Digital Commons Network^™

Steroid Receptor Coactivator 3-Deficient Regulatory T Cells Eradicate Multiple Solid Tumors In Syngeneic Mouse Models, Nuri Sung, Eunsu Kim, Yosef Gilad, Yuri Park, Adam M Dean, Yan Xia, Jianming Xu, Clifford C Dacso, David M Lonard, Sang Jun Han

Faculty, Staff and Students Publications

Steroid receptor coactivator 3 (SRC-3) is highly expressed in regulatory T cells (Tregs) and is important for their immunosuppressive activity. Recently, we demonstrated that disrupting SRC-3 expression in Tregs eliminates triple-negative breast cancer (TNBC) and prostate cancer in syngeneic animal models by generating an anti-tumor immune microenvironment without inducing immune-related adverse events (irAEs). Further analysis of these mice revealed that SRC-3 knockout (KO) Tregs infiltrated breast tumors and facilitated the infiltration of CD8

Complementary Vertebrate Wac Models Exhibit Phenotypes Relevant To Desanto-Shinawi Syndrome, Kang-Han Lee, Marwan Shinawi, Et Al.

2020-Current year OA Pubs

Monogenic syndromes are associated with neurodevelopmental changes that result in cognitive impairments and neurobehavioral phenotypes, including autism and seizures. Limited studies and resources are available to make meaningful headway into the underlying molecular mechanisms that result in these symptoms. One such example is DeSanto-Shinawi Syndrome (DESSH), a rare disorder caused by pathogenic variants in the

Assessment Of Timp1, Transgelin-2, And Procalcitonin As Protein Biomarkers For Diagnosis And Prognosis Of Bloodstream Infection In A Critically Ill Cohort, Sajal Tiwary, Caroline A O'Neil, Sydney Lawless, Olivia Arter, Meghan Brown, Brittany Roemmich, Carleigh Samuels, Jennie H Kwon, Christopher W Farnsworth

2020-Current year OA Pubs

BACKGROUND: Bloodstream infections (BSI) are a significant contributor to morbidity and mortality among hospitalized patients. Rapid diagnosis of BSI is critical for timely and appropriate clinical management, but current diagnostic strategies have a prolonged turnaround time or only identify select pathogens with minimal prognostic information.

METHODS: We examined serial serologic samples from 77 intensive care unit (ICU) patients at time points before, during, and after diagnosis of presumptive BSI to identify host-derived protein biomarkers associated with specific organisms and with clinical outcomes in BSI. ICU patients with and without BSI were included. Two candidate biomarkers, tissue metalloproteinase 1 (TIMP-1) and …

Androgens Mediate Sexual Dimorphism In Pilarowski-Bjornsson Syndrome., Kimberley Jade Anderson, Eirny Tholl Thorolfsdottir, Ilana M. Nodelman, Sara Tholl Halldorsdottir, Stefania Benonisdottir, Malak A. Alghamdi, Naif A M Almontashiri, Brenda J. Barry, Matthias Begemann, Jacquelyn F. Britton, Sarah Burke, Benjamin Cogne, Ana S A Cohen, Carles De Diego Boguñá, Evan E. Eichler, Elizabeth C. Engle, Jill A. Fahrner, Laurence Faivre, Mélanie Fradin, Nico Fuhrmann, Christine W. Gao, Gunjan Garg, Dagmar Grečmalová, Mina Grippa, Jacqueline R. Harris, Kendra Hoekzema, Tova Hershkovitz, Sydney Hubbard, Katrien Janssens, Julie A. Jurgens, Stanislav Kmoch, Cordula Knopp, Meral Aktas Koptagel, Farah A. Ladha, Pablo Lapunzina, Tobias Lindau, Marije Meuwissen, Andreina Minicucci, Emily Neuhaus, Mathilde Nizon, Lenka Nosková, Kristen Park, Chirag Patel, Rolph Pfundt, Pankaj Prasun, Nils Rahner, Nathaniel H. Robin, Carey Ronspies, Jasmin Roohi, Jill Rosenfeld, Margarita Saenz, Carol J. Saunders, Zornitza Stark, Isabelle Thiffault, Sarah Thull, Danita Velasco, Clara Velmans, Jolijn Verseput, Antonio Vitobello, Tianyun Wang, Karin Weiss, Ingrid M. Wentzensen, Genay Pilarowski, Thor Eysteinsson, Madelyn Gillentine, Kári Stefánsson, Agnar Helgason, Gregory D. Bowman, Hans Tomas Bjornsson

