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Pediatric Glioma Immune Profiling Identifies Tim3 As A Therapeutic Target In Braf Fusion Pilocytic Astrocytoma, Shashwat Tripathi, Hinda Najem, Corey Dussold, Sebastian Pacheco, Ruochen Du, Moloud Sooreshjani, Lisa Hurley, James P Chandler, Roger Stupp, Adam M Sonabend, Craig M Horbinski, Rimas V Lukas, Joanne Xiu, Giselle Lopez, Theodore P Nicolaides, Valerie Brown, Nitin R Wadhwani, Sandi K Lam, Charles David James, Ganesh Rao, Maria G Castro, Amy B Heimberger, Michael Decuypere Aug 2024

Pediatric Glioma Immune Profiling Identifies Tim3 As A Therapeutic Target In Braf Fusion Pilocytic Astrocytoma, Shashwat Tripathi, Hinda Najem, Corey Dussold, Sebastian Pacheco, Ruochen Du, Moloud Sooreshjani, Lisa Hurley, James P Chandler, Roger Stupp, Adam M Sonabend, Craig M Horbinski, Rimas V Lukas, Joanne Xiu, Giselle Lopez, Theodore P Nicolaides, Valerie Brown, Nitin R Wadhwani, Sandi K Lam, Charles David James, Ganesh Rao, Maria G Castro, Amy B Heimberger, Michael Decuypere

Faculty, Staff and Students Publications

Despite being the leading cause of cancer-related childhood mortality, pediatric gliomas have been relatively understudied, and the repurposing of immunotherapies has not been successful. Whole-transcriptome sequencing, single-cell sequencing, and sequential multiplex immunofluorescence were used to identify an immunotherapeutic strategy that could be applied to multiple preclinical glioma models. MAPK-driven pediatric gliomas have a higher IFN signature relative to other molecular subgroups. Single-cell sequencing identified an activated and cytotoxic microglia (MG) population designated MG-Act in BRAF-fused, MAPK-activated pilocytic astrocytoma (PA), but not in high-grade gliomas or normal brain. T cell immunoglobulin and mucin domain 3 (TIM3) was expressed on MG-Act and …


Awareness Of Nutrition's Impact On Mental Health And Ketogenic Diet’S Therapeutic Potential For Mental Illness And Other Chronic Disorders, Innocent Nsengiyumva Aug 2024

Awareness Of Nutrition's Impact On Mental Health And Ketogenic Diet’S Therapeutic Potential For Mental Illness And Other Chronic Disorders, Innocent Nsengiyumva

Theses and Graduate Projects

Mental health affects millions of people worldwide, and current pharmaceutical treatment approaches often lead to worse outcomes, weight gain, and increased cardiovascular risk. The ketogenic diet offers hope in the treatment of schizophrenia and other neurological and psychiatric disorders. The aim of this project is to explore public awareness of nutritional psychiatry and the ketogenic diet’s clinical utility for various conditions including schizophrenia, mood disorders, Parkinson’s, and multiple sclerosis. Study participants (n=108) completed a 12-question survey about individual nutritional habits and current knowledge of KD. Responses were obtained from medical students, practicing healthcare professionals, college undergraduate students, and members of …


A Social Media Game To Increase Physical Activity Among Older Adult Women: Protocol Of A Randomized Controlled Trial To Evaluate Challenge, Michael C Robertson, Maria Chang Swartz, Karen M Basen-Engquist, Yisheng Li, Kristofer Jennings, Debbe Thompson, Tom Baranowski, Elena Volpi, Elizabeth J Lyons Aug 2024

A Social Media Game To Increase Physical Activity Among Older Adult Women: Protocol Of A Randomized Controlled Trial To Evaluate Challenge, Michael C Robertson, Maria Chang Swartz, Karen M Basen-Engquist, Yisheng Li, Kristofer Jennings, Debbe Thompson, Tom Baranowski, Elena Volpi, Elizabeth J Lyons

