Digital Commons Network^™

Loss Of The Maternal Effect Gene Nlrp2 Impairs Embryonic And Extra-Embryonic Development, Revealing A Novel Genetic Cause Of Congenital Anomalies†, Momal Sharif, Zahra Anvar, Imen Chakchouk, Sara H El-Dessouky, Roni Zemet, Eric C Kao, Wessam E Sharaf-Eldin, Ying-Wooi Wan, Zhandong Liu, Pengfei Liu, Michael Jochum, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

Maternal-effect genes (MEGs) play a crucial role in early mammalian development, and their dysfunction can lead to severe embryonic and extra-embryonic abnormalities. NLRP2, a MEG that encodes a subcortical maternal complex (SCMC) protein, has been implicated in preimplantation development, but its role after implantation remains underexplored. In this study, we investigated the developmental consequences of maternal Nlrp2 loss-of-function in a maternal knockout (KO) mouse model at embryonic day 11.5. Embryos derived from Nlrp2-KO females have abnormal yolk sac vasculature, increased embryonic resorption, craniofacial abnormalities, neural tube defects, and congenital heart defects. Placental architecture is disrupted with an altered junctional zone …

Amino Acid Signaling In Skeletal Muscle Is Blunted By Prematurity In A Piglet Model, Antonio C Ramos Dos Santos, Agus Suryawan, Ki Beom Jang, Rosemarie D Parada, Mahmoud A Mohammad, Marta L Fiorotto, Teresa A Davis

Faculty, Staff and Students Publications

Background: Preterm (PT) infants are at increased risk for reduced postnatal lean mass accretion. We established that the feeding-induced stimulation of protein synthesis in skeletal muscle is blunted in piglets born PT compared with those born at term.

Objectives: We evaluated the extent to which key components of the amino acid-sensing pathways that regulate mechanistic target of rapamycin complex 1 (mTORC1) activation contribute to anabolic resistance in skeletal muscle of piglets born PT compared with those born term.

Methods: Piglets delivered by cesarean section 10 d PT (n = 23) or at term (n = 22) were administered total parenteral …

Exploring The Role Of Astrocyte System Xc– In Excitatory/Inhibitory Balance, Samantha Olivia Sutton

Theses - ALL

Astrocytes play a central role in maintaining excitatory/inhibitory (E/I) balance in the central nervous system by supporting intracellular glutathione (GSH) synthesis and regulating extracellular glutamate. System xc– (Sxc–), an obligate cystine/glutamate antiporter encoded by SLC7a11, couples the import of L-cystine with the export of L-glutamate. It is highly expressed throughout the cortex, hippocampus, striatum, and cerebellum, where its activity provides cystine—the rate-limiting substrate for cysteine-dependent GSH production—and contributes to ambient glutamatergic tone. Although global loss of Sxc– alters seizure threshold and redox homeostasis, whether these effects arise specifically from the loss of astrocytic Sxc– has remained unresolved. This thesis examined …

Eif3d And Eif3e Mediate Selective Translational Control Of Hypoxia That Can Be Inhibited By Small Molecules, Stephen C Purdy, Kate Matlin, Christopher Alderman, Amber Baldwin, Natasha Shrivastava, Goksu Sarioglu, Somnath Dutta, Kristofor J Webb, Arthur Wolin, Dillon P Boulton, Annika Gustafson, Jyoti Kapali, John D Landua, Michael T Lewis, M Cecilia Caino, James C Costello, William Old, Xiang Wang, Rui Zhao, Heide L Ford, Neelanjan Mukherjee

Faculty, Staff and Students Publications

Exposure to hypoxia is linked to increased cellular plasticity and enhanced metastasis, effects that are primarily attributed to the transcriptional activation of large gene programs downstream of hypoxia-inducible factors (HIFs). However, translational effects in hypoxia, which likely precede transcriptional effects, have remained largely unexplored. Using ribosome profiling, we uncovered a selective translational response in acute hypoxia that is eukaryotic initiation factor (eIF)3d/eIF3e dependent and controls downstream hypoxic responses, including HIF1α accumulation and cellular invasion. We further demonstrated that eIF3e copy number and eIF3e and eIF3d expression signatures are associated with worsened outcomes for patients with breast cancer. Finally, we identified …