Manuscripts, Articles, Book Chapters and Other Papers

Sex-specific penetrance in autosomal-dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1^R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety, and hypotonia. Orchiectomy unmasks a growth-deficiency phenotype in male Chd1^R616Q/+ mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants …

Mitochondrial Trna-Derived Fragments As Candidate Metastasis-Modifying Rna, Katy L. Swancutt, R. Mckinnon Walsh, Sydney Quijano, Emily Schueddig, Devin C. Koestler, Adam D. Scheid, Tony Vanden Bush, Yi Jing, Isidore Rigoutsos, Danny R. Welch

Computational Medicine Center Faculty Papers

UNLABELLED: How mitochondrial DNA (mtDNA) polymorphisms influence complex phenotypes remains poorly understood. Using mitochondrial-nuclear exchange mice, we previously showed that mtDNA single-nucleotide polymorphisms (SNP) modify metastasis, cardiovascular disease, and epigenetic marks independently of metabolic differences. The only mtDNA SNP correlating with these phenotypes resides in the gene encoding mitochondrial transfer RNA (tRNA)-arginine [mt-tRNAArg (UCG), mt-TR], suggesting a role for non-protein-coding loci. In this study, we identify and preliminarily characterize previously undescribed tRNA-derived fragments (tRF) generated from mt-TRs. Northern blotting revealed distinct tRF that are differentially expressed among mtDNA SNPs, between lung and liver, and between sexes. Surprisingly, small RNA sequencing …

Altered Postnatal Chromatin Development In The Nucleus Accumbens Primes Enduring Stress Sensitivity, Rebekah L Rashford, Lisa Z Fang, Michael Deberardine, Hye Ji J Kim, Laura W Hirschfield, Ella Cervi, Mason R Barrett, Jeremy M Thompson, Meaghan C Creed, Catherine Jensen Peña

2020-Current year OA Pubs

Early life stress (ELS) sensitizes individuals to subsequent stressors to increase lifetime risk for psychiatric disorders. Within the nucleus accumbens (NAc)-a key limbic and reward-associated brain region-ELS sensitizes both cellular and transcriptional response to later stress, which are programmed by enduring epigenetic changes. Among the histone modifications persistently enriched by ELS in NAc is H3K4me1, which is associated with open chromatin and epigenetic priming of genomic enhancers. Here, we sought to determine whether H3K4me1 enrichment in NAc was sufficient to prime cellular and behavioral responses to adult stress. Viral-mediated overexpression of the histone H3 monomethyltransferase

Redo-Transcatheter Aortic Valve Replacement With Self-Expanding Valves: A U.S. Registry Analysis., Toby Rogers, Vinayak N Bapat, Stanley J Chetcuti, Harold L Dauerman, John K Forrest, Sachin S Goel, Kendra J Grubb, Wah Wah Htun, Rishi Puri, Michael J Reardon, Gilbert H L Tang, Amit N Vora, Steven J Yakubov, Ruth Eisenberg, Guilherme F Attizzani

Heart and Vascular Articles

BACKGROUND: Redo-transcatheter aortic valve replacement (TAVR) for failed transcatheter heart valves is expected to increase, but data on outcomes with self-expanding valves remain limited.