Faculty, Staff and Student Publications

BACKGROUND: Older adult women often do not engage in sufficient physical activity (PA) and can encounter biological changes that exacerbate the negative effects of inadequate activity. Wearable activity monitors can facilitate PA initiation, but evidence of sustained behavior change is lacking. Supplementing wearable technologies with intervention content that evokes enjoyment, interest, meaning, and personal values associated with PA may support long term adherence. In this paper, we present the protocol of an NIA-funded study designed to evaluate the efficacy of CHALLENGE for increasing step count and motivation for PA in insufficiently active older women (Challenges for Healthy Aging: Leveraging Limits …


Interleukin-21 Engineering Enhances Nk Cell Activity Against Glioblastoma Via Cebpd, Mayra Shanley, May Daher, Jinzhuang Dou, Sufang Li, Rafet Basar, Hind Rafei, Merve Dede, Joy Gumin, Jezreel Pantaleόn Garcίa, Ana Karen Nunez Cortes, Shan He, Corry M Jones, Sunil Acharya, Natalie W Fowlkes, Donghai Xiong, Sanjay Singh, Hila Shaim, Samantha Claire Hicks, Bin Liu, Abhinav Jain, Mohammad Fayyad Zaman, Qi Miao, Ye Li, Nadima Uprety, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Vakul Mohanty, Patrick Zhang, Scott E Evans, Elizabeth J Shpall, Frederick F Lang, Ken Chen, Katayoun Rezvani Aug 2024

Interleukin-21 Engineering Enhances Nk Cell Activity Against Glioblastoma Via Cebpd, Mayra Shanley, May Daher, Jinzhuang Dou, Sufang Li, Rafet Basar, Hind Rafei, Merve Dede, Joy Gumin, Jezreel Pantaleόn Garcίa, Ana Karen Nunez Cortes, Shan He, Corry M Jones, Sunil Acharya, Natalie W Fowlkes, Donghai Xiong, Sanjay Singh, Hila Shaim, Samantha Claire Hicks, Bin Liu, Abhinav Jain, Mohammad Fayyad Zaman, Qi Miao, Ye Li, Nadima Uprety, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Vakul Mohanty, Patrick Zhang, Scott E Evans, Elizabeth J Shpall, Frederick F Lang, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as …


Stargardt’S: Trends In Treatment Modalities, Dallas Myers Aug 2024

Stargardt’S: Trends In Treatment Modalities, Dallas Myers

Theses and Graduate Projects

Background: This review is aimed at furthering understanding of Stargardt’s, including disease pathophysiology, treatment methods, and the future of vision restoration.

Purpose: Stargardt’s (STGD) was initially discovered in 1909, but it was not fully understood until 1997. It is the most common form of inherited macular degeneration. There are few resources for patients and providers regarding treatment options and lifestyle recommendations.

Methods: A comprehensive literature review was conducted using NIH, UpToDate, and Google Scholar. Specific terms are further detailed in the review. Inclusion criteria were studies focused on STGD patients. Exclusion criteria for were those that only …


Dual Inhibition Of The Trka And Jak2 Pathways Using Entrectinib And Pacritinib Suppresses The Growth And Metastasis Of Her2-Positive And Triple-Negative Breast Cancers, Angelina T Regua, Shivani Bindal, Mariana K Najjar, Chuling Zhuang, Munazza Khan, Austin B J Arrigo, Anneliese O Gonzalez, Xinhai R Zhang, Jay-Jiguang Zhu, Kounosuke Watabe, Hui-Wen Lo Aug 2024

Dual Inhibition Of The Trka And Jak2 Pathways Using Entrectinib And Pacritinib Suppresses The Growth And Metastasis Of Her2-Positive And Triple-Negative Breast Cancers, Angelina T Regua, Shivani Bindal, Mariana K Najjar, Chuling Zhuang, Munazza Khan, Austin B J Arrigo, Anneliese O Gonzalez, Xinhai R Zhang, Jay-Jiguang Zhu, Kounosuke Watabe, Hui-Wen Lo