Liberal Or Restrictive Postoperative Transfusion In Patients At High Cardiac Risk: The Top Randomized Clinical Trial, Panos Kougias, Sherene E Sharath, Min Zhan, Jeffrey L Carson, L Erin Norman, Zhibao Mi, Rupsi Pal, Hasan Dosluoglu, J Gregory Modrall, George A Sarosi, Peter Nelson, Shipra Arya, Alexandra Scrymgeour, Jade Ollison, Lawrence A Calais, Vijay Nambi, L Parker Gregg, Shuaib M Abdullah, Shirling Tsai, Natasha Becker, Justin C Choi, Louisa Chiu, Salvatore Scali, Neal R Barshes, Samir Awad, Mohammed Moursi, Matthew C Koopmann, Mitchell Sally, Daniel Ihnat, Archana Ramaswamy, Warren Gasper, Edith Tzeng, Mark A Wilson, Gale Tang, Grant Huang, Kousick Biswas

Faculty, Staff and Students Publications

Importance: Postoperative red blood cell transfusion guidelines recommend transfusion for hemoglobin levels less than 7 g/dL. However, the safety of this strategy in patients at high risk of cardiac events undergoing major operations remains unclear.

Objective: To evaluate the risk of death or major ischemic events within 90 days after a liberal transfusion strategy compared with a restrictive transfusion strategy in patients at high risk of cardiac events who had undergone major vascular or general surgery operations and developed postoperative anemia.

Design, setting, and participants: This parallel, single-blind, randomized clinical superiority trial included 1428 veterans (≥18 y) at high cardiac …

The Mitochondria Is The Source Of Hepatic Amyloid Precursor Protein And Peripheral Amyloid Beta: Implications Of Alcohol-Induced Liver Steatosis In Alzheimer's Disease, Josephine Chu, Ross A. Steinberg, Brian Carson, Devaraj Venkatapura Chandrashekar, Rachita K. Sumbria, Derick Han

Pharmacy Faculty Articles and Research

Background

Alcohol-induced liver injury occurs in the pericentral region of the liver and can induce mitochondrial remodeling and exacerbate Alzheimer's Disease (AD) progression. Subpopulations of mitochondria: general mitochondria (GM), peridroplet mitochondria (PDM) and endoplasmic reticulum(ER)-bound mitochondria (ERM) maintain cellular homeostasis via energy synthesis, lipid homeostasis, and regulation of intracellular calcium. Hepatic amyloid precursor protein (APP) is a source of peripheral amyloid beta (aB) and affects AD pathology in the brain. Understanding the localization and expression of hepatic APP in mitochondrial subpopulations are critical to understanding aB metabolism and may play a role in identifying a potential mechanism for metabolic dysfunction. …

Sox11 Modulates Bcr Signaling Through The Pax5/Cd19 Axis For Therapeutic Targeting In Btk-Resistant Mantle Cell Lymphoma, Rudra Prasad Dutta, Heng-Huan Lee, Violetta V Leshchenko, Ravi Prakash Shukla, Fangfang Yan, Yang Liu, H Ümit Kaniskan, Xing Qiu, Jian Jin, Lapo Alinari, Michael Wang, Samir Parekh

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is an incurable subtype of B-cell non-Hodgkin lymphoma. Despite multiple approved Bruton tyrosine kinase inhibitors (BTKis), resistance to BTKi continues to pose a major clinical challenge. The transcription factor sex determining region Y-box 11 (SOX11) is expressed in most patients with MCL and is associated with poor outcomes. We have previously demonstrated SOX11-dependent B-cell receptor (BCR) signaling in transgenic models of MCL. Here, we report that SOX11 drives BCR signaling via the transcriptional activation of the PAX5/CD19 axis. The translational potential of these results is significant as single-cell RNA sequencing data show that SOX11 is overexpressed …

Coordinated Changes In Stromal And Hematopoietic Cells That Define The Perinatal To Juvenile Transition In The Mouse Thymus, Anusha Vasudev, Colin R Moore, Aparna Calindi, Seung Woo Kang, Bryan R Helm, Jayashree Srinivasan, Siddhartha Shah, Erin Baker, Ruiting Zong, Nandini Singarapu, Scott Casey, Andrew N Macintyre, Ken S Lau, Laura P Hale, Qi Liu, Nancy R Manley, Lauren I R Ehrlich, Ellen R Richie