OBJECTIVES: The aims of this study were to evaluate procedural, clinical, and quality-of-life outcomes following redo-TAVR using self-expanding Evolut valves and to compare these outcomes with those among a contemporary native TAVR cohort.

METHODS: Outcomes after redo-TAVR with Evolut R, Evolut PRO, and Evolut PRO+ valves in the Society of Thoracic Surgeons/American College of Cardiology TVT (Transcatheter Valve Therapy) Registry were analyzed and compared with outcomes after native-valve TAVR using the same valve platform during the …

Hemodynamic Characterization Of Cardiac Dysfunction After Traumatic Brain Injury Using A Controlled Cortical Impact Model In Male Rats, Preston So, Amit Iyengar, Noah Weingarten, Mrinal Patel, Jessica Dominic, Andrew Belec, Joyce Ho, Samuel Shin, Pavan Atluri

Division of Cardiology Faculty Papers

Traumatic brain injury (TBI) is associated with cardiovascular dysfunction that worsens clinical outcomes, yet the underlying mechanisms are poorly under stood. Clinical studies are limited by heterogeneity, highlighting the need for con trolled experimental models. Controlled cortical impact (CCI) provides precise control of injury severity, and invasive pressure- volume (PV) loop analysis allows detailed hemodynamic assessment. Adult male Wistar rats underwent sham op eration or mild or severe CCI- induced TBI. PV- loop assessment and transtho racic echocardiography were performed at 8 or 24 h after TBI or sham. Serum epinephrine (EPI) and norepinephrine (NE) were quantified by ELISA. At …

Telomere-To-Telomere Genome Assembly And A Pangenome For The Rat., Kai Li, Julia L Ciosek, Sergey Koren, Adam M Phillippy, Yaming Zhu, William A Lauer, Shelise Y Brooks, Gerard G Bouffard, Brandon D Pickett, Beth L Dumont, Melissa L Smith, Theodore S Kalbfleisch, Peter A Doris

Faculty Research 2026

We report a complete rodent telomere-to-telomere genome assembly from the brown rat, Rattus norvegicus. Annotation was enriched with multi-tissue long-read RNA sequencing and uncovered numerous novel genes. Assembly of both sex chromosomes reveals the absence of gene coding in the presumed pseudo-autosomal regions and the presence of centromeric satellite repeats on distal chromosome Y (chrY). We provide evidence of meiotic conjunction between Xp and Yq. The genome assembly reveals several expanded autosomal regions enriched for testis-expressed genes. Finally, we have generated a pangenome from recent high-quality assemblies of 8 distinct inbred rat strain genomes. This allows the strain-specific distribution of …

Telomere-To-Telomere Genome Assembly And A Pangenome For The Rat, Kai Li, Julia L Ciosek, Sergey Koren, Adam M Phillippy, Yaming Zhu, William A Lauer, Shelise Y Brooks, Gerard G Bouffard, Brandon D Pickett, Beth L Dumont, Melissa L Smith, Theodore S Kalbfleisch, Peter A Doris

The Brown Foundation: Institute of Molecular Medicine

We report a complete rodent telomere-to-telomere genome assembly from the brown rat, Rattus norvegicus. Annotation was enriched with multi-tissue long-read RNA sequencing and uncovered numerous novel genes. Assembly of both sex chromosomes reveals the absence of gene coding in the presumed pseudo-autosomal regions and the presence of centromeric satellite repeats on distal chromosome Y (chrY). We provide evidence of meiotic conjunction between Xp and Yq. The genome assembly reveals several expanded autosomal regions enriched for testis-expressed genes. Finally, we have generated a pangenome from recent high-quality assemblies of 8 distinct inbred rat strain genomes. This allows the strain-specific distribution of …