Faculty, Staff and Student Publications

HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness …


Mitochondrial Permeability Transition Dictates Mitochondrial Maturation Upon Switch In Cellular Identity Of Hematopoietic Precursors, Sandeep P Dumbali, Paulina D Horton, Travis I Moore, Pamela L Wenzel Aug 2024

Mitochondrial Permeability Transition Dictates Mitochondrial Maturation Upon Switch In Cellular Identity Of Hematopoietic Precursors, Sandeep P Dumbali, Paulina D Horton, Travis I Moore, Pamela L Wenzel

Faculty, Staff and Student Publications

The mitochondrial permeability transition pore (mPTP) is a supramolecular channel that regulates exchange of solutes across cristae membranes, with executive roles in mitochondrial function and cell death. The contribution of the mPTP to normal physiology remains debated, although evidence implicates the mPTP in mitochondrial inner membrane remodeling in differentiating progenitor cells. Here, we demonstrate that strict control over mPTP conductance shapes metabolic machinery as cells transit toward hematopoietic identity. Cells undergoing the endothelial-to-hematopoietic transition (EHT) tightly control chief regulatory elements of the mPTP. During EHT, maturing arterial endothelium restricts mPTP activity just prior to hematopoietic commitment. After transition in cellular …


3d Chromatin Architecture, Brd4, And Mediator Have Distinct Roles In Regulating Genome-Wide Transcriptional Bursting And Gene Network, Pawel Trzaskoma, Seolkyoung Jung, Aleksandra Pękowska, Christopher H Bohrer, Xiang Wang, Faiza Naz, Stefania Dell'orso, Wendy D Dubois, Ana Olivera, Supriya V Vartak, Yongbing Zhao, Subhashree Nayak, Andrew Overmiller, Maria I Morasso, Vittorio Sartorelli, Daniel R Larson, Carson C Chow, Rafael Casellas, John J O'Shea Aug 2024

3d Chromatin Architecture, Brd4, And Mediator Have Distinct Roles In Regulating Genome-Wide Transcriptional Bursting And Gene Network, Pawel Trzaskoma, Seolkyoung Jung, Aleksandra Pękowska, Christopher H Bohrer, Xiang Wang, Faiza Naz, Stefania Dell'orso, Wendy D Dubois, Ana Olivera, Supriya V Vartak, Yongbing Zhao, Subhashree Nayak, Andrew Overmiller, Maria I Morasso, Vittorio Sartorelli, Daniel R Larson, Carson C Chow, Rafael Casellas, John J O'Shea

Faculty, Staff and Student Publications

Discontinuous transcription is evolutionarily conserved and a fundamental feature of gene regulation; yet, the exact mechanisms underlying transcriptional bursting are unresolved. Analyses of bursting transcriptome-wide have focused on the role of cis-regulatory elements, but other factors that regulate this process remain elusive. We applied mathematical modeling to single-cell RNA sequencing data to infer bursting dynamics transcriptome-wide under multiple conditions to identify possible molecular mechanisms. We found that Mediator complex subunit 26 (MED26) primarily regulates frequency, MYC regulates burst size, while cohesin and Bromodomain-containing protein 4 (BRD4) can modulate both. Despite comparable effects on RNA levels among these perturbations, acute depletion …


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 Aug 2024

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 Aug 2024

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 …


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 Aug 2024

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 …


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

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 Aug 2024

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 …


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 Aug 2024

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 Aug 2024

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 …


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 Aug 2024

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 Aug 2024

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 …


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 Aug 2024

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 …


Ultrashort Pulsed Laser Treatment Is Effective At Sterilizing Metal Surfaces For Planetary Protection, Kaleb Mcquillan Aug 2024

