Medicine and Health Sciences Commons^™

Progressive, Long-Term Hearing Loss In Congenital Cmv Disease After Ganciclovir Therapy, Tatiana M Lanzieri, Alison Chantal Caviness, Peggy Blum, Gail Demmler-Harrison

Faculty, Staff and Students Publications

BACKGROUND: Long-term hearing outcomes among children with symptomatic congenital cytomegalovirus (CMV) disease who received 6-week ganciclovir therapy early in life are unknown.

METHODS: Longitudinal study of 76 children with symptomatic congenital CMV disease, born 1983-2005, who were categorized into three groups: group A treated with ganciclovir; group B untreated who had microcephaly, chorioretinitis, or sensorineural hearing loss (SNHL; ≥25 dB) diagnosed in the first month of life (congenital); and group C untreated who did not meet criteria for group B.

RESULTS: Patients in groups A (n = 17), B (n = 27), and C (n = 32) were followed to …

Characterization Of The Copd Alveolar Niche Using Single-Cell Rna Sequencing, Maor Sauler, John E Mcdonough, Taylor S Adams, Neeharika Kothapalli, Thomas Barnthaler, Rhiannon B Werder, Jonas C Schupp, Jessica Nouws, Matthew J Robertson, Cristian Coarfa, Tao Yang, Maurizio Chioccioli, Norihito Omote, Carlos Cosme, Sergio Poli, Ehab A Ayaub, Sarah G Chu, Klaus H Jensen, Jose L Gomez, Clemente J Britto, Micha Sam B Raredon, Laura E Niklason, Andrew A Wilson, Pascal N Timshel, Naftali Kaminski, Ivan O Rosas

Faculty, Staff and Students Publications

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, however our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. Here, we analyze single-cell RNA sequencing profiles of explanted lung tissue from subjects with advanced COPD or control lungs, and we validate findings using single-cell RNA sequencing of lungs from mice exposed to 10 months of cigarette smoke, RNA sequencing of isolated human alveolar epithelial cells, functional in vitro models, and in situ hybridization and immunostaining of human lung tissue samples. We identify a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant …

Allogeneic Transplant And Car-T Therapy After Autologous Transplant Failure In Dlbcl: A Noncomparative Cohort Analysis, Mehdi Hamadani, Ajay K Gopal, Marcelo Pasquini, Soyoung Kim, Xianmiao Qiu, Sairah Ahmed, Aleksandr Lazaryan, Vijaya Raj Bhatt, Andrew Daly, Premal Lulla, Stefan Ciurea, Jordan Gauthier, Vaibhav Agrawal, Natalie S Grover, Lazaros Lekakis, Dipenkumar Modi, Parastoo B Dahi, Megan M Herr, P Connor Johnson, Hamza Hashmi, Peiman Hematti, Frederick L Locke

Faculty, Staff and Students Publications

Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR)-T cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto)HCT. Although the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis, we report outcomes of patients with DLBCL (≥18 years) undergoing a reduced intensity alloHCT or CAR-T therapy with axicabtagene ciloleucel during 2012 to 2019 after a prior auto-HCT failure and apply the CIBMTR prognostic …

Antibody Responses Of Healthy Adults To The P27 Peptide Of Respiratory Syncytial Virus Fusion Protein, Brittani N Blunck, Letisha Aideyan, Xunyan Ye, Vasanthi Avadhanula, Laura Ferlic-Stark, Lynn Zechiedrich, Brian E Gilbert, Pedro A Piedra

Faculty, Staff and Students Publications

The respiratory syncytial virus (RSV) fusion (F) protein undergoes two furin-cleavage events to become fusion competent, resulting in the release of a twenty-seven amino acid peptide (p27). Recent studies indicate that the p27 region of the F protein was an immunodominant antigen in young children. In this study, we evaluated the kinetics of the serum antibody response to the p27 peptide following natural RSV reinfection in adults. Nineteen healthy adults under sixty-five years of age were enrolled during the 2018-2019 RSV season in Houston, TX. Blood was collected at three study visits and RSV infection status was defined by changes …

An Estrogen-Sensitive Hypothalamus-Midbrain Neural Circuit Controls Thermogenesis And Physical Activity, Hui Ye, Bing Feng, Chunmei Wang, Kenji Saito, Yongjie Yang, Lucas Ibrahimi, Sarah Schaul, Nirali Patel, Leslie Saenz, Pei Luo, Penghua Lai, Valeria Torres, Maya Kota, Devin Dixit, Xing Cai, Na Qu, Ilirjana Hyseni, Kaifan Yu, Yuwei Jiang, Qingchun Tong, Zheng Sun, Benjamin R Arenkiel, Yanlin He, Pingwen Xu, Yong Xu

Faculty, Staff and Students Publications

Estrogen receptor–α (ERα) expressed by neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (ERαvlVMH) regulates body weight in females, but the downstream neural circuits mediating this biology remain largely unknown. Here we identified a neural circuit mediating the metabolic effects of ERαvlVMH neurons. We found that selective activation of ERαvlVMH neurons stimulated brown adipose tissue (BAT) thermogenesis, physical activity, and core temperature and that ERαvlVMH neurons provide monosynaptic glutamatergic inputs to 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN). Notably, the ERαvlVMH → DRN circuit responds to changes in ambient temperature and nutritional states. We further showed …

Comprehensive Structure And Functional Adaptations Of The Yeast Nuclear Pore Complex, Christopher W Akey, Digvijay Singh, Christna Ouch, Ignacia Echeverria, Ilona Nudelman, Joseph M Varberg, Zulin Yu, Fei Fang, Yi Shi, Junjie Wang, Daniel Salzberg, Kangkang Song, Chen Xu, James C Gumbart, Sergey Suslov, Jay Unruh, Sue L Jaspersen, Brian T Chait, Andrej Sali, Javier Fernandez-Martinez, Steven J Ludtke, Elizabeth Villa, Michael P Rout

Faculty, Staff and Students Publications

Nuclear pore complexes (NPCs) mediate the nucleocytoplasmic transport of macromolecules. Here we provide a structure of the isolated yeast NPC in which the inner ring is resolved by cryo-EM at sub-nanometer resolution to show how flexible connectors tie together different structural and functional layers. These connectors may be targets for phosphorylation and regulated disassembly in cells with an open mitosis. Moreover, some nucleoporin pairs and transport factors have similar interaction motifs, which suggests an evolutionary and mechanistic link between assembly and transport. We provide evidence for three major NPC variants that may foreshadow functional specializations at the nuclear periphery. Cryo-electron …

Using Cryo-Et To Distinguish Platelets During Pre-Acute Myeloid Leukemia From Steady State Hematopoiesis, Yuewei Wang, Tong Huo, Yu-Jung Tseng, Lan Dang, Zhili Yu, Wenjuan Yu, Zachary Foulks, Rebecca L Murdaugh, Steven J Ludtke, Daisuke Nakada, Zhao Wang

Faculty, Staff and Students Publications

Early diagnosis of acute myeloid leukemia (AML) in the pre-leukemic stage remains a clinical challenge, as pre-leukemic patients show no symptoms, lacking any known morphological or numerical abnormalities in blood cells. Here, we demonstrate that platelets with structurally abnormal mitochondria emerge at the pre-leukemic phase of AML, preceding detectable changes in blood cell counts or detection of leukemic blasts in blood. We visualized frozen-hydrated platelets from mice at different time points during AML development in situ using electron cryo-tomography (cryo-ET) and identified intracellular organelles through an unbiased semi-automatic process followed by quantitative measurement. A large proportion of platelets exhibited changes …

Rspo2 And Rankl Signal Through Lgr4 To Regulate Osteoclastic Premetastatic Niche Formation And Bone Metastasis, Zhiying Yue, Xin Niu, Zengjin Yuan, Qin Qin, Wenhao Jiang, Liang He, Jingduo Gao, Yi Ding, Yanxi Liu, Ziwei Xu, Zhenxi Li, Zhengfeng Yang, Rong Li, Xiwen Xue, Yankun Gao, Fei Yue, Xiang H-F Zhang, Guohong Hu, Yi Wang, Yi Li, Geng Chen, Stefan Siwko, Alison Gartland, Ning Wang, Jianru Xiao, Mingyao Liu, Jian Luo

Faculty, Staff and Students Publications

Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate premetastatic niche and bone tropism are largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through Gαq and β-catenin signaling. …

Effect Of P2y12 Inhibitors On Survival Free Of Organ Support Among Non-Critically Ill Hospitalized Patients With Covid-19: A Randomized Clinical Trial, Jeffrey S Berger, Lucy Z Kornblith, Michelle N Gong, Harmony R Reynolds, Mary Cushman, Yu Cheng, Bryan J Mcverry, Keri S Kim, Renato D Lopes, Bassel Atassi, Scott Berry, Grant Bochicchio, Murillo De Oliveira Antunes, Michael E Farkouh, Yonatan Greenstein, Erinn M Hade, Kristin Hudock, Robert Hyzy, Pooja Khatri, Andrei Kindzelski, Bridget-Anne Kirwan, Lisa Baumann Kreuziger, Patrick R Lawler, Eric Leifer, Jose Lopez-Sendon Moreno, Jose Lopez-Sendon, James F Luther, Lilia Nigro Maia, John Quigley, Robert Sherwin, Lana Wahid, Jennifer Wilson, Judith S Hochman, Matthew D Neal, Activ-4a Investigators

Faculty, Staff and Students Publications

IMPORTANCE: Platelets represent a potential therapeutic target for improved clinical outcomes in patients with COVID-19.

OBJECTIVE: To evaluate the benefits and risks of adding a P2Y12 inhibitor to anticoagulant therapy among non-critically ill patients hospitalized for COVID-19.

DESIGN, SETTING, AND PARTICIPANTS: An open-label, bayesian, adaptive randomized clinical trial including 562 non-critically ill patients hospitalized for COVID-19 was conducted between February 2021 and June 2021 at 60 hospitals in Brazil, Italy, Spain, and the US. The date of final 90-day follow-up was September 15, 2021.

INTERVENTIONS: Patients were randomized to a therapeutic dose of heparin plus a P2Y12 inhibitor (n = …

Clonal Hematopoiesis Mutations In Patients With Lung Cancer Are Associated With Lung Cancer Risk Factors, Wei Hong, Ang Li, Yanhong Liu, Xiangjun Xiao, David C Christiani, Rayjean J Hung, James Mckay, John Field, Christopher I Amos, Chao Cheng

Faculty, Staff and Students Publications

Clonal hematopoiesis (CH) is a phenomenon caused by expansion of white blood cells descended from a single hematopoietic stem cell. While CH can be associated with leukemia and some solid tumors, the relationship between CH and lung cancer remains largely unknown. To help clarify this relationship, we analyzed whole-exome sequencing (WES) data from 1,958 lung cancer cases and controls. Potential CH mutations were identified by a set of hierarchical filtering criteria in different exonic regions, and the associations between the number of CH mutations and clinical traits were investigated. Family history of lung cancer (FHLC) may exert diverse influences on …

Glynac (Glycine And N-Acetylcysteine) Supplementation Improves Impaired Mitochondrial Fuel Oxidation And Lowers Insulin Resistance In Patients With Type 2 Diabetes: Results Of A Pilot Study, Rajagopal V Sekhar

Faculty, Staff and Students Publications

Patients with type 2 diabetes (T2D) are known to have mitochondrial dysfunction and increased insulin resistance (IR), but the underlying mechanisms are not well understood. We reported previously that (a) adequacy of the antioxidant glutathione (GSH) is necessary for optimal mitochondrial fatty-acid oxidation (MFO); (b) supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC) in mice corrected GSH deficiency, reversed impaired MFO, and lowered oxidative stress (OxS) and IR; and (c) supplementing GlyNAC in patients with T2D improved GSH synthesis and concentrations, and lowered OxS. However, the effect of GlyNAC on MFO, MGO (mitochondrial glucose oxidation), IR and plasma FFA …

Mapk4 Promotes Triple Negative Breast Cancer Growth And Reduces Tumor Sensitivity To Pi3k Blockade, Wei Wang, Dong Han, Qinbo Cai, Tao Shen, Bingning Dong, Michael T Lewis, Runsheng Wang, Yanling Meng, Wolong Zhou, Ping Yi, Chad J Creighton, David D Moore, Feng Yang

Faculty, Staff and Students Publications

About 15-20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity …

Mutations In Hcfc1 And Ronin Result In An Inborn Error Of Cobalamin Metabolism And Ribosomopathy, Tiffany Chern, Annita Achilleos, Xuefei Tong, Matthew C Hill, Alexander B Saltzman, Lucas C Reineke, Arindam Chaudhury, Swapan K Dasgupta, Yushi Redhead, David Watkins, Joel R Neilson, Perumal Thiagarajan, Jeremy B A Green, Anna Malovannaya, James F Martin, David S Rosenblatt, Ross A Poché

Faculty, Staff and Students Publications

Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously …

Secretogranin Iii Stringently Regulates Pathological But Not Physiological Angiogenesis In Oxygen-Induced Retinopathy, Chang Dai, Prabuddha Waduge, Liyang Ji, Chengchi Huang, Ye He, Hong Tian, Elizabeth Zuniga-Sanchez, Amit Bhatt, Iok-Hou Pang, Guanfang Su, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized …

Associations Between Resources And Practices Of Ild Centers And Outcomes In Patients With Idiopathic Pulmonary Fibrosis: Data From The Ipf-Pro Registry, Joao A De Andrade, Tejaswini Kulkarni, Megan L Neely, Anne S Hellkamp, Amy Hajari Case, Daniel A Culver, Kalpalatha Guntupalli, Shaun Bender, Craig S Conoscenti, Laurie D Snyder, Ipf-Pro Registry Investigators

Faculty, Staff and Students Publications

BACKGROUND: Performance benchmarks for the management of idiopathic pulmonary fibrosis (IPF) have not been established. We used data from the IPF-PRO Registry, an observational registry of patients with IPF managed at sites across the US, to examine associations between the characteristics of the enrolling sites and patient outcomes.

METHODS: An online survey was used to collect information on the resources, operations, and self-assessment practices of IPF-PRO Registry sites that enrolled ≥ 10 patients. Site variability in 1-year event rates of clinically relevant outcomes, including death, death or lung transplant, and hospitalization, was assessed. Models were adjusted for differences in patient …

3’Aqtl-Atlas: An Atlas Of 3’Utr Alternative Polyadenylation Quantitative Trait Loci Across Human Normal Tissues, Ya Cui, Fanglue Peng, Dan Wang, Yumei Li, Jason Sheng Li, Lei Li, Wei Li

Faculty, Staff and Students Publications

Genome-wide association studies (GWAS) have identified thousands of non-coding single-nucleotide polymorphisms (SNPs) associated with human traits and diseases. However, functional interpretation of these SNPs remains a significant challenge. Our recent study established the concept of 3' untranslated region (3'UTR) alternative polyadenylation (APA) quantitative trait loci (3'aQTLs), which can be used to interpret ∼16.1% of GWAS SNPs and are distinct from gene expression QTLs and splicing QTLs. Despite the growing interest in 3'aQTLs, there is no comprehensive database for users to search and visualize them across human normal tissues. In the 3'aQTL-atlas (https://wlcb.oit.uci.edu/3aQTLatlas), we provide a comprehensive list of 3'aQTLs containing …

In Situ Structure Of The Acrab-Tolc Efflux Pump At Subnanometer Resolution, Muyuan Chen, Xiaodong Shi, Zhili Yu, Guizhen Fan, Irina I Serysheva, Matthew L Baker, Ben F Luisi, Steven J Ludtke, Zhao Wang

Faculty, Staff and Students Publications

The tripartite AcrAB-TolC assembly, which spans both the inner and outer membranes in Gram-negative bacteria, is an efflux pump that contributes to multidrug resistance. Here, we present the in situ structure of full-length Escherichia coli AcrAB-TolC determined at 7 Å resolution by electron cryo-tomography. The TolC channel penetrates the outer membrane bilayer through to the outer leaflet and exhibits two different configurations that differ by a 60° rotation relative to the AcrB position in the pump assembly. AcrA protomers interact directly with the inner membrane and with AcrB via an interface located in proximity to the AcrB ligand-binding pocket. Our …