Non-Enzymatic Hepatic Abhd6 Interacts With Akt-Foxo1 Axis To Regulate Metabolic Health, Guannan Li, Laurence T Maeyens, Jiyuan Yin, Jan-Bernd Funcke, Chanmin Joung, Ruizhen Li, Ziying Xu, Ting Wu, Xin Li, Nisi Jiang, Mbolle Ekane, Maria Paula Lopez, Pengju Cao, Sijia He, Adam B Salmon, S R Murthy Madiraju, Marc Prentki, Juli Bai, James F Nelson, Xianlin Han, Yi Zhu, Shangang Zhao

Children’s Nutrition Research Center Staff Publications

The enzymatic role of ABHD6 in insulin secretion and resistance is well documented. However, its non-enzymatic function, especially its effects on metabolic health, including selective hepatic insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD), is poorly understood. To define the role of ABHD6 in liver physiology, we generated liver-specific ABHD6 knockout mice, as well as liver-specific native and enzymatically inactive mutant ABHD6 overexpression mouse models. We demonstrate that non-enzymatic ABHD6 contributes to the regulation of selective hepatic insulin resistance and MASLD progression. Mechanistically, we show that ABHD6 localizes to the nucleus and interacts with Akt/FoxO1 axis to regulate insulin …

Effects Of Concurrent Neuropathologies With Alzheimer Disease Neuropathologic Change On Cognitive Decline: Minimal Impact Of Vascular Brain Injury Compared With Other Combinations, Sarah M Yasuda, Charles Mock, Kathryn Gauthreaux, Kwun C G Chan, C Dirk Keene, Jessica E Culhane, Yen-Chi Chen, Walter Kukull

2020-Current year OA Pubs

We examined cognitive changes associated with several neuropathologic entities, alone and in combination. We studied 808 participants from the National Alzheimer's Coordinating Center to assess associations between neuropathologic diagnoses (from autopsy) and neuropsychologic test scores (trajectories over time for 5 domains: overall cognition, episodic memory, attention, language, executive function). Neuropathologies included: Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), vascular brain injury (VBI), and limbic-predominant age-related TDP43 encephalopathy neuropathologic change (LATE-NC). Using linear mixed-effects models, we examined trajectories of cognitive decline for ADNC alone compared to ADNC plus LBD, VBI, or LATE-NC. We also examined differences between observed trajectories …

Indications, Techniques, And Safety Of Cryotherapy And Cryobiopsy Via Flexible Bronchoscopy In Pediatric Patients, Alex J Katz, Haley Haskett, Kubra M Bozkanat, Aoife Corcoran, Lauren M C Grant, Antoinette Wannes Daou, Sin Tran, Esra Caylan, Alfin Vicencio, Dan T Benscoter, Cherie A Torres-Silva, Sara M Zak, Gregory Burg, Lisa R Young, Pelton Phinizy, Shailendra Das, Richard Paul Boesch, Erik B Hysinger, Joseph Piccione

Faculty, Staff and Students Publications

Rationale: Cryotherapy and its diagnostic analogue, cryobiopsy, are emerging techniques via bronchoscopy with a wide range of clinical applications. While the use of cryotherapy and cryobiopsy has been established in adult pulmonary medicine, pediatric data describing the indications, procedural specifics, outcomes, and complications are limited.

Objective: To describe the indications, procedural specifics, outcomes, and complications of cryotherapy and cryobiopsy use in pediatric bronchoscopy.

Methods: A multicenter retrospective observational study was conducted at 5 pediatric hospitals in the United States. Patients aged 0 to 21 years who underwent cryotherapy or cryobiopsy via bronchoscopy between January 2017 and January 2025 were included. …

Acute Opioid Responses Are Modulated By Dynamic Interactions Of Oprm1 And Fgf12, Paige M Lemen, Alexander S Hatoum, Arpana Agrawal, Et Al.