Ultrashort Pulsed Laser Treatment Is Effective At Sterilizing Metal Surfaces For Planetary Protection, Kaleb Mcquillan

Department of Electrical and Computer Engineering: Dissertations, Theses, and Student Research

To prevent forward contamination from microbes aboard spacecraft intended for exploration of solar system bodies there is a need for effective sterilization methods. However, current techniques are both time-consuming and expensive. For example, dry heat sterilization requires removal from the assembly site and several days of treatment. Furthermore, some components such as optics and electronics are not compatible with current sterilization techniques. In this thesis, a novel femtosecond laser surface processing technique for the rapid sterilization of spacecraft hardware is reported. Femtosecond lasers produce extremely high photon fluxes (1029 photons/s*cm2, ~0.03 J/cm2) in extremely short …


Early Cold Stored Platelet Transfusion Following Severe Injury: A Randomized Clinical Trial, Jason L Sperry, Francis X Guyette, Bedda L Rosario-Rivera, Matthew E Kutcher, Lucy Z Kornblith, Bryan A Cotton, Chad T Wilson, Kenji Inaba, Eva V Zadorozny, Laura E Vincent, Ashley M Harner, Emily T Love, Joseph E Doherty, Joseph Cuschieri, Aaron E Kornblith, Erin E Fox, Yu Bai, Marcus K Hoffman, Catherine P Seger, Jay Hudgins, Sheila Mallett-Smith, Matthew D Neal, Christine M Leeper, Philip C Spinella, Mark H Yazer, Stephen R Wisniewski, Cold Stored Platelet For Hemorrhagic Shock (Crisp-Hs) Study Group Aug 2024

Early Cold Stored Platelet Transfusion Following Severe Injury: A Randomized Clinical Trial, Jason L Sperry, Francis X Guyette, Bedda L Rosario-Rivera, Matthew E Kutcher, Lucy Z Kornblith, Bryan A Cotton, Chad T Wilson, Kenji Inaba, Eva V Zadorozny, Laura E Vincent, Ashley M Harner, Emily T Love, Joseph E Doherty, Joseph Cuschieri, Aaron E Kornblith, Erin E Fox, Yu Bai, Marcus K Hoffman, Catherine P Seger, Jay Hudgins, Sheila Mallett-Smith, Matthew D Neal, Christine M Leeper, Philip C Spinella, Mark H Yazer, Stephen R Wisniewski, Cold Stored Platelet For Hemorrhagic Shock (Crisp-Hs) Study Group

Faculty, Staff and Student Publications

OBJECTIVE: To determine the feasibility, efficacy, and safety of early cold stored platelet transfusion compared with standard care resuscitation in patients with hemorrhagic shock.

BACKGROUND: Data demonstrating the safety and efficacy of early cold stored platelet transfusion are lacking following severe injury.

METHODS: A phase 2, multicenter, randomized, open label, clinical trial was performed at 5 US trauma centers. Injured patients at risk of large volume blood transfusion and the need for hemorrhage control procedures were enrolled and randomized. The intervention was the early transfusion of a single apheresis cold stored platelet unit, stored for up to 14 days versus …


Influential Factors And Predicting Dose Delivery Accuracy For Imaging And Radiation Oncology Core’S Phantom Program Using Machine Learning, Hunter Mehrens Aug 2024

Influential Factors And Predicting Dose Delivery Accuracy For Imaging And Radiation Oncology Core’S Phantom Program Using Machine Learning, Hunter Mehrens

Dissertations and Theses (Open Access)

IROC’s mission is to help ensure consistent and comparable, high-quality radiotherapy across clinics that participate in national clinical trials. To obtain this mission, IROC’s phantom program provides a third-party end-to-end check of the clinical workflow of a patient receiving radiotherapy. The goal of the phantom audit is to compare the dose delivered to the dose planned by the treatment system ensuring dose delivery accuracy. While IROC’s phantoms are better equipped to catch dose delivery errors compared to a clinic’s QA process, the end-to-end process and reporting of results is time-consuming creating a bottleneck for clinical trial participation. Furthermore, IROC’s passing …


The Role Of An Ultraconserved Long Non-Coding Rna In B-Cell Lymphomagenesis, Swati Mohapatra Aug 2024

The Role Of An Ultraconserved Long Non-Coding Rna In B-Cell Lymphomagenesis, Swati Mohapatra

Dissertations and Theses (Open Access)

Ultraconserved regions (UCRs) are genomic segments with perfect (100%) conservation between the orthologous regions of human, rat, and mouse genomes. UCRs can be transcribed into mono-exonic long non-coding RNAs (lncRNAs) known as transcribed ultraconserved regions (T-UCRs). These regions, despite lacking protein-coding potential, are increasingly recognized for their regulatory roles in gene expression, including the modulation of non-coding RNA (ncRNA) transcripts. NcRNAs play crucial roles in cellular processes, including oncogenic transformation, with emerging evidence revealing their ability to encode small peptides known as ncRNA-encoded peptides (ncPEPs). These peptides, originating from small open reading frames (smORFs), contribute to diverse cellular functions and …


Genotype-By-Environment Interactions In Nonalcoholic Fatty Liver Disease And Chronic Illness Among Mexican Americans: The Role Of Acculturation Stress, Eron Manusov, Vincent Diego, Marcio Almeida, David Ortiz, Joanne E. Curran, Jacob Galan, Ana C. Leandro, Sandra Laston, John Blangero, Sarah Williams-Blangero Aug 2024

Genotype-By-Environment Interactions In Nonalcoholic Fatty Liver Disease And Chronic Illness Among Mexican Americans: The Role Of Acculturation Stress, Eron Manusov, Vincent Diego, Marcio Almeida, David Ortiz, Joanne E. Curran, Jacob Galan, Ana C. Leandro, Sandra Laston, John Blangero, Sarah Williams-Blangero

School of Medicine Publications

This study examines the complex interplay of genetic and environmental interactions that shape chronic illness risk. Evidence is mounting for the role of genetic expression and the immune response in the pathogenesis of chronic disease. In the Rio Grande Valley of south Texas, where 90% of the population is Mexican American, chronic illnesses (including obesity, diabetes, nonalcoholic liver disease, and depression) are reaching epidemic proportions. This study leverages an ongoing family study of the genetic determinants of risk for obesity, diabetes, hypertension, hyperlipidemia, and depression in a Mexican American population. Data collected included blood pressure, BMI, hepatic transaminases, HbA1c, depression …


Practice Patterns And Barriers To Vascular Genetic Testing Among Vascular Surgeons, James M Dittman, Siddharth K Prakash, Prem Chand Gupta, Wojciech Wiszniewski, Niten Singh, Matthew R Smeds, Sherene Shalhub Aug 2024

Practice Patterns And Barriers To Vascular Genetic Testing Among Vascular Surgeons, James M Dittman, Siddharth K Prakash, Prem Chand Gupta, Wojciech Wiszniewski, Niten Singh, Matthew R Smeds, Sherene Shalhub

Faculty, Staff and Student Publications

Introduction: Engaging patients living with or at risk of aortic dissection via the Aortic Dissection Collaborative, physician education in vascular genetics was identified as a research priority. We surveyed vascular surgeons to characterize practice patterns, motivations, and barriers regarding aortopathy genetic testing.

Methods: An anonymous 27-question survey was distributed on social media platforms between November and December 2022. Domains included demographics, vascular genetic education, testing attitudes and utilization, and experience in treating patients with genetic vascular aortopathies. The analysis included summary statistics and unpaired t-test to compare responses by interest in incorporating testing and practice type.

Results: A total of …


Assessing The State Of Obesity Care: Quality, Access, Guidelines, And Standards, Lee M Kaplan, Caroline M Apovian, Jamy D Ard, David B Allison, Louis J Aronne, Rachel L Batterham, Luca Busetto, Dror Dicker, Deborah B Horn, Aaron S Kelly, Jeffrey I Mechanick, Jonathan Q Purnell, Ximena Ramos-Salas, Assessing The State Of Obesity Care Writing Group Aug 2024

Assessing The State Of Obesity Care: Quality, Access, Guidelines, And Standards, Lee M Kaplan, Caroline M Apovian, Jamy D Ard, David B Allison, Louis J Aronne, Rachel L Batterham, Luca Busetto, Dror Dicker, Deborah B Horn, Aaron S Kelly, Jeffrey I Mechanick, Jonathan Q Purnell, Ximena Ramos-Salas, Assessing The State Of Obesity Care Writing Group

Faculty, Staff and Student Publications

BACKGROUND: An international panel of obesity medicine experts from multiple professional organizations examined patterns of obesity care and current obesity treatment guidelines to identify areas requiring updating in response to emerging science and clinical evidence.

AIMS: The panel focused on multiple medical health and societal issues influencing effective treatment of obesity and identified several unmet needs in the definition, assessment, and care of obesity.

METHODS: The panel was held in Leesburg, Virginia in September 2019.

RESULTS: The panelists recommended addressing these unmet needs in obesity medicine through research, education, evaluation of delivery and payment of care, and updating clinical practice …


Vertebrate And Invertebrate Animal Infection Models Of Candida Auris Pathogenicity, Melissa Martinez, Danielle A Garsin, Michael C Lorenz Aug 2024

Vertebrate And Invertebrate Animal Infection Models Of Candida Auris Pathogenicity, Melissa Martinez, Danielle A Garsin, Michael C Lorenz

Faculty, Staff and Student Publications

Candida auris is an emerging fungal pathogen with several concerning qualities. First recognized in 2009, it has arisen in multiple geographically distinct genomic clades nearly simultaneously. C. auris strains are typically multidrug resistant and colonize the skin much better than most other pathogenic fungi; it also persists on abiotic surfaces, enabling outbreaks due to transmission in health care facilities. All these suggest a biology substantially different from the 'model' fungal pathogen, Candida albicans and support intensive investigation of C. auris biology directly. To uncover novel virulence mechanisms in this species requires the development of appropriate animal infection models. Various studies …


A Multi-National Survey To Identify Clinicians’ Perspectives Concerning Proton Pump Inhibitors In Patients With Systemic Sclerosis, Giulia Bandini, Alessia Alunno, Filipe Oliveira Pinheiro, Corrado Campochiaro, Ilaria Galetti, Pietro Matucci Cerinic, Barbara Ruaro, Alberto Moggi Pignone, Silvia Bellando Randone, Lorenzo Dagna, Marco Matucci Cerinic, Zsuzsanna H Mcmahan, Michael Hughes Aug 2024

A Multi-National Survey To Identify Clinicians’ Perspectives Concerning Proton Pump Inhibitors In Patients With Systemic Sclerosis, Giulia Bandini, Alessia Alunno, Filipe Oliveira Pinheiro, Corrado Campochiaro, Ilaria Galetti, Pietro Matucci Cerinic, Barbara Ruaro, Alberto Moggi Pignone, Silvia Bellando Randone, Lorenzo Dagna, Marco Matucci Cerinic, Zsuzsanna H Mcmahan, Michael Hughes

Faculty, Staff and Student Publications

Objectives: Proton Pump Inhibitors (PPIs) are widely used in SSc for gastroesophageal reflux disease (GERD). However, there is little evidence to support their empirical use and long-term safety has been questioned. Our objective was to better describe clinicians' attitudes toward PPIs prescription and use in SSc patients.

Methods: Clinicians involved in the care of SSc patients were invited through international physician networks and social media to participate in an online survey.

Results: Responses from 227 clinicians from 36 countries were evaluable. The majority 'agreed' (41.4 %) or 'strongly agreed' (45.4 %) that GERD is a major cause of morbidity in …


Meniscus Tears In Elite Athletes: Treatment Considerations, Clinical Outcomes, And Return To Play, Erick M Marigi, Michael R Davies, Robert G Marx, Scott A Rodeo, Riley J Williams Aug 2024

Meniscus Tears In Elite Athletes: Treatment Considerations, Clinical Outcomes, And Return To Play, Erick M Marigi, Michael R Davies, Robert G Marx, Scott A Rodeo, Riley J Williams

Faculty, Staff and Student Publications

PURPOSE OF REVIEW: Management of meniscal injuries in the elite athlete is a difficult problem secondary to the high demands of athletic competition, the need for a timely return to sport, and the desire to maximize performance over time. The purpose of this review is to provide an up-to-date summary on the current literature and trends regarding the management of meniscus injuries with a special consideration for elite athletes.

RECENT FINDINGS: Historically, partial meniscectomy has been the primary treatment option for meniscus injuries. However, in recent years there has been an increased emphasis on meniscus preservation due to the increased …


Comparative Toxicological Assessment Of 2 Bisphenols Using A Systems Approach: Evaluation Of The Behavioral And Transcriptomic Responses Of Danio Rerio To Bisphenol A And Tetrabromobisphenol A, Michael G Morash, Morgan W Kirzinger, John C Achenbach, Ananda B Venkatachalam, Jessica Nixon, Susanne Penny, Joëlle Pinsonnault Cooper, Deborah E Ratzlaff, Cindy L A Woodland, Lee D Ellis Aug 2024

Comparative Toxicological Assessment Of 2 Bisphenols Using A Systems Approach: Evaluation Of The Behavioral And Transcriptomic Responses Of Danio Rerio To Bisphenol A And Tetrabromobisphenol A, Michael G Morash, Morgan W Kirzinger, John C Achenbach, Ananda B Venkatachalam, Jessica Nixon, Susanne Penny, Joëlle Pinsonnault Cooper, Deborah E Ratzlaff, Cindy L A Woodland, Lee D Ellis

Faculty, Staff and Student Publications

The zebrafish (Danio rerio) is becoming a critical component of new approach methods (NAMs) in chemical risk assessment. As a whole organism in vitro NAM, the zebrafish model offers significant advantages over individual cell-line testing, including toxicokinetic and toxicodynamic competencies. A transcriptomic approach not only allows for insight into mechanism of action for both apical endpoints and unobservable adverse outcomes, but also changes in gene expression induced by lower, environmentally relevant concentrations. In this study, we used a larval zebrafish model to assess the behavioral and transcriptomic alterations caused by subphenotypic concentrations of 2 chemicals with the same structural backbone, …


Disparities In Exposure To Tobacco On Television Or Streaming Platforms, Henry K Onyeaka, Onyema G Chido-Amajuoyi, Itunu Sokale, Kobi V Ajayi, A Eden Evins, Hermioni L Amonoo, Sanjay Shete Aug 2024

Disparities In Exposure To Tobacco On Television Or Streaming Platforms, Henry K Onyeaka, Onyema G Chido-Amajuoyi, Itunu Sokale, Kobi V Ajayi, A Eden Evins, Hermioni L Amonoo, Sanjay Shete

Faculty, Staff and Student Publications

Importance: With the rise in popularity of streaming platforms concerns about exposure to tobacco advertising and promotion have emerged. While tobacco marketing and promotion through traditional television (TV) media channels has been extensively studied, less is known about exposure to tobacco through TV or streaming platforms and its associated factors.

Objective: To examine the prevalence and factors associated with exposure to tobacco products advertised, marketed, or promoted on TV or streaming platforms among US adults.

Design, setting, and participants: This cross-sectional study used data from the National Cancer Institute's Health Information National Trends Survey (HINTS 6), conducted from March 7 …