Aav5 Delivery Of Crispr-Cas9 Supports Effective Genome Editing In Mouse Lung Airway, Shun-Qing Liang, Christopher J Walkey, Alexa E Martinez, Qin Su, Mary E Dickinson, Dan Wang, William R Lagor, Jason D Heaney, Guangping Gao, Wen Xue

Faculty, Staff and Students Publications

Genome editing in the lung has the potential to provide long-term expression of therapeutic protein to treat lung genetic diseases. Yet efficient delivery of CRISPR to the lung remains a challenge. The NIH Somatic Cell Genome Editing (SCGE) Consortium is developing safe and effective methods for genome editing in disease tissues. Methods developed by consortium members are independently validated by the SCGE small animal testing center to establish rigor and reproducibility. We have developed and validated a dual adeno-associated virus (AAV) CRISPR platform that supports effective editing of a lox-stop-lox-Tomato reporter in mouse lung airway. After intratracheal injection of the …

Autophagosomes Fuse To Phagosomes And Facilitate The Degradation Of Apoptotic Cells In Caenorhabditis Elegans, Omar Peña-Ramos, Lucia Chiao, Xianghua Liu, Xiaomeng Yu, Tianyou Yao, Henry He, Zheng Zhou

Faculty, Staff and Students Publications

Autophagosomes are double-membrane intracellular vesicles that degrade protein aggregates, intracellular organelles, and other cellular components. During the development of the nematode Caenorhabditis elegans, many somatic and germ cells undergo apoptosis. These cells are engulfed and degraded by their neighboring cells. We discovered a novel role of autophagosomes in facilitating the degradation of apoptotic cells using a real-time imaging technique. Specifically, the double-membrane autophagosomes in engulfing cells are recruited to the surfaces of phagosomes containing apoptotic cells and subsequently fuse to phagosomes, allowing the inner vesicle to enter the phagosomal lumen. Mutants defective in the production of autophagosomes display significant …

The Efficacy And Safety Of Thrombopoietin Receptor Agonists In Patients With Chronic Liver Disease Undergoing Elective Procedures: A Systematic Review And Meta-Analysis, Ingrid Lindquist, Sven R Olson, Ang Li, Hanny Al-Samkari, Janice H Jou, Owen J T Mccarty, Joseph J Shatzel

Faculty, Staff and Students Publications

Thrombopoietin receptor agonists (TPO-RAs) can mitigate preprocedural thrombocytopenia in patients with chronic liver disease (CLD) however their effects on procedural outcomes is unclear. In this meta-analysis, we aimed to better define the efficacy, thrombotic risk and bleeding mitigation associated with the use of preoperative TPO-RAs in patients with CLD. We performed a systematic review and meta-analysis of randomized placebo-controlled clinical trials to assess the use of preprocedural TPO-RAs in patients with CLD, searching MEDLINE, EMBASE and the Cochrane library database. Six publications comprising eight randomized trials (1229 patients; 717 received TPO-RAs, 512 received placebo) and three unique TPO-RAs were retrieved. …

Embryonic Hypotaurine Levels Contribute To Strain-Dependent Susceptibility In Mouse Models Of Valproate-Induced Neural Tube Defects, John W Steele, Ying Linda Lin, Nellie Chen, Bogdan J Wlodarczyk, Qiuying Chen, Nabeel Attarwala, Madhu Venkatesalu, Robert M Cabrera, Steven S Gross, Richard H Finnell

Faculty, Staff and Students Publications

Valproic acid (VPA, valproate, Depakote) is a commonly used anti-seizure medication (ASM) in the treatment of epilepsy and a variety of other neurological disorders. While VPA and other ASMs are efficacious for management of seizures, they also increase the risk for adverse pregnancy outcomes, including neural tube defects (NTDs). Thus, the utility of these drugs during pregnancy and in women of childbearing potential presents a continuing public health challenge. Elucidating the underlying genetic or metabolic risk factors for VPA-affected pregnancies may lead to development of non-teratogenic ASMs, novel prevention strategies, or more targeted methods for managing epileptic pregnancies. To address …

Identification Of Lung Cancer Drivers By Comparison Of The Observed And The Expected Numbers Of Missense And Nonsense Mutations In Individual Human Genes, Olga Y Gorlova, Marek Kimmel, Spiridon Tsavachidis, Christopher I Amos, Ivan P Gorlov

Faculty, Staff and Students Publications

Largely, cancer development is driven by acquisition and positive selection of somatic mutations that increase proliferation and survival of tumor cells. As a result, genes related to cancer development tend to have an excess of somatic mutations in them. An excess of missense and/or nonsense mutations in a gene is an indicator of its cancer relevance. To identify genes with an excess of potentially functional missense or nonsense mutations one needs to compare the observed and expected numbers of mutations in the gene. We estimated the expected numbers of missense and nonsense mutations in individual human genes using (i) the …

Retrobulbar Hematoma In A Patient With Thyroid Eye Disease, Christina Y Weng

Faculty, Staff and Students Publications

A 37-year-old female with a history of thyroid eye disease presented after trauma to the right side of her face. Visual acuity was light perception and a relative afferent pupillary defect was detected. There was gross proptosis of the unruptured right globe with diffuse conjunctival hemorrhage. Computed tomography revealed an intraconal retrobulbar hematoma (RBH) with anterior herniation of the globe. The extraocular muscles were thickened, consistent with her thyroid eye disease, and her superior rectus was avulsed. The optic nerve was on stretch, but there was no evidence of transection. The patient ultimately underwent enucleation with the plan for an …

Modified Vaccinia Ankara Expressing Eehv1a Glycoprotein B Elicits Humoral And Cell-Mediated Immune Responses In Mice, Taylor Pursell, Jennifer L Spencer Clinton, Jie Tan, Rongsheng Peng, Paul D Ling

Faculty, Staff and Students Publications

Elephant endotheliotropic herpesvirus (EEHV) can cause lethal hemorrhagic disease (EEHV-HD) in Asian elephants and is the largest cause of death in captive juvenile Asian elephants in North America and Europe. EEHV-HD also has been documented in captive and wild elephants in their natural range countries. A safe and effective vaccine to prevent lethal EEHV infection would significantly improve conservation efforts for this endangered species. Recent studies from our laboratory suggest that EEHV morbidity and mortality are often associated with primary infection. Therefore, we aim to generate a vaccine, particularly for EEHV1 naïve animals, with the goal of preventing lethal EEHV-HD. …

Hypermethylation Of Pi3k-Akt Signalling Pathway Genes Is Associated With Human Neural Tube Defects, Tian Tian, Xinyuan Lai, Kuanhui Xiang, Xiao Han, Shengju Yin, Robert M Cabrera, John W Steele, Yunping Lei, Xuanye Cao, Richard H Finnell, Linlin Wang, Aiguo Ren

Faculty, Staff and Students Publications

Neural tube defects (NTDs) are a group of common and severe congenital malformations. The PI3K-AKT signalling pathway plays a crucial role in the neural tube development. There is limited evidence concerning any possible association between aberrant methylation in PI3K-AKT signalling pathway genes and NTDs. Therefore, we aimed to investigate potential associations between aberrant methylation of PI3K-AKT pathway genes and NTDs. Methylation studies of PI3K-AKT pathway genes utilizing microarray genome-methylation data derived from neural tissues of ten NTD cases and eight non-malformed controls were performed. Targeted DNA methylation analysis was subsequently performed in an independent cohort of 73 NTD cases and …

Targeting The Pro-Survival Protein Bcl-2 To Prevent Breast Cancer, Adelaide Young, Wen Bu, Weiyu Jiang, Amy Ku, Jyoti Kapali, Sagar Dhamne, Lan Qin, Susan G Hilsenbeck, Yi-Chieh Nancy Du, Yi Li

Faculty, Staff and Students Publications

Current chemopreventive strategies require 3-5 years of continuous treatment and have the concerns of significant side effects; therefore, new chemopreventive agents that require shorter and safer treatments are urgently needed. In this study, we developed a new murine model of breast cancer that mimics human breast cancer initiation and is ideal for testing the efficacy of chemopreventive therapeutics. In this model, introduction of lentivirus carrying a PIK3CA gene mutant commonly found in breast cancers infects a small number of the mammary cells, leading to atypia first and then to ductal carcinomas that are positive for both estrogen receptor and progesterone …

Decidualization Of Human Endometrial Stromal Cells Requires Steroid Receptor Coactivator-3, Vineet K Maurya, Maria M Szwarc, David M Lonard, William E Gibbons, San-Pin Wu, Bert W O'Malley, Francesco J Demayo, John P Lydon

Faculty, Staff and Students Publications

Steroid receptor coactivator-3 (SRC-3; also known as NCOA3 or AIB1) is a member of the multifunctional p160/SRC family of coactivators, which also includes SRC-1 and SRC-2. Clinical and cell-based studies as well as investigations on mice have demonstrated pivotal roles for each SRC in numerous physiological and pathophysiological contexts, underscoring their functional pleiotropy. We previously demonstrated the critical involvement of SRC-2 in murine embryo implantation as well as in human endometrial stromal cell (HESC) decidualization, a cellular transformation process required for trophoblast invasion and ultimately placentation. We show here that, like SRC-2, SRC-3 is expressed in the epithelial and stromal …

Initial Experiences Using Plasma Rich In Growth Factors To Treat Keratoneuralgia, Margaret Wang, Sowmya Yennam, Stephen Pflugfelder

Faculty, Staff and Students Publications

Keratoneuralgia, a clinical diagnosis of sensitized corneal pain without visible ocular surface damage, generally has minimal response to conventional therapies. Causes include refractive surgery and chronic dry eye. We evaluated the efficacy of Plasma Rich in Growth Factors (PRGF), a novel treatment prepared using a commercially available kit, in patients with keratoneuralgia. A retrospective chart review identified patients who had the clinical diagnosis of keratoneuralgia and were treated with PRGF for at least 3 months from October 2015 to April 2020 at a single academic institution. Both objective eye exam findings and concurrent treatments were obtained at baseline, 3 months, …

Il-17 Producing Lymphocytes Cause Dry Eye And Corneal Disease With Aging In Rxrα Mutant Mouse, Jehan Alam, Ghasem Yazdanpanah, Rinki Ratnapriya, Nicholas Borcherding, Cintia S De Paiva, Dequan Li, Rodrigo Guimaraes De Souza, Zhiyuan Yu, Stephen C Pflugfelder

Faculty, Staff and Students Publications

PURPOSE: To investigate IL-17 related mechanisms for developing dry eye disease in the Pinkie mouse strain with a loss of function RXRα mutation.

METHODS: Measures of dry eye disease were assessed in the cornea and conjunctiva. Expression profiling was performed by single-cell RNA sequencing (scRNA-seq) to compare gene expression in conjunctival immune cells. Conjunctival immune cells were immunophenotyped by flow cytometry and confocal microscopy. The activity of RXRα ligand 9-cis retinoic acid (RA) was evaluated in cultured monocytes and γδ T cells.

RESULTS: Compared to wild type (WT) C57BL/6, Pinkie has increased signs of dry eye disease, including decreased tear …

Rev-Erb Is Essential In Cardiac Fibroblasts Homeostasis, Xiaokang Luo, Shiyang Song, Lei Qi, Chih-Liang Tien, Hui Li, Weiyi Xu, Theodore Lemuel Mathuram, Thomas Burris, Yuanbiao Zhao, Zheng Sun, Lilei Zhang

Faculty, Staff and Students Publications

REV-ERB agonists have shown antifibrotic effects in the heart and other organs. The function of REV-ERB in the cardiac fibroblasts remains unstudied. Here, we characterize the functional difference of REV-ERB in mouse embryonic fibroblasts and cardiac fibroblasts using genetic deletion of REV-ERBα and ß in vitro. We show that REV-ERB α/β double deleted cardiac fibroblasts have reduced viability and proliferation, but increased migration and myofibroblasts activation. Thus, REV-ERB α/β has essential cell-autonomous role in cardiac fibroblasts in maintaining them in a healthy, quiescent state. We also show that existing REV-ERB agonist SR9009 strongly suppresses cardiac fibroblasts activation but in …