2020-Current year OA Pubs

We generated time-series data for 105 morphine- and naloxone-related traits across ~700 BXD mice (64 diverse strains for both sexes) for 3 hr after a single morphine injection. Variations in responses were mapped using genome sequencing-based genotypes. The locomotor responses to morphine mapped to the µ opioid receptor gene (

Myeloid Mmp14 Couples Extracellular Proteolysis To Inflammatory And Metabolic Remodeling During Obesity, Long J Shao, Fathima Elizondo, Feng Gao, Elizabeth L Lieu, Bharati Reddi, Maryam Elizondo, Iqbal Mahmud, Kristin Eckel-Mahan, Philipp E Scherer, Xin Ge, Huaizhu Wu, Sean Hartig, Kai Sun

The Brown Foundation: Institute of Molecular Medicine

Macrophages orchestrate tissue remodeling, inflammation, and metabolic dysfunction in obesity, but the role of macrophage-intrinsic extracellular proteolysis in immunometabolic regulation remains unclear. Matrix metalloproteinase-14 (MMP14), a membrane-bound protease, is strongly induced during monocyte-to-macrophage differentiation and further elevated in adipose tissue macrophages from high-fat diet (HFD)-fed mice. Pharmacological inhibition or myeloid-specific deletion of Mmp14 impaired macrophage differentiation, proliferation, migration, phagocytosis, and inflammatory activation in response to obesity-associated adipose tissue signals. Mechanistically, MMP14 promoted inflammatory programming by increasing endotrophin generation and enhancing TLR4-NFκB signaling. MMP14 also reprogrammed macrophage lipid metabolism by suppressing lipolysis and promoting lipid accumulation, altering metabolic communication with neighboring …

Single-Dose Administration Of Therapeutic Divalent Sirna Targeting Mecp2 Prevents Lethality In An Mecp2 Duplication Mouse Model., Vignesh N Hariharan, Ashley Summers, Amy E Clipperton-Allen, Jillian Caiazzi, Samuel R Hildebrand, Daniel O' Reilly, Qi Tang, Zachary Kennedy, Dimas Echeverria, Nicholas Mchugh, David Cooper, Jacquelyn Sousa, Chantal Ferguson, Hassan H Fakih, Laurent P. Bogdanik, Monica Coenraads, Anastasia Khvorova

Faculty Research 2026

MECP2 duplication syndrome (MDS) is a rare X-linked neurodevelopmental disorder caused by duplications of the dosage-sensitive methyl-CpG-binding protein 2 (MECP2) gene. Developing therapies for MDS is challenging due to the variability in MECP2 expression among patients and the risk of inducing Rett syndrome through excessive pharmacological intervention. Reducing dosage to optimize silencing often compromises durability and necessitates increased dosing frequency. We present here a series of fully chemically modified small interfering RNAs (siRNAs) designed for isoform-selective and total Mecp2 silencing. Among these, we identify six lead siRNA candidates across two chemical scaffolds, achieving targeted total Mecp2 expression reductions ranging from …

Loss Of Atp-Dependent Citrate Lyase Drives Left Ventricular Dysfunction By Metabolic Remodeling, Shijie Liu, Seth T Gammon, Lin Tan, Yaqi Gao, Kyoungmin Kim, Mahmoud H Elbatreek, Adrian Arrieta, Ian K Williamson, Rebecca L Salazar, Janet Pham, Angela Davidian, Radhika Khanna Neicheril, Benjamin D Gould, Heidi Vitrac, Alia Sadiq, An Q Dinh, Evan C Lien, Francisca N De Luna Vitorino, Joanna M Gongora, Sara A Martinez, Melanie T Odenkirk, Anna K Boatman, Jessie R Chappel, Lawrence S C Czer, Evan P Kransdorf, David J Lefer, Blake M Hanson, Benjamin A Garcia, Erin M Baker, Matthew G Vander Heiden, Philip L Lorenzi, Heinrich Taegtmeyer, David Piwnica-Worms, James F Martin, Anja Karlstaedt

Faculty, Staff and Student Publications

Background: Metabolic adaptation and maladaptation are hallmarks of the failing heart and may be a target for therapeutic interventions. For example, sustained glucose oxidation during cardiac stress is associated with increased activity and abundance of ACL (ATP-dependent citrate lyase, Acly), which produces acetyl-coenzyme A (CoA) from citrate and CoA and supports de novo lipid synthesis. However, our understanding of how ACL supports cardiac metabolic adaptation and its potential to modulate disease pathophysiology has not yet been investigated.

