpoints is recurrently associated with altered expression or DNA methylation, respectively, including tumor suppressor genes ATRX and CDKN2A. Altered DNA methylation near enhancers associates with nearby somatic SV breakpoints, including MYC and MYCN. A subset of genes with SV-CGI methylation associations …

Loss Of Transient Receptor Potential Channel 5 Causes Obesity And Postpartum Depression, Yongxiang Li, Tessa M Cacciottolo, Na Yin, Yang He, Hesong Liu, Hailan Liu, Yuxue Yang, Elana Henning, Julia M Keogh, Katherine Lawler, Edson Mendes De Oliveira, Eugene J Gardner, Katherine A Kentistou, Panayiotis Laouris, Rebecca Bounds, Ken K Ong, John R B Perry, Inês Barroso, Longlong Tu, Jonathan C Bean, Meng Yu, Kristine M Conde, Mengjie Wang, Olivia Ginnard, Xing Fang, Lydia Tong, Junying Han, Tia Darwich, Kevin W Williams, Yongjie Yang, Chunmei Wang, Shelagh Joss, Helen V Firth, Yong Xu, I Sadaf Farooqi

Duncan NRI Faculty and Staff Publications

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of …

Pan-Cancer Proteogenomics Expands The Landscape Of Therapeutic Targets, Sara R Savage, Xinpei Yi, Jonathan T Lei, Bo Wen, Hongwei Zhao, Yuxing Liao, Eric J Jaehnig, Lauren K Somes, Paul W Shafer, Tobie D Lee, Zile Fu, Yongchao Dou, Zhiao Shi, Daming Gao, Valentina Hoyos, Qiang Gao, Bing Zhang

Faculty, Staff and Students Publications

Fewer than 200 proteins are targeted by cancer drugs approved by the Food and Drug Administration (FDA). We integrate Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomics data from 1,043 patients across 10 cancer types with additional public datasets to identify potential therapeutic targets. Pan-cancer analysis of 2,863 druggable proteins reveals a wide abundance range and identifies biological factors that affect mRNA-protein correlation. Integration of proteomic data from tumors and genetic screen data from cell lines identifies protein overexpression- or hyperactivation-driven druggable dependencies, enabling accurate predictions of effective drug targets. Proteogenomic identification of synthetic lethality provides a strategy to target tumor …

Cefiderocol Heteroresistance Associated With Mutations In Tonb-Dependent Receptor Genes In Pseudomonas Aeruginosa Of Clinical Origin, Stephanie L Egge, Samie A Rizvi, Shelby R Simar, Manuel Alcalde, Jose R W Martinez, Blake M Hanson, An Q Dinh, Rodrigo P Baptista, Truc T Tran, Samuel A Shelburne, Jose M Munita, Cesar A Arias, Morgan Hakki, William R Miller

Faculty, Staff and Student Publications

The siderophore-cephalosporin cefiderocol (FDC) presents a promising treatment option for carbapenem-resistant (CR) P. aeruginosa (PA). FDC circumvents traditional porin and efflux-mediated resistance by utilizing TonB-dependent receptors (TBDRs) to access the periplasmic space. Emerging FDC resistance has been associated with loss of function mutations within TBDR genes or the regulatory genes controlling TBDR expression. Further, difficulties with antimicrobial susceptibility testing (AST) and unexpected negative clinical treatment outcomes have prompted concerns for heteroresistance, where a single lineage isolate contains resistant subpopulations not detectable by standard AST. This study aimed to evaluate the prevalence of TBDR mutations among clinical isolates of P. aeruginosa …

Stem-Loop And Circle-Loop Tads Generated By Directional Pairing Of Boundary Elements Have Distinct Physical And Regulatory Properties, Wenfan Ke, Miki Fujioka, Paul Schedl, James Jaynes

Department of Biochemistry and Molecular Biology Faculty Papers

The chromosomes in multicellular eukaryotes are organized into a series of topologically independent loops called TADs. In flies, TADs are formed by physical interactions between neighboring boundaries. Fly boundaries exhibit distinct partner preferences, and pairing interactions between boundaries are typically orientation-dependent. Pairing can be head-to-tail or head-to-head. The former generates a stem-loop TAD, while the latter gives a circle-loop TAD. The TAD that encompasses the Drosophila even skipped (eve) gene is formed by the head-to-tail pairing of the nhomie and homie boundaries. To explore the relationship between loop topology and the physical and regulatory landscape, we flanked the nhomie boundary …