Faculty, Staff and Student Publications

Perinatal T cells have distinctive phenotypes and functions that may be due in part to age-associated features of stromal cells in the perinatal thymus. We identify age-associated changes in mouse thymic epithelial cells, mesenchyme, endothelium, and hematopoietic antigen-presenting cells from birth to one month of age using single-cell transcriptional profiling, flow cytometry, and imaging. Coordinated cellular and molecular changes occur at 7-14 days of age, designated "transitional ages," as thymus growth switches to homeostasis. E2F target gene expression declines, and the expression of type I interferon response genes increases across diverse cell types at transitional ages. Alterations in thymic stromal …

Discovery Of Small Molecules And A Druggable Groove That Regulate Dna Binding And Release Of The Ap-1 Transcription Factor Δfosb, Sean Mcneme, Yun Young Yim, Ashwani Kumar, Yi Li, Brandon Hughes, Corey Peyton St Romain, Galina Aglyamova, Jianping Chen, Nghi D Nguyen, Shanghua Fan, Gabriel S Stephens, Wen-Ning Zhao, Samantha Kruzshak, Molly Estill, Corrine Brener, Solange Tofani, Anil Kumar, Earnest P Chen, Nadeen Takatka, Alfred J Robison, Haiying Chen, Reid T Powell, Stephen J Haggarty, Clifford Stephan, Eric J Nestler, Jeannie Chin, Mischa Machius, Jia Zhou, Gabby Rudenko

Faculty, Staff and Students Publications

ΔFOSB, a member of the AP-1 family of transcription factors, mediates long-term neuroadaptations underlying drug addiction, seizure-related cognitive decline, dyskinesias, and several other chronic conditions. AP-1 transcription factors are notoriously difficult to modulate pharmacologically due to the absence of well-defined binding pockets. Here, we identify a novel site on ΔFOSB, located outside the DNA-binding cleft, that accommodates small molecules. We show that sulfonic acid-containing compounds bind to this site via an induced-fit mechanism, reorienting side chains critical for DNA binding, and that they may hinder the ΔFOSB bZIP α-helix from binding to the major groove of DNA. In vivo, direct …

Epcam Activates The Erk-Egr1 Signaling Axis And Promotes Tnf-Α-Induced The Progression Of Anaplastic Thyroid Cancer, Chi-Chiu Lee, Yi-Jen Su, Sushree Shankar Panda, Chiung-Yi Chiu, Chung-Hsuan Wu, Tsai-Ming Lu, Pi-Chun Li, Yen-Lin Huang, Ruey-Long Hong, Shao-Hsi Hung, Cassian Yee, Stephen Y Lai, Han-Chung Wu

Faculty, Staff and Student Publications

Background: Epithelial cell adhesion molecule (EpCAM) is a pleotropic transmembrane glycoprotein comprising an extracellular domain (EpEX), a single transmembrane domain, and an intracellular domain (EpICD). For several types of cancer, high EpCAM expression is associated with tumor progression, metastasis, immune evasion, and overall poor prognosis. A rare but aggressive form of thyroid cancer, anaplastic thyroid cancer (ATC), has a mean survival time of only 3–6 months after diagnosis.

Methods: The levels of EpEX and EpICD cleavage in clinical patient samples was evaluated by using tissue microarray. Capture enzyme-linked immunosorbent assay (ELISA) was conducted to explore the of shedding EpEX and …

Development Of A Procedure For Prion Surveillance In The Laboratory Setting, Damian Gorski, Isaac Schauer, Kane Spicker, Ananya Tupaki-Sreepurna, Fei Wang, Claudio Soto, Sandra Pritzkow

Faculty, Staff and Student Publications

Infectious prions readily adhere to common surfaces, retain infectivity, and are highly resistant to conventional decontamination, posing significant biosafety challenges in the medical and research environments. Recent occupational exposures underscore the urgency of improving safety measures. Here, we describe an approach combining foam-swab surface sampling and protein misfolding cyclic amplification to enhance prion surveillance. Our results demonstrate the ability to detect prions most relevant to human health directly from contaminated surfaces, even at 100 million-fold dilutions of the brain. We applied our method to assess the completeness of prion decontamination and show that high prion quantities can resist even approved …

Metabolomic Profiling Reveals Brain Lipid Alterations In Pex7-Deficient Models Of Rhizomelic Chondrodysplasia Punctata, Riya Sankhe, Meredith I Williams, Wedad Fallatah, Laura Mackay, Mary Layne Brown, Pranjali Bhagwat, Sarah H Elsea, Nancy Braverman, Michael F Wangler

Duncan NRI Faculty and Staff Publications

Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisomal disorder characterized by skeletal shortening, intellectual disability, seizures, cataracts, and reduced lifespans. RCDP1 is caused by biallelic loss-of-function variants in PEX7, which encodes a protein required for importing select enzymes into the peroxisome matrix, including those essential for ether lipid synthesis (e.g., plasmalogens) and the branched-chain fatty acid catabolism. Plasmalogen deficiency is a hallmark of RCDP1 and other peroxisomal disorders, including RCDP types 2-5 (RCDP2-5) and Zellweger spectrum disorders (ZSD). Here, we performed comprehensive metabolomic profiling of clinical samples from RCDP patients and Pex7-deficient mouse models. We identified profound …

Adaptive Neuromodulation Dialogues: Navigating Current Challenges And Emerging Innovations In Neuromodulation System Development, Frederik Lampert, Matthew R Baker, Michael A Jensen, Amir H Ayyoubi, Christian Bentler, Jessica L Bowersock, Rosana Esteller, Jeffrey A Herron, Graham W Johnson, Daryl R Kipke, Christopher K Kovach, Vaclav Kremen, Filip Mivalt, Joseph S Neimat, Theoden I Netoff, Enrico Opri, Alexander Rockhill, Joshua M Rosenow, Kristin K Sellers, Nathan P Staff, Chandra Prakash Swamy, Ashwin Viswanathan, Gerwin Schalk, Timothy Denison, Dora Hermes, Nuri F Ince, Peter Brunner, Gregory A Worrell, Kai J Miller

Faculty, Staff and Students Publications

Adaptive neuromodulation systems and implantable brain-computer interfaces have made notable strides in recent years, translating experimental prototypes into clinical applications and garnering substantial attention from the public. This surge in interest is accompanied by increased scrutiny related to the safety, efficacy, and ethical implications of these systems, all of which must be directly addressed as we introduce new neurotechnologies. In response, we have synthesized the insights resulting from discussions between groups of experts in the field and summarized them into five key domains essential to therapeutic device development: (1) analyzing current landscape of neuromodulation devices and translational platforms (2) identifying …

3d Modeling Of Brain Removal With Cranial Nerve Preservation, Lauren Blank, Sophia Cox, Avery Preston

Student Scholar Symposium

3D Modeling of Brain Removal with Cranial Nerve Preservation Abstract: Visual- spatial skills are essential in learning anatomy as they allow students to mentally visualize and manipulate the three-dimensional structure of the human body. Traditional dissectors like Grant’s Dissector typically provide only 2D images to guide brain removal. These manuals often do not include the occipital wedge approach, which favors cranial nerve preservation during brain dissection. A 3D model that assists students in learning a non-traditional dissection approach through manipulating a brain model will help improve mental rotation skills, especially benefiting those with weaker spatial abilities. In collaboration with Lipscomb …

Endocrine Disruptors, Obesity, And Metabolic Syndrome, Tuğba Barlas, Alev Eroğlu Altinova, Meriç Coşkun, Ethem Turgay Ceri̇t

Turkish Journal of Medical Sciences

The global prevalence of obesity and metabolic syndrome (MetS) is rising worldwide, and increasing evidence suggests that chemical exposures—particularly endocrine disruptors (EDs)—represent a significant contributing factor. EDs can act as obesogens, increasing the risk of weight gain and related metabolic conditions, including type 2 diabetes, dyslipidemia, hypertension, and cardiovascular disease. They may also alter the basal metabolic rate, gut microbiota composition, and hormonal regulation of appetite and satiety. EDs are reported to exert their effects mainly through the peroxisome proliferator-activated receptor gamma pathway, which is primarily expressed in adipose tissue and is a key regulator of adipogenesis. Common consumer products …

Endocrine Disruptors And Children's Health, Ersen Karakiliç, Durmuş Doğan, Emre Sedar Saygili

Turkish Journal of Medical Sciences

Endocrine-disrupting chemicals (EDCs) are environmental contaminants that disrupt hormonal regulation by mimicking, inhibiting, or modifying endocrine signaling pathways. EDCs are commonly present in plastics, pesticides, industrial byproducts, and personal care products and pose substantial health risks, particularly to vulnerable groups such as infants and children. Early-life exposure is especially concerning due to the developing detoxification systems, the immaturity of the blood–brain barrier, and the ongoing organ differentiation, making these periods highly susceptible to EDCs’ harmful effects. Moreover, exposure during critical developmental periods, such as sex differentiation and neurodevelopment, can lead to significant long-term developmental impairments that persist into later life.Perinatal …

Endocrine Disrupting Chemicals And Adrenal Gland​, Gülay Şi̇mşek Bağir, Melek Eda Ertörer

Turkish Journal of Medical Sciences

Endocrine disrupting chemicals (EDCs) are exogenous compounds that have hormone-like effects inside the body. Endocrine disruptors can affect adrenal glands in humans and animals. Adrenocortical dysfunction related to chemical exposure has been reported in the literature.The human adrenal gland is crucial for the synthesis of steroid hormones (glucocorticoids, mineralocorticoids, and androgens) and amino acid-derived hormones (epinephrine and norepinephrine). All steps in the adrenocortical steroidogenesis pathway are potential targets for chemical inhibition, including the adrenocorticotropic hormone receptor, steroidogenic acute regulatory protein, mitochondrial cytochrome P450 (CYP) enzymes (CYP11A1, CYP17, CYP21, CYP11B1, and CYP11B2), and 3-hydroxysteroid dehydrogenase D4,5 isomerase. EDCs either inhibit the …

Endocrine-Disrupting Chemicals In Metabolic Bone Diseases, Including Osteoporosis, Betül Gündüz, Eli̇f Kiliç Kan, Ayşegül Atmaca

Turkish Journal of Medical Sciences

Endocrine disruptors are chemical substances widely utilized across various industrial sectors. Due to their structural similarity to natural ligands, they bind to receptors and influence the endocrine system via agonist–antagonist mechanisms. Exposure occurs through the consumption of contaminated food and water, inhalation of polluted air and dust, and dermal contact. Owing to their dynamic remodeling capacity, bones represent potential targets for endocrine-disrupting chemicals. These chemicals can disrupt bone formation, skeletal development, hormonal regulation, and calcium metabolism. Sensitivity to endocrine-disrupting chemicals is greatest during the prenatal and early postnatal periods. This review summarizes the effects of endocrine-disrupting chemicals on bone tissue.

The Influence Of Endocrine Disrupters On Gut Microbiota, Kader Ugur

Turkish Journal of Medical Sciences

Endocrine disruptors (EDs) are closely associated with the second brain, the microbiota-derived enteric nervous system, commonly referred to as the gut microbiota. The microbiota plays a crucial role in human health and the development of diseases. In today’s industrialized world, the presence of EDs in air, water, and soil leads to primary human exposure through dermal contact and ingestion. The impact of these EDs on the microbiota remains unclear. EDs that disrupt the balance of the gut microbiota may contribute to a range of disorders, including metabolic (obesity, diabetes mellitus), cardiovascular (vascular stenosis, cerebrovascular disease), reproductive (infertility, ovarian and testicular …

Endocrine-Disrupting Chemicals And Thyroid Cancer, Özge Baş Aksu, Mustafa Şahi̇n

Turkish Journal of Medical Sciences

Environmental endocrine-disrupting chemicals (EDCs) have emerged as a critical global health concern because of their role in various diseases, including thyroid cancer. Defined as exogenous substances that disrupt endocrine system functions, EDCs can affect multiple generations through mechanisms such as hormone receptor modulation, altered hormone synthesis, and epigenetic modifications.The increasing global incidence of thyroid cancer has heightened interest in environmental factors, with EDC exposure recognized as a significant contributor. Compounds such as heavy metals, persistent organic pollutants, per- and polyfluoroalkyl substances, and bisphenol A play crucial roles in disrupting thyroid homeostasis. Emerging evidence underscores the synergistic effects of multiple EDC …

Effects Of Endocrine Disruptors On The Neurological System, Kadi̇rcan Karatoprak, Soner Cander

Turkish Journal of Medical Sciences

Background/aim: There is increasing interest in endocrine disrupting chemicals because of the potential effects on neurological health. These chemicals are widely found in various consumer products and industrial processes, and can lead to serious disorders of the endocrine system by disrupting hormone synthesis, expression, and function. The aim of this review was to examine epidemiological and experimental findings by investigating the link between exposure to endocrine disrupting chemicals and adverse neurological outcomes.

Materials and methods: In the preparation of this review, a PubMed literature search was conducted using the words “endocrine disruptors,” “neuroendocrine effects,” “neurobehavioral effects,” and “neurodevelopmental effects” and …

Endocrine Disruptors And Pregnancy, Betül Yi̇ği̇t Yalçin, Gamze Bi̇li̇k Oyman, Ayşe Kubat Üzüm

Turkish Journal of Medical Sciences

Sensitivity to endocrine disruptors is higher in early life. In pregnant women, endocrine disruptor chemicals can be passed to the baby through the placenta or through breast milk during lactation, leading to long-term and permanent adverse effects. These endocrine disruptors may cause adverse effects in women such as infertility, implantation defects, premature birth, spontaneous abortions, gestational hypertension, gestational diabetes. Exposure to endocrine disruptors in the intrauterine period may result in adverse effects on the reproductive system, metabolic changes, low birth weight, retardation in mental and physical development and also may be associated with congenital malformations. It is of great importance …

Endocrine Disruptors, Insulin Resistance, And Diabetes, Meri̇ç Coşkun, Ethem Turgay Ceri̇t, Tuğba Barlas, Alev Eroğlu Altinova

Turkish Journal of Medical Sciences

Endocrine-disrupting chemicals (EDCs) are compounds that interfere with hormone synthesis, secretion, metabolism, or excretion. Evidence indicates that increased exposure to EDCs is associated with insulin resistance and, most notably, type 2 diabetes worldwide. This suggests a diabetogenic effect that is independent of obesity, underscoring the complex mechanisms and broad impact of EDCs on metabolic health. Key pathways include hormone mimicry and antagonism, altered hormone metabolism, inflammatory responses, and mitochondrial dysfunction. This review summarises the mechanisms through which EDCs contribute to these conditions and evaluates the epidemiological and experimental evidence supporting these associations.

The Effects Of Endocrine Disruptors On The Female Reproductive System, Riza Gökhan Baykal, Reyhan Ersoy

Turkish Journal of Medical Sciences

Endocrine-disrupting chemicals (EDCs) are a diverse, comprehensive group of mostly synthetic chemicals that disrupt many physiological functions in humans and animals. EDCs are particularly disruptive to the female reproductive system. Reproductive function in women is a dynamic process regulated by the hypothalamic–pituitary–ovarian axis. EDCs show their effects on the reproductive system through estrogenic, antiestrogenic, androgenic, and antiandrogenic effects or by directly affecting gonadotropin-releasing hormone secretion. Disruption in the menstrual cycle, decrease in fertility, infertility, increased risk of miscarriage, polycystic ovary syndrome, endometriosis, early or delayed puberty, and hormone-sensitive cancers can be listed as the main negative effects of endocrine disruptors …

Effects Of Endocrine Disruptors On Thyroid Hormone Synthesis And Function And Consequences Of Fetal Exposure, Esra Eraslan Aydemi̇r, Mustafa Şahi̇n

Turkish Journal of Medical Sciences

Fetal development relies on intricate maternal-fetal-placental interactions, with thyroid hormones playing a critical role in growth and neurogenesis. Exposure to endocrine-disrupting chemicals (EDCs) during pregnancy has emerged as a significant risk factor for thyroid dysfunction and its associated developmental and cognitive disorders. EDCs, including bisphenol A (BPA), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), perfluorinated compounds (PFAS), pesticides, and heavy metals, disrupt thyroid hormone synthesis, secretion, and metabolism. Mechanisms include binding to thyroid hormone receptors, impairing the hypothalamic-pituitary-thyroid axis, and altering thyroid peroxidase activity. BPA exposure, for instance, reduces free and total T4 levels and interferes with deiodinase activity. Similarly, …

Mbnl Loss Of Function In Smooth Muscle As A Model For Myotonic Dystrophy Associated Gastrointestinal Dysmotility, Janel A M Peterson, Jesus A Frias, Andrew N Miller, Krishnakant G Soni, Yi Zhang, Zheng Xia, John W Day, Geoffrey A Preidis, Thomas A Cooper

Faculty, Staff and Students Publications

Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy and severely affects multiple organ systems, including the brain, heart, skeletal muscle, and gastrointestinal (GI) tract. Despite 80% of individuals with DM1 experiencing GI dysfunction that affects their daily life, the mechanisms of GI dysmotility in DM1 remain an understudied aspect of the disease. DM1 is caused by a CTG repeat expansion in the DMPK gene that, when expressed as an expanded CUG repeat RNA, sequesters and reduces the activity of the muscleblind-like (MBNL) RNA-binding protein family. We developed a mouse line with conditional, smooth muscle-specific knockout of …

Vesicle-Mediated Mitochondrial Clearance Presents An Actionable Metabolic Vulnerability In Triple-Negative Breast Cancer, Jody Vykoukal, Yihui Chen, Mingxin Zuo, Riccardo Ballarò, Monica J Hong, Hansini Krishna, Daniela B Rodriquez-Perera, Hiroyuki Katayama, Ehsan Irajizad, Ranran Wu, Ricardo A León-Letelier, Jennifer B Dennison, Angelica M Gutierrez, Adriana Paulucci-Holthauzen, Timothy C Thompson, Leona Rusling, Yining Cai, Fu Chung Hsiao, Soyoung Park, Banu Arun, Samir Hanash, Johannes F Fahrmann

Faculty, Staff and Student Publications

Selective autophagy of mitochondria is known to promote cancer cell survival and progression, including in triple-negative breast cancer (TNBC). Here, we apply an integrated multi-omics approach together with functional experimental analyses to investigate metabolic adaptations that support mitochondrial quality control in TNBC. We detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by a program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle-mediated intracellular clearance of mitochondrial damage. Targeting of this onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase, results in ceramide-mediated compensatory mitophagy and cancer cell death …

Lung Adenocarcinoma Surfaceome Remodeling With Egfr Inhibitors Uncovers Placental Alkaline Phosphatase As A Target For Combination Therapy, Yihui Chen, Rongzhang Dou, Monica J Hong, Hanwen Xu, Jody Vykoukal, Ricardo A León-Letelier, Yining Cai, Soyoung Park, Ehsan Irajizad, Fu Chung Hsiao, Jennifer B Dennison, Edwin J Ostrin, Johannes F Fahrmann, Hiroyuki Katayama, Samir M Hanash

Faculty, Staff and Student Publications

Treatment of lung adenocarcinomas (LUADs) that exhibit activated epidermal growth factor receptor (EGFR) with EGFR tyrosine kinase inhibitors (TKIs) has limited efficacy. Assessment of the impact of EGFR TKI on the LUAD surfaceome remodeling reveals potential therapeutic targets. We identify placental type alkaline phosphatase (ALPP), which has restricted expression in normal tissues, among upregulated surface proteins following EGFR TKI treatment of both TKI sensitive as well as resistant cells. EGF treatment represses ALPP expression, whereas EGFR TKIs upregulate its expression through dephosphorylation and activation of FoxO3a, a transcriptional regulator that binds to the promoter region of ALPP. The combination of …

Facts And Hopes Of Chimeric Antigen Receptor-Redirected Nk T Cells, Amy N Courtney, Xin Zhou, Gengwen Tian, Ying Wang, Leonid S Metelitsa, Gianpietro Dotti

Faculty, Staff and Students Publications

Chimeric antigen receptor (CAR)-engineered invariant NK T cells (CAR-NKT) are a novel cell platform for cancer immunotherapy. Unlike conventional T cells, NKTs are characterized by innate antitumor properties, minimal alloreactivity, and a unique ability to modulate the tumor microenvironment. This article provides a comprehensive overview of preclinical and early clinical studies evaluating CAR-NKTs in both autologous and allogeneic clinical settings. We discuss the contributions of CAR signaling domains, cytokine coexpression, and other functional measures that correlate with CAR-NKT persistence, function, and metabolic fitness. We also discuss the critical role of immunocompetent animal models in elucidating the interactions of CAR-NKTs with …

Mitochondrial Complex Ii Orchestrates Divergent Effects In Cd4+ And Cd8+ T Cells, Keisuke Seike, Shih-Chun A Chu, Yuichi Sumii, Takashi Ikeda, Meng-Chih Wu, Laure Maneix, Dongchang Zhao, Yaping Sun, Marcin Cieslik, Pavan Reddy

Faculty, Staff and Students Publications

Mitochondrial metabolism orchestrates T cell functions, yet the role of specific mitochondrial components in distinct T cell subsets remains poorly understood. Here, we explored the role of mitochondrial complex II (MC II), the only complex from the electron transport chain (ETC) that plays a role in both ETC and metabolism, in regulating T cell functions. Surprisingly, MC II exerts divergent effects on CD4+ and CD8+ T cell activation and function. Using T cell-specific MC II subunit, succinate dehydrogenase A-deficient (SDHA-deficient) mice, we integrated single-cell RNA-seq and metabolic profiling, with in vitro and in vivo T cell functional assays to illuminate …