Methods: We used human heart tissue samples from healthy donors and patients with nonischemic cardiomyopathy. Next, we used CRISPR (clustered, regularly interspaced …

Molecular Mechanism Leading To Human Coronary Atherosclerosis Assessed By Proteomic Analysis And Rna Sequences, Sarah J Parker, Chunhong Mao, David L Caudell, Austin Lyle Seals, Yizhi Wang, Thomas D Green, Joseph M Mcclung, Joshua T Maxwell, Jacolby T Roddey, Kiarash Shakeriastani, Chiung-Ting Wu, Yingzhou Lu, Do-Kyun Kim, Justyna Fert-Bober, Dongping Du, Archana Bhat, Niveda Sundararaman, Matthew Ayres, Rakhi Pandey, Saurabh Bhardwaj, Genesio M Karere, Dana Troxclair, Fannie Jackson, Gordon L Love, Richard Vander Heide, James Hixson, Jennifer E Van Eyk, Yue Wang, David Herrington

Faculty, Staff and Student Publications

Background and aims: Atherosclerosis results from cellular and extracellular changes in the arterial wall, preceded by molecular shifts that initiate disease and drive tissue conversion, yet these changes are not yet fully described. More data are needed concerning these early changes in the coronary artery molecular landscape that signify the initiation of atherosclerosis and the subsequent tissue pheno-conversion to atherosclerotic plaque. This report summarizes results from a large biorepository of human coronary artery tissue, applying state-of-the-art omics technology, advanced data analytic methods, and an arterial organoid model system to predict molecular dynamics and identify potential regulatory mechanisms that could interrupt …

Neurofilament Light Chain (Nfl) As A Surrogate Outcome Measure For Gm2 Gangliosidoses., Kyriakos Martakis, Nicolas J. Abreu, Joshua J. Baker, Peter R. Baker Ii, Ian Billington, T Andrew Burrow, Mallory Factor, Taylor Fields, Cassandra Fields, Jennifer L. Gannon, Megan Grosso, Jorgji Kerthi, Marc C. Patterson, Brian J. Shayota, Michael Strupp, Lennard Strupp, Tatiana Bremova-Ert

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: The GM2 gangliosidoses (GM2) are ultra-rare neurodegenerative disorders caused by deficient hexosaminidase A and/or B activity, leading to lysosomal GM2 ganglioside accumulation. Disease onset ranges from infancy to adulthood, with earlier onset associated with more rapid progression. Neurofilament light chain (NfL), a sensitive marker of axonal injury, has been extensively investigated as a biomarker for neurodegenerative disorders, including GM2.

METHODS: To evaluate its clinical utility as a biomarker for GM2, NfL was measured in patients with GM2 enrolled in a Phase 2b, multinational, rater-blinded study of levacetylleucine [NCT03759665], and in its open-label Extension Phase (EP).

RESULTS: Nineteen participants had …

Combining Menin And Mek Inhibition To Target Poor Prognosis Kmt2a-Rearranged Ras Pathway-Mutant Acute Myeloid Leukemia., Nastassja Scheidegger, Constanze Schneider, Gabriela Alexe, Yi-Cheng Wang, Todd A. Alonzo, Allen Basanthakumar, Wallace A. Bourgeois, Julia Dudkiewicz-Garbicz, Delan Khalid, Lucy A. Merickel, Jennifer A. Perry, Rhonda E. Ries, Silvi Salhotra, Audrey Taillon, Alan S. Gamis, Richard Aplenc, Marian H. Harris, Mark Wