Digital Commons Network^™

A, B, C'S Of Trk Receptors And Their Ligands In Ocular Repair, Akash Gupta, Jeremias G Galletti, Zhiyuan Yu, Kevin Burgess, Cintia S De Paiva

Faculty, Staff and Students Publications

Neurotrophins are a family of closely related secreted proteins that promote differentiation, development, and survival of neurons, which include nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4. All neurotrophins signal through tropomyosin receptor kinases (TrkA, TrkB, and TrkC) which are more selective to NGF, brain-derived neurotrophic factor, and neurotrophin-3, respectively. NGF is the most studied neurotrophin in the ocular surface and a human recombinant NGF has reached clinics, having been approved to treat neurotrophic keratitis. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 are less studied neurotrophins in the ocular surface, even though brain-derived neurotrophic factor is well characterized in …

Gene Therapy Knockdown Of Hippo Signaling Resolves Arrhythmic Events In Pigs After Myocardial Infarction, Sui Zhang, Shijie Liu, John P Leach, Ke Li, Emerson C Perin, James F Martin

Faculty, Staff and Students Publications

No abstract provided.

Cerebral Blood Flow And Cardiovascular Risk Effects On Resting Brain Regional Homogeneity, Bhim M Adhikari, L Elliot Hong, Zhiwei Zhao, Danny J J Wang, Paul M Thompson, Neda Jahanshad, Alyssa H Zhu, Stefan Holiga, Jessica A Turner, Theo G M Van Erp, Vince D Calhoun, Kathryn S Hatch, Heather Bruce, Stephanie M Hare, Joshua Chiappelli, Eric L Goldwaser, Mark D Kvarta, Yizhou Ma, Xiaoming Du, Thomas E Nichols, Alan R Shuldiner, Braxton D Mitchell, Juergen Dukart, Shuo Chen, Peter Kochunov

Faculty, Staff and Student Publications

Regional homogeneity (ReHo) is a measure of local functional brain connectivity that has been reported to be altered in a wide range of neuropsychiatric disorders. Computed from brain resting-state functional MRI time series, ReHo is also sensitive to fluctuations in cerebral blood flow (CBF) that in turn may be influenced by cerebrovascular health. We accessed cerebrovascular health with Framingham cardiovascular risk score (FCVRS). We hypothesize that ReHo signal may be influenced by regional CBF; and that these associations can be summarized as FCVRS→CBF→ReHo. We used three independent samples to test this hypothesis. A test-retest sample of N = 30 healthy …

Anti-Diabetic Effects Of Glp1 Analogs Are Mediated By Thermogenic Interleukin-6 Signaling In Adipocytes, Absalon D Gutierrez, Zhanguo Gao, Vala Hamidi, Liang Zhu, Karla Bermudez Saint Andre, Kayla Riggs, Monika Ruscheinsky, Hongyu Wang, Yongmei Yu, Charles Miller, Hernan Vasquez, Heinrich Taegtmeyer, Mikhail G Kolonin

Faculty, Staff and Student Publications

Mechanisms underlying anti-diabetic effects of GLP1 analogs remain incompletely understood. We observed that in prediabetic humans exenatide treatment acutely induces interleukin-6 (IL-6) secretion by monocytes and IL-6 in systemic circulation. We hypothesized that GLP1 analogs signal through IL-6 in adipose tissue (AT) and used the mouse model to test if IL-6 receptor (IL-6R) signaling underlies the effects of the GLP1-IL-6 axis. We show that liraglutide transiently increases IL-6 in mouse circulation and IL-6R signaling in AT. Metronomic liraglutide treatment resulted in AT browning and thermogenesis linked with STAT3 activation. IL-6-blocking antibody treatment inhibited STAT3 activation in AT and suppressed liraglutide-induced …

Tumor-Intrinsic Sirpa Promotes Sensitivity To Checkpoint Inhibition Immunotherapy In Melanoma, Zhicheng Zhou, Mei-Ju May Chen, Yikai Luo, Kamalika Mojumdar, Xin Peng, Hu Chen, Shweta V Kumar, Rehan Akbani, Yiling Lu, Han Liang

Faculty, Staff and Student Publications

Checkpoint inhibition immunotherapy has revolutionized cancer treatment, but many patients show resistance. Here we perform integrative transcriptomic and proteomic analyses on emerging immuno-oncology targets across multiple clinical cohorts of melanoma under anti-PD-1 treatment, on both bulk and single-cell levels. We reveal a surprising role of tumor-intrinsic SIRPA in enhancing antitumor immunity, in contrast to its well-established role as a major inhibitory immune modulator in macrophages. The loss of SIRPA expression is a marker of melanoma dedifferentiation, a key phenotype linked to immunotherapy efficacy. Inhibition of SIRPA in melanoma cells abrogates tumor killing by activated CD8+ T cells in a co-culture …

Increased Circulating Cortisol After Vaginal Birth Is Associated With Increased Fgf19 Secretion In Neonatal Pigs, Caitlin Vonderohe, Gregory Guthrie, Barbara Stoll, Valeria Melendez Hebib, Harry Dawson, Douglas Burrin

Children’s Nutrition Research Center Staff Publications

The influence of birth modality (scheduled cesarean or spontaneous vaginal) on the development of the newborn has been a source of controversy in neonatology. The impact of cesarean vs vaginal birth on the development of bile acid and fibroblast growth factor 19 (FGF19) signaling is unknown. Our aim was to determine the effect of birth modality and gestational age (preterm vs term) on plasma hormone levels, bile acid pool distribution, expression of genes in the bile acid-FXR-FGF19 pathway, and plasma levels of FGF19 at birth and on day 3 of life in neonatal pigs. Four sows underwent cesarean delivery on …

Repeated Out-Of-Africa Expansions Of Helicobacter Pylori Driven By Replacement Of Deleterious Mutations, Harry A Thorpe, Elise Tourrette, Koji Yahara, Filipa F Vale, Siqi Liu, Mónica Oleastro, Teresa Alarcon, Tsachi-Tsadok Perets, Saeid Latifi-Navid, Yoshio Yamaoka, Beatriz Martinez-Gonzalez, Ioannis Karayiannis, Timokratis Karamitros, Dionyssios N Sgouras, Wael Elamin, Ben Pascoe, Samuel K Sheppard, Jukka Ronkainen, Pertti Aro, Lars Engstrand, Lars Agreus, Sebastian Suerbaum, Kaisa Thorell, Daniel Falush

Faculty, Staff and Students Publications

Helicobacter pylori lives in the human stomach and has a population structure resembling that of its host. However, H. pylori from Europe and the Middle East trace substantially more ancestry from modern African populations than the humans that carry them. Here, we use a collection of Afro-Eurasian H. pylori genomes to show that this African ancestry is due to at least three distinct admixture events. H. pylori from East Asia, which have undergone little admixture, have accumulated many more non-synonymous mutations than African strains. European and Middle Eastern bacteria have elevated African ancestry at the sites of these mutations, implying …

Pancreatic Tumor Microenvironmental Acidosis And Hypoxia Transform Gold Nanorods Into Cell-Penetrant Particles For Potent Radiosensitization, Pradipta Ranjan Rauta, Yuri Mackeyev, Keith Sanders, Joseph B K Kim, Valeria V Gonzalez, Yasmin Zahra, Muhammad A Shohayeb, Belal Abousaida, Geraldine V Vijay, Okan Tezcan, Paul Derry, Anton V Liopo, Eugene R Zubarev, Rickey Carter, Pankaj Singh, Sunil Krishnan

Faculty, Staff and Student Publications

Coating nanoparticles with stealth epilayers increases circulation time by evading opsonization, macrophage phagocytosis, and reticuloendothelial sequestration. However, this also reduces internalization by cancer cells upon reaching the tumor. We designed gold nanorods (GNRs) with an epilayer that retains stealth properties in circulation but transforms spontaneously in the acidotic tumor microenvironment to a cell-penetrating particle. We used a customized stoichiometric ratio of l-glutamic acid and l-lysine within an amphiphilic polymer of poly(l-glutamic acid-co-l-lysine), or P(Glu-co-Lys), to effect this transformation in acidotic environments. P(Glu-co-Lys)-GNRs were internalized by cancer cells to facilitate potent in vitro radiosensitization. When administered intravenously in mice, they accumulate …

Pancreatic Tumor Microenvironmental Acidosis And Hypoxia Transform Gold Nanorods Into Cell-Penetrant Particles For Potent Radiosensitization, Pradipta Ranjan Rauta, Yuri Mackeyev, Keith Sanders, Joseph B K Kim, Valeria V Gonzalez, Yasmin Zahra, Muhammad A Shohayeb, Belal Abousaida, Geraldine V Vijay, Okan Tezcan, Paul Derry, Anton V Liopo, Eugene R Zubarev, Rickey Carter, Pankaj Singh, Sunil Krishnan

Faculty, Staff and Student Publications

Coating nanoparticles with stealth epilayers increases circulation time by evading opsonization, macrophage phagocytosis, and reticuloendothelial sequestration. However, this also reduces internalization by cancer cells upon reaching the tumor. We designed gold nanorods (GNRs) with an epilayer that retains stealth properties in circulation but transforms spontaneously in the acidotic tumor microenvironment to a cell-penetrating particle. We used a customized stoichiometric ratio of l-glutamic acid and l-lysine within an amphiphilic polymer of poly(l-glutamic acid-co-l-lysine), or P(Glu-co-Lys), to effect this transformation in acidotic environments. P(Glu-co-Lys)-GNRs were internalized by cancer cells to facilitate potent in vitro radiosensitization. When administered intravenously in mice, they accumulate …

Targeting The Mdm2-P53 Pathway In Dedifferentiated Liposarcoma, Raymond S Traweek, Brandon M Cope, Christina L Roland, Emily Z Keung, Elise F Nassif, Derek J Erstad

Faculty, Staff and Student Publications

Dedifferentiated liposarcoma (DDLPS) is an aggressive adipogenic cancer with poor prognosis. DDLPS tumors are only modestly sensitive to chemotherapy and radiation, and there is a need for more effective therapies. Genetically, DDLPS is characterized by a low tumor mutational burden and frequent chromosomal structural abnormalities including amplification of the 12q13-15 chromosomal region and the MDM2 gene, which are defining features of DDLPS. The MDM2 protein is an E3 ubiquitin ligase that targets the tumor suppressor, p53, for proteasomal degradation. MDM2 amplification or overexpression in human malignancies is associated with cell-cycle progression and worse prognosis. The MDM2-p53 interaction has thus garnered …

Erk Inhibitor Ulixertinib Inhibits High-Risk Neuroblastoma Growth In Vitro And In Vivo, Yang Yu, Yanling Zhao, Jongmin Choi, Zhongcheng Shi, Linjie Guo, John Elizarraras, Andy Gu, Feng Cheng, Yanxin Pei, Dai Lu, Muller Fabbri, Saurabh Agarwal, Chunchao Zhang, Sung Yun Jung, Jennifer H Foster, Jianhua Yang

Faculty, Staff and Students Publications

Neuroblastoma (NB) is a pediatric tumor of the peripheral nervous system. Approximately 80% of relapsed NB show RAS-MAPK pathway mutations that activate ERK, resulting in the promotion of cell proliferation and drug resistance. Ulixertinib, a first-in-class ERK-specific inhibitor, has shown promising antitumor activity in phase 1 clinical trials for advanced solid tumors. Here, we show that ulixertinib significantly and dose-dependently inhibits cell proliferation and colony formation in different NB cell lines, including PDX cells. Transcriptomic analysis revealed that ulixertinib extensively inhibits different oncogenic and neuronal developmental pathways, including EGFR, VEGF, WNT, MAPK, NGF, and NTRK1. The proteomic analysis further revealed …

Omics Analyses Of A Somatic Trp53r245w/+ Breast Cancer Model Identify Cooperating Driver Events Activating Pi3k/Akt/Mtor Signaling, Xiaojie Yu, Yun Zhang, Shunbin Xiong, Joy M Mcdaniel, Chang Sun, Gilda P Chau, Jovanka Gencel-Augusto, Dhruv Chachad, Rhiannon L Morrissey, Xiayu Rao, Jing Wang, Guillermina Lozano

Faculty, Staff and Student Publications

Alterations of the tumor suppressor

Two Neuronal Peptides Encoded From A Single Transcript Regulate Mitochondrial Complex Iii In Drosophila, Justin A Bosch, Berrak Ugur, Israel Pichardo-Casas, Jordan Rabasco, Felipe Escobedo, Zhongyuan Zuo, Ben Brown, Susan Celniker, David A Sinclair, Hugo J Bellen, Norbert Perrimon

Duncan NRI Faculty and Staff Publications

Naturally produced peptides (<100 amino acids) are important regulators of physiology, development, and metabolism. Recent studies have predicted that thousands of peptides may be translated from transcripts containing small open-reading frames (smORFs). Here, we describe two peptides in Drosophila encoded by conserved smORFs, Sloth1 and Sloth2. These peptides are translated from the same bicistronic transcript and share sequence similarities, suggesting that they encode paralogs. Yet, Sloth1 and Sloth2 are not functionally redundant, and loss of either peptide causes animal lethality, reduced neuronal function, impaired mitochondrial function, and neurodegeneration. We provide evidence that Sloth1/2 are highly expressed in neurons, imported to mitochondria, and regulate mitochondrial complex III assembly. These results suggest that phenotypic analysis of smORF genes in Drosophila can provide a wealth of information on the biological functions of this poorly characterized class of …

A High-Resolution 3d Atlas Of The Spectrum Of Tuberculous Andcovid-19 Lung Lesions, Gordon Wells, Joel N Glasgow, Kievershen Nargan, Kapongo Lumamba, Rajhmun Madansein, Kameel Maharaj, Leon Y Perumal, Malcolm Matthew, Robert L Hunter, Hayden Pacl, Jacelyn E Peabody Lever, Denise D Stanford, Satinder P Singh, Prachi Bajpai, Upender Manne, Paul V Benson, Steven M Rowe, Stephan Le Roux, Alex Sigal, Muofhe Tshibalanganda, Carlyn Wells, Anton Du Plessis, Mpumelelo Msimang, Threnesan Naidoo, Adrie J C Steyn

Faculty, Staff and Student Publications

Our current understanding of the spectrum of TB and COVID-19 lesions in the human lung is limited by a reliance on low-resolution imaging platforms that cannot provide accurate 3D representations of lesion types within the context of the whole lung. To characterize TB and COVID-19 lesions in 3D, we applied micro/nanocomputed tomography to surgically resected, postmortem, and paraffin-embedded human lung tissue. We define a spectrum of TB pathologies, including cavitary lesions, calcium deposits outside and inside necrotic granulomas and mycetomas, and vascular rearrangement. We identified an unusual spatial arrangement of vasculature within an entire COVID-19 lobe, and 3D segmentation of …

High-Contrast Detection Of Somatostatin Receptor Subtype-2 For Fluorescence-Guided Surgery, Servando Hernandez Vargas, Solmaz Aghaamiri, Sukhen C Ghosh, Michael P Luciano, Luis C Borbon, Po Hien Ear, James R Howe, Jennifer M Bailey-Lundberg, Gregory D Simonek, Daniel M Halperin, Hop S Tran Cao, Naruhiko Ikoma, Martin J Schnermann, Ali Azhdarinia

Faculty, Staff and Student Publications

Dye design can influence the ability of fluorescently labeled imaging agents to generate tumor contrast and has become an area of significant interest in the field of fluorescence-guided surgery (FGS). Here, we show that the charge-balanced near-infrared fluorescent (NIRF) dye FNIR-Tag enhances the imaging properties of a fluorescently labeled somatostatin analogue.

Blockade Of Fgf2/Fgfr2 Partially Overcomes Bone Marrow Mesenchymal Stromal Cells Mediated Progression Of T-Cell Acute Lymphoblastic Leukaemia, Chen Tian, Yueyang Li, Lina Wang, Junqi Si, Yaxin Zheng, Junnan Kang, Yafei Wang, M James You, Guoguang Zheng

Faculty, Staff and Student Publications

The development of acute lymphoblastic leuakemia (ALL) is partly attributed to the effects of bone marrow (BM) microenvironment, especially mesenchymal stromal cells (MSCs), which interact bilaterally with leukaemia cells, leading to ALL progression. In order to find MSCs-based microenvironment targeted therapeutic strategies, Notch1-induced T-cell ALL (T-ALL) mice models were used and dynamic alterations of BM-MSCs with increased cell viability during T-ALL development was observed. In T-ALL mice derived stroma-based condition, leukaemia cells showed significantly elevated growth capacity indicating that MSCs participated in leukaemic niche formation. RNA sequence results revealed that T-ALL derived MSCs secreted fibroblast growth factor 2 (FGF2), which …

Mitochondrial Protective Effects Caused By The Administration Of Mefenamic Acid In Sepsis, Diogo Dominguini, Monique Michels, Leticia B Wessler, Emilio L Streck, Tatiana Barichello, Felipe Dal-Pizzol

Faculty, Staff and Student Publications

The pathophysiology of sepsis may involve the activation of the NOD-type receptor containing the pyrin-3 domain (NLPR-3), mitochondrial and oxidative damages. One of the primary essential oxidation products is 8-oxoguanine (8-oxoG), and its accumulation in mitochondrial DNA (mtDNA) induces cell dysfunction and death, leading to the hypothesis that mtDNA integrity is crucial for maintaining neuronal function during sepsis. In sepsis, the modulation of NLRP-3 activation is critical, and mefenamic acid (MFA) is a potent drug that can reduce inflammasome activity, attenuating the acute cerebral inflammatory process. Thus, this study aimed to evaluate the administration of MFA and its implications for …

Management Of Trigeminal Neuralgia With Botulinum Toxin Type A: Report Of Two Cases, Craig Pearl, Brendan Moxley, Andrew Perry, Nagi Demian, Cyndie Dallaire-Giroux

Faculty, Staff and Student Publications

Trigeminal neuralgia is a chronic pain condition associated with sharp, shock-like pain in one or more divisions of the trigeminal nerve. For patients who do not respond well to pharmacotherapy, there is growing evidence that Botulinum toxin type A injections into the trigeminal ganglion provide pain relief for several weeks up to several months at a time. One option is to administer injections into the trigeminal ganglion in Meckel's cave by inserting a needle through the Pterygopalatine Fossa using fluoroscopy to guide and confirm the proper needle placement. However, there is evidence that Botulinum toxin travels across nerve synapses; thus, …

A Comprehensive Review On Nutraceuticals: Therapy Support And Formulation Challenges, Vivek Puri, Manju Nagpal, Inderbir Singh, Manjinder Singh, Gitika Arora Dhingra, Kampanart Huanbutta, Divya Dheer, Ameya Sharma, Tanikan Sangnim

Faculty, Staff and Student Publications

Nutraceuticals are the nourishing components (hybrid of nutrition and pharmaceuticals) that are biologically active and possess capability for maintaining optimal health and benefits. These products play a significant role in human health care and its endurance, most importantly for the future therapeutic development. Nutraceuticals have received recognition due to their nutritional benefits along with therapeutic effects and safety profile. Nutraceuticals are globally growing in the field of services such as health care promotion, disease reduction, etc. Various drug nutraceutical interactions have also been elaborated with various examples in this review. Several patents on nutraceuticals in agricultural applications and in various …

Hormonal Therapies Up-Regulate Manf And Overcome Female Susceptibility To Immune Checkpoint Inhibitor Myocarditis, Yaohua Zhang, Chengcao Sun, Yajuan Li, Juan Qin, Kaushik Amancherla, Ying Jing, Qingsong Hu, Ke Liang, Zhao Zhang, Youqiong Ye, Lisa A Huang, Tina K Nguyen, Sergey D Egranov, Zilong Zhao, Andrew Wu, Yutao Xi, Jun Yao, Mien-Chie Hung, George A Calin, Jie Cheng, Bora Lim, Lorenz H Lehmann, Joe-Elie Salem, Douglas B Johnson, Michael A Curran, Dihua Yu, Leng Han, Radbod Darabi, Liuqing Yang, Javid J Moslehi, Chunru Lin

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-programmed cell death 1 and anti-cytotoxic T lymphocyte antigen-4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI myocarditis …

Broad-Acting Therapeutic Effects Of Mir-29b-Chitosan On Hypertension And Diabetic Complications, David M Jensen, Peng Han, Lingegowda S Mangala, Gabriel Lopez-Berestein, Anil K Sood, Jing Liu, Alison J Kriegel, Kristie Usa, Michael E Widlansky, Mingyu Liang

Faculty, Staff and Student Publications

MicroRNA miR-29 promotes endothelial function in human arterioles in part by targeting LYPLA1 and increasing nitric oxide production. In addition, miR-29 is a master inhibitor of extracellular matrix gene expression, which may attenuate fibrosis but could also weaken tissue structure. The goal of this study was to test whether miR-29 could be developed as an effective, broad-acting, and safe therapeutic. Substantial accumulation of miR-29b and effective knockdown of Lypla1 in several mouse tissues were achieved using a chitosan-packaged, chemically modified miR-29b mimic (miR-29b-CH-NP) injected systemically at 200 μg/kg body weight. miR-29b-CH-NP, injected once every 3 days, significantly attenuated angiotensin II-induced …

Modified Messengers: Flatworm Stem Cells And Regeneration Are Guarded By Rna Methylation, Blair W Benham-Pyle

Faculty, Staff and Students Publications

The contribution of RNA modifications to whole-body regeneration remains unclear. In this issue, Dagan et al (2022) show that m6a mRNA pathway components are critically required for stem cell differentiation, survival, and tissue renewal in the planarian Schmidtea mediterranea.

Secreted Fas Decoys Enhance The Antitumor Activity Of Engineered And Bystander T Cells In Fas Ligand-Expressing Solid Tumors, Pradip Bajgain, Alejandro G Torres Chavez, Kishore Balasubramanian, Lindsey Fleckenstein, Premal Lulla, Helen E Heslop, Juan Vera, Ann M Leen

Faculty, Staff and Students Publications

T-cell immunotherapy has demonstrated remarkable clinical outcomes in certain hematologic malignancies. However, efficacy in solid tumors has been suboptimal, partially due to the hostile tumor microenvironment composed of immune-inhibitory molecules. One such suppressive agent abundantly expressed in solid tumors is Fas ligand (FasL), which can trigger apoptosis of Fas-expressing effector cells such as T cells and natural killer (NK) cells. To alleviate this FasL-induced suppression of tumor-specific immune cells in solid tumors, we describe here the development of a Fas decoy that is secreted by engineered cells upon activation and sequesters the ligand, preventing it from engaging with Fas on …

Role Of Invasive Hemodynamics In Shock Management: Is A Pulmonary Artery Catheter Always Necessary?, Ajay J. Kirtane

Journal of Shock and Hemodynamics

The pulmonary artery (PA) catheter can be a useful tool in the management of patients with cardiogenic shock; however, there are challenges with the use of this catheter, and clinicians must balance the risks and benefits. In addition, clinicians must properly interpret data generated from a PA catheter in the context of other data to optimize a patient's hemodynamics.

Cholinergic Receptor-Wnt Pathway Controls Immune Activation By Sensing Intestinal Dysfunction, Jie Ren, Yu Sang, Alejandro Aballay

Faculty, Staff and Student Publications

Alterations in the intestinal physiology caused by pathogen colonization result in immune activation. To provide insights into the mechanisms underlying the control of immune activation by changes in intestinal homeostasis, we conducted a forward genetic screen for suppressors of immune activation by intestinal distension in Caenorhabditis elegans. Our results indicate that C. elegans ACC-4, a member of a family of acetylcholine receptors, is required in immune activation by defects in the defecation motor program or by pathogen infection. ACC-4 acts postsynaptically in non-cholinergic RIM neurons to regulate several immune genes and a Wnt-mediated host immune response. These findings uncover a …

Bile Acids Regulate The Epithelial Na+ Channel In Native Tissues Through Direct Binding At Multiple Sites, Xue-Ping Wang, Viktor Tomilin, Andrew J Nickerson, Runze Tian, Merve Ertem, Abagail Mckernan, Xiaoguang Lei, Oleh Pochynyuk, Ossama B Kashlan

Faculty, Staff and Student Publications

Bile acids, originally known to emulsify dietary lipids, are now established signalling molecules that regulate physiological processes. Signalling targets several proteins that include the ion channels involved in regulating intestinal motility and bile viscosity. Studies show that bile acids regulate the epithelial sodium channel (ENaC) in cultured cell models and heterologous expression systems. ENaC plays both local and systemic roles in regulating extracellular fluids. Here we investigated whether bile acids regulate ENaC expressed in native tissues. We found that taurocholic acid and taurohyodeoxycholic acid regulated ENaC in both the distal nephron and distal colon. We also tested the hypothesis that …

Immune Dysfunction Signatures Predict Outcomes And Define Checkpoint Blockade-Unresponsive Microenvironments In Acute Myeloid Leukemia, Sergio Rutella, Jayakumar Vadakekolathu, Francesco Mazziotta, Stephen Reeder, Tung-On Yau, Rupkatha Mukhopadhyay, Benjamin Dickins, Heidi Altmann, Michael Kramer, Hanna A Knaus, Bruce R Blazar, Vedran Radojcic, Joshua F Zeidner, Andrea Arruda, Bofei Wang, Hussein A Abbas, Mark D Minden, Sarah K Tasian, Martin Bornhäuser, Ivana Gojo, Leo Luznik

Faculty, Staff and Student Publications

Background

Immune exhaustion and senescence are dominant dysfunctional states of effector T cells and major hurdles for the success of cancer immunotherapy. In the current study, we characterized how acute myeloid leukemia (AML) promotes the generation of senescent-like CD8⁺ T cells and whether they have prognostic relevance.

METHODS

We analyzed NanoString, bulk RNA-Seq and single-cell RNA-Seq data from independent clinical cohorts comprising 1,896 patients treated with chemotherapy and/or immune checkpoint blockade (ICB).

Results

We show that senescent-like bone marrow CD8⁺ T cells were impaired in killing autologous AML blasts and that their proportion negatively correlated with overall survival …

Development Of A Novel Mouse Model Of Menopause-Associated Asthma, William P Pederson, Laurie M Ellerman, Estevan C Sandoval, Scott Boitano, Jennifer B Frye, Kristian P Doyle, Heddwen L Brooks, Francesca Polverino, Julie G Ledford

Faculty, Staff and Students Publications

No abstract provided.

Assessing Urinary Phenol And Paraben Mixtures In Pregnant Women With And Without Gestational Diabetes Mellitus: A Case-Control Study, Wei-Jen Chen, Candace Robledo, Erin M Davis, Jean R Goodman, Chao Xu, Jooyeon Hwang, Amanda E Janitz, Tabitha Garwe, Antonia M Calafat, Jennifer D Peck

Faculty, Staff and Student Publications

Prior studies have identified the associations between environmental phenol and paraben exposures and increased risk of gestational diabetes mellitus (GDM), but no study addressed these exposures as mixtures. As methods have emerged to better assess exposures to multiple chemicals, our study aimed to apply Bayesian kernel machine regression (BKMR) to evaluate the association between phenol and paraben mixtures and GDM. This study included 64 GDM cases and 237 obstetric patient controls from the University of Oklahoma Medical Center. Mid-pregnancy spot urine samples were collected to quantify concentrations of bisphenol A (BPA), benzophenone-3, triclosan, 2,4-dichlorophenol, 2,5-dichlorophenol, butylparaben, methylparaben, and propylparaben. Multivariable …

Clinical Significance And Potential Role Of Trimethylamine N-Oxide In Neurological And Neuropsychiatric Disorders, Sowjanya Mudimela, Narahari Koppa Vishwanath, Anilkumar Pillai, Rodrigo Morales, Sean P Marrelli, Tatiana Barichello, Vijayasree V Giridharan

Faculty, Staff and Student Publications

Research in the last three decades has attracted the attention of many scientists and industrialists on the gut microbiome and its metabolites. Among many of these metabolites, trimethylamine oxide. Dietary choline, phosphatidylcholine, carnitine, and betaine produces TMAO that with other gut metabolites such as TMA (trimethylamine), and short-chain fatty acids (SCFA) enter the circulation. Finally they reach the brain through the blood-brain barrier (BBB) where they are involved in several physiological functions such as brain development, neurogenesis, and behavior. Gut-microbiota composition is influenced by diet, lifestyle, antibiotics, and age resulting in dysbiosis. Several studies have confirmed that altered TMAO levels …