Pathophysiology In Brain Arteriovenous Malformations: Focus On Endothelial Dysfunctions And Endothelial-To-Mesenchymal Transition, Jae Yeong Jeong, Adrian E Bafor, Bridger H Freeman, Peng R Chen, Eun S Park, Eunhee Kim

Faculty, Staff and Student Publications

Brain arteriovenous malformations (bAVMs) substantially increase the risk for intracerebral hemorrhage (ICH), which is associated with significant morbidity and mortality. However, the treatment options for bAVMs are severely limited, primarily relying on invasive methods that carry their own risks for intraoperative hemorrhage or even death. Currently, there are no pharmaceutical agents shown to treat this condition, primarily due to a poor understanding of bAVM pathophysiology. For the last decade, bAVM research has made significant advances, including the identification of novel genetic mutations and relevant signaling in bAVM development. However, bAVM pathophysiology is still largely unclear. Further investigation is required to …

Correction: Multilocus Pathogenic Variants Contribute To Intrafamilial Clinical Heterogeneity: A Retrospective Study Of Sibling Pairs With Neurodevelopmental Disorders, Tugce Bozkurt-Yozgatli, Davut Pehlivan, Richard A Gibbs, Ugur Sezerman, Jennifer E Posey, James R Lupski, Zeynep Coban-Akdemir

Faculty, Staff and Students Publications

No abstract provided.

Comparative Plan Analysis: Helical Tomotherapy Vs. Linac Vmat For Lower Extremity Sarcomas, Marie E. Dibona

Masters Projects

Abstract

Introduction

Soft tissue sarcomas (STS) affect about 13,500 people annually in the United States, and those in the lower extremities present unique challenges in radiation therapy due to the wide variability in tumor sizes, sometimes exceeding 30cm. Traditional treatment involves C-Arm linear accelerators using Volumetric Modulated Radiation Therapy (VMAT), which provides precise targeting while sparing nearby organs. Helical Tomotherapy (HT) is another option, delivering radiation in a helical pattern with a binary MLC for a uniform dose distribution. However, no studies have compared VMAT and HT for lower extremity sarcomas of different sizes. This study aims to compare these …

Diagnostic Utility Of Dna Methylation Analysis In Genetically Unsolved Pediatric Epilepsies And Chd2 Episignature Refinement, Christy W Laflamme, Cassandra Rastin, Soham Sengupta, Helen E Pennington, Sophie J Russ-Hall, Amy L Schneider, Emily S Bonkowski, Edith P Almanza Fuerte, Talia J Allan, Miranda Perez-Galey Zalusky, Joy Goffena, Sophia B Gibson, Denis M Nyaga, Nico Lieffering, Malavika Hebbar, Emily V Walker, Daniel Darnell, Scott R Olsen, Pandurang Kolekar, Mohamed Nadhir Djekidel, Wojciech Rosikiewicz, Haley Mcconkey, Jennifer Kerkhof, Michael A Levy, Raissa Relator, Dorit Lev, Tally Lerman-Sagie, Kristen L Park, Marielle Alders, Gerarda Cappuccio, Nicolas Chatron, Leigh Demain, David Genevieve, Gaetan Lesca, Tony Roscioli, Damien Sanlaville, Matthew L Tedder, Sachin Gupta, Elizabeth A Jones, Monika Weisz-Hubshman, Shamika Ketkar, Hongzheng Dai, Kim C Worley, Jill A Rosenfeld, Hsiao-Tuan Chao, Undiagnosed Diseases Network, Geoffrey Neale, Gemma L Carvill, University Of Washington Center For Rare Disease Research, Zhaoming Wang, Samuel F Berkovic, Lynette G Sadleir, Danny E Miller, Ingrid E Scheffer, Bekim Sadikovic, Heather C Mefford

Faculty, Staff and Students Publications

Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also …

Identification And Characterization Of A Skin Microbiome On Caenorhabditis Elegans Suggests Environmental Microbes Confer Cuticle Protection, Nadia B Haghani, Robert H Lampe, Buck S Samuel, Sreekanth H Chalasani, Molly A Matty

Faculty, Staff and Students Publications

In the wild, C. elegans are emersed in environments teeming with a veritable menagerie of microorganisms. The C. elegans cuticular surface serves as a barrier and first point of contact with their microbial environments. In this study, we identify microbes from C. elegans natural habitats that associate with its cuticle, constituting a simple “skin microbiome.” We rear our animals on a modified CeMbio, mCeMbio, a consortium of ecologically relevant microbes. We first combine standard microbiological methods with an adapted micro skin-swabbing tool to describe the skin-resident bacteria on the C. elegans surface. Furthermore, we conduct 16S rRNA gene sequencing studies …

Intermittent Clearance Of P21-Highly-Expressing Cells Extends Lifespan And Confers Sustained Benefits To Health And Physical Function, Binsheng Wang, Lichao Wang, Nathan S Gasek, Chia-Ling Kuo, Jia Nie, Taewan Kim, Pengyi Yan, Junyu Zhu, Blake L Torrance, Yueying Zhou, Lisa C Flores, Colton Allen, Allison M Andrade, Chun Guo, Rachel L Cohn, Evan R Jellison, Jenna M Bartley, George A Kuchel, Sheng Li, Tamar Pirtskhalava, Tamar Tchkonia, Sumit Yadav, Laura Haynes, James L Kirkland, Yuji Ikeno, Ming Xu

Faculty, Staff and Student Publications

A key challenge in aging research is to extend lifespan in tandem with slowing down functional decline so that the life with good health (healthspan) can be extended. Here, we show that monthly clearance of a small number of cells, which highly express p21Cip1 (p21high), starting from 20 months improves cardiac and metabolic function, and extends both median and maximum lifespan in mice. Importantly, by assessing health and physical function of these mice monthly until death, we show that clearance of p21high cells improves physical function at all remaining stages of life, suggesting healthspan extension. Mechanistically, …

Pkd1 Mutant Clones Within Cirrhotic Livers Inhibit Steatohepatitis Without Promoting Cancer, Min Zhu, Yunguan Wang, Tianshi Lu, Jason Guo, Lin Li, Meng-Hsiung Hsieh, Purva Gopal, Yi Han, Naoto Fujiwara, Darren P Wallace, Alan S L Yu, Xiangyi Fang, Crystal Ransom, Sara Verschleisser, David Hsiehchen, Yujin Hoshida, Amit G Singal, Adam Yopp, Tao Wang, Hao Zhu

Faculty, Staff and Student Publications

Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency …

Whole Genome Sequencing Based Analysis Of Inflammation Biomarkers In The Trans-Omics For Precision Medicine (Topmed) Consortium, Min-Zhi Jiang, Sheila M Gaynor, Xihao Li, Eric Van Buren, Adrienne Stilp, Erin Buth, Fei Fei Wang, Regina Manansala, Stephanie M Gogarten, Zilin Li, Linda M Polfus, Shabnam Salimi, Joshua C Bis, Nathan Pankratz, Lisa R Yanek, Peter Durda, Russell P Tracy, Stephen S Rich, Jerome I Rotter, Braxton D Mitchell, Joshua P Lewis, Bruce M Psaty, Katherine A Pratte, Edwin K Silverman, Robert C Kaplan, Christy Avery, Kari E North, Rasika A Mathias, Nauder Faraday, Honghuang Lin, Biqi Wang, April P Carson, Arnita F Norwood, Richard A Gibbs, Charles Kooperberg, Jessica Lundin, Ulrike Peters, Josée Dupuis, Lifang Hou, Myriam Fornage, Emelia J Benjamin, Alexander P Reiner, Russell P Bowler, Xihong Lin, Paul L Auer, Laura M Raffield, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Inflammation Working Group

Faculty, Staff and Student Publications

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1). We identified 22 distinct single-variant …

Intouch Week Of August 5, 2024, New York Medical College

InTouch

• School of Medicine Class of 2028 Marks Start of Medical School Journey
• CDM Secures Grants to Expand Critical Emergency Training Programs
• NYMC SOM Student Senate Launches New Academic Year with Fresh Initiatives
• NYMC’s Center for Human Rights Helps Migrants Navigate the Asylum Process
• CDM Provided Summer Trainings

Podocyte Cell-Specific Npr1 Is Required For Blood Pressure And Renal Homeostasis In Male And Female Mice: Role Of Sex-Specific Differences, Chandramohan Ramasamy, Kandasamy Neelamegam, Samivel Ramachandran, Huijing Xia, Daniel R. Kapusta, Farhad R. Danesh, Kailash N. Pandey

School of Graduate Studies Faculty Publications

Atrial and brain natriuretic peptides (ANP and BNP) bind to guanylyl cyclase A/natriuretic peptide receptor A (GC-A/NPRA), stimulating natriuresis and diuresis and reducing blood pressure (BP), but the role of ANP/NPRA signaling in podocytes (highly specialized epithelial cells covering the outer surfaces of renal glomerular capillaries) remains unclear. This study aimed to determine the effect of conditional deletion of podocyte-specific Npr1 (encoding NPRA) gene knockout (KO) in male and female mice. Tamoxifen-treated wild-type control (PD Npr1 f/f; WT), heterozygous (PD-Cre-Npr1 f/+; HT), and KO (PD-Cre-Npr1 f/-) mice were fed a normal-, low-, or high-salt diet for 4 wk. Podocytes isolated …

Women In Stem Becoming Independent: Our Shared Motivation And Enthusiasm Are Our Driving Force, Liudmila Andreeva, Lidia Bosurgi, Shu Zhen Chong, Coco Chu, Yejing Ge, Esther Hoste, Kellie A Jurado, Jette Lengefeld, Archita Mishra, Stefanie Wculek, Arabella Young

Faculty, Staff and Student Publications

This year at JEM, we are highlighting women in science by sharing their stories and amplifying their voices. In this Viewpoint, we hear from a cross section of women, across multiple research fields, discussing their science and the process of setting up a lab as an independent researcher.

The Oncolytic Adenovirus Delta-24-Rgd In Combination With Onc201 Induces A Potent Antitumor Response In Pediatric High-Grade And Diffuse Midline Glioma Models, Daniel De La Nava, Iker Ausejo-Mauleon, Virginia Laspidea, Marisol Gonzalez-Huarriz, Andrea Lacalle, Noelia Casares, Marta Zalacain, Lucía Marrodan, Marc García-Moure, Maria C Ochoa, Antonio Carlos Tallon-Cobos, Reyes Hernandez-Osuna, Javier Marco-Sanz, Laasya Dhandapani, Irati Hervás-Corpión, Oren J Becher, Javad Nazarian, Sabine Mueller, Timothy N Phoenix, Jasper Van Der Lugt, Mikel Hernaez, Elizabeth Guruceaga, Carl Koschmann, Sriram Venneti, Joshua E Allen, Matthew D Dun, Juan Fueyo, Candelaria Gomez-Manzano, Jaime Gallego Perez-Larraya, Ana Patiño-García, Sara Labiano, Marta M Alonso

Faculty, Staff and Student Publications

BACKGROUND: Pediatric high-grade gliomas (pHGGs), including diffuse midline gliomas (DMGs), are aggressive pediatric tumors with one of the poorest prognoses. Delta-24-RGD and ONC201 have shown promising efficacy as single agents for these tumors. However, the combination of both agents has not been evaluated.

METHODS: The production of functional viruses was assessed by immunoblotting and replication assays. The antitumor effect was evaluated in a panel of human and murine pHGG and DMG cell lines. RNAseq, the seahorse stress test, mitochondrial DNA content, and γH2A.X immunofluorescence were used to perform mechanistic studies. Mouse models of both diseases were used to assess the …

Tumour-Intrinsic Endomembrane Trafficking By Arf6 Shapes An Immunosuppressive Microenvironment That Drives Melanomagenesis And Response To Checkpoint Blockade Therapy, Yinshen Wee, Junhua Wang, Emily C Wilson, Coulson P Rich, Aaron Rogers, Zongzhong Tong, Evelyn Degroot, Y N Vashisht Gopal, Michael A Davies, H Atakan Ekiz, Joshua K H Tay, Chris Stubben, Kenneth M Boucher, Juan M Oviedo, Keke C Fairfax, Matthew A Williams, Sheri L Holmen, Roger K Wolff, Allie H Grossmann

Faculty, Staff and Student Publications

Tumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development. This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with …

Translational Modeling-Based Evidence For Enhanced Efficacy Of Standard-Of-Care Drugs In Combination With Anti-Microrna-155 In Non-Small-Cell Lung Cancer, Prashant Dogra, Vrushaly Shinglot, Javier Ruiz-Ramírez, Joseph Cave, Joseph D Butner, Carmine Schiavone, Dan G Duda, Ahmed O Kaseb, Caroline Chung, Eugene J Koay, Vittorio Cristini, Bulent Ozpolat, George A Calin, Zhihui Wang

Faculty, Staff and Student Publications

BACKGROUND: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects.

METHODS: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs.

RESULTS: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg …

Lipid Droplet-Associated Hydrolase Mobilizes Stores Of Liver X Receptor Sterol Ligands And Protects Against Atherosclerosis, Young-Hwa Goo, Janeesh Plakkal Ayyappan, Francis D Cheeran, Sushant Bangru, Pradip K Saha, Paula Baar, Sabine Schulz, Todd A Lydic, Bernhard Spengler, Andreas H Wagner, Auinash Kalsotra, Vijay K Yechoor, Antoni Paul

Faculty, Staff and Students Publications

Foam cells in atheroma are engorged with lipid droplets (LDs) that contain esters of regulatory lipids whose metabolism remains poorly understood. LD-associated hydrolase (LDAH) has a lipase structure and high affinity for LDs of foam cells. Using knockout and transgenic mice of both sexes, here we show that LDAH inhibits atherosclerosis development and promotes stable lesion architectures. Broad and targeted lipidomic analyzes of primary macrophages and comparative lipid profiling of atheroma identified a broad impact of LDAH on esterified sterols, including natural liver X receptor (LXR) sterol ligands. Transcriptomic analyzes coupled with rescue experiments show that LDAH modulates the expression …

Kinesin Facilitates Phenotypic Targeting Of Therapeutic Resistance In Advanced Prostate Cancer, Maddison Archer, Diane Begemann, Edgar Gonzalez-Kozlova, Prerna R Nepali, Estefania Labanca, Peter Shepherd, Navneet Dogra, Nora Navone, Natasha Kyprianou

Faculty, Staff and Student Publications

Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes in patients with metastatic castration-resistant prostate cancer. Previous work showed that dynamic interconversions between epithelial-mesenchymal transition to mesenchymal-epithelial transition defines the phenotypic landscape of prostate tumors, as a potential driver of the emergence of therapeutic resistance. In this study, we use in vitro and in vivo preclinical MDA PCa patient-derived xenograft models of resistant human prostate cancer to determine molecular mechanisms of cross-resistance between antiandrogen therapy and taxane chemotherapy, underlying the therapeutically resistant phenotype. Transcriptomic profiling revealed that resistant and sensitive prostate cancer C4-2B cells have a unique differential …

Brca1-Mediated Dual Regulation Of Ferroptosis Exposes A Vulnerability To Gpx4 And Parp Co-Inhibition In Brca1-Deficient Cancers, Guang Lei, Chao Mao, Amber D Horbath, Yuelong Yan, Shirong Cai, Jun Yao, Yan Jiang, Mingchuang Sun, Xiaoguang Liu, Jun Cheng, Zhihao Xu, Hyemin Lee, Qidong Li, Zhengze Lu, Li Zhuang, Mei-Kuang Chen, Anagha Alapati, Timothy A Yap, Mien-Chie Hung, Mingjian James You, Helen Piwnica-Worms, Boyi Gan

Faculty, Staff and Student Publications

Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i …

Rosiglitazone And Trametinib Exhibit Potent Anti-Tumor Activity In A Mouse Model Of Muscle Invasive Bladder Cancer, Sakina A Plumber, Tiffany Tate, Hikmat Al-Ahmadie, Xiao Chen, Woonyoung Choi, Merve Basar, Chao Lu, Aaron Viny, Ekatherina Batourina, Jiaqi Li, Kristjan Gretarsson, Besmira Alija, Andrei Molotkov, Gregory Wiessner, Byron Hing Lung Lee, James Mckiernan, David J Mcconkey, Colin Dinney, Bogdan Czerniak, Cathy Lee Mendelsohn

Faculty, Staff and Student Publications

Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. …

Znf397 Deficiency Triggers Tet2-Driven Lineage Plasticity And Ar-Targeted Therapy Resistance In Prostate Cancer, Yaru Xu, Yuqiu Yang, Zhaoning Wang, Martin Sjöström, Yuyin Jiang, Yitao Tang, Siyuan Cheng, Su Deng, Choushi Wang, Julisa Gonzalez, Nickolas A Johnson, Xiang Li, Xiaoling Li, Lauren A Metang, Atreyi Mukherji, Quanhui Xu, Carla R Tirado, Garrett Wainwright, Xinzhe Yu, Spencer Barnes, Mia Hofstad, Yu Chen, Hong Zhu, Ariella B Hanker, Ganesh V Raj, Guanghui Zhu, Housheng H He, Zhao Wang, Carlos L Arteaga, Han Liang, Felix Y Feng, Yunguan Wang, Tao Wang, Ping Mu

Faculty, Staff and Students Publications

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming that allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified zinc finger protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a ten-eleven translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our …

Caspase-2 Is Essential For Proliferation And Self-Renewal Of Nucleophosmin-Mutated Acute Myeloid Leukemia, Dharaniya Sakthivel, Alexandra N Brown-Suedel, Karla E Lopez, Suruchi Salgar, Luiza E Coutinho, Francesca Keane, Shixia Huang, Kenneth Mc Sherry, Chloé I Charendoff, Kevin P Dunne, Dexter J Robichaux, Alexander Vargas-Hernández, Baochau Le, Crystal S Shin, Alexandre F Carisey, Marcin Poreba, Jonathan M Flanagan, Lisa Bouchier-Hayes

Faculty, Staff and Students Publications

Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm (NPM1c+). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a proapoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm and DNA damage–induced apoptosis is caspase-2 dependent in NPM1c+ but not in NPM1wt AML cells. Strikingly, in NPM1c+ cells, caspase-2 loss results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate …

Parameter Estimation For Stroke Patients Using Brain Ct Perfusion Imaging With Deep Temporal Convolutional Neural Network, Shake Ibna Abir

Masters Theses & Specialist Projects

Acute ischemic stroke, caused by cerebral artery blockage, is a leading cause of long-term disability and mortality. Effective management relies on accurate, timely assessments from neuroimaging data. Computed tomography perfusion (CTP) imaging is crucial in evaluating stroke patients, offering detailed maps of cerebral perfusion to identify irreversibly damaged tissue and at-risk areas. This detailed assessment is essential for informed therapeutic decisions.

Key perfusion parameters derived from CTP imaging, including cerebral blood volume (CBV), cerebral blood flow (CBF), time to peak (TTP), and mean transit time (MTT), are crucial for understanding the extent and nature of cerebral ischemia, providing valuable insights …

Dean's Research Newsletter, August 2024, Neil W. Schluger

SOM Dean's Research Newsletter

No abstract provided.

Biological Sex Influences Daily Locomotor Rhythms In Mice Held Under Different Housing Conditions, Amanda Pastrick, Matthew Diaz, Griffin Adaya, Victoria Montinola, Madeline Arzbecker, Deborah A. M. Joye, Jennifer A. Evans

Biomedical Sciences Faculty Research and Publications

Daily rhythms are programmed by a central circadian clock that is modulated by photoperiod. Here, we recorded locomotor activity rhythms in C57Bl/6 or mPer2^Luc mice of both sexes held under different housing conditions. First, we confirm that the structure of locomotor activity rhythms differs between male and female mice in both genetic backgrounds. Male mice exhibit a nightly “siesta,” whereas female mice fluctuate between nights with and without a nightly siesta, which corresponds with changes in locomotor activity levels, circadian period, and vaginal cytology. The nightly siesta is modulated by the presence of a running wheel in both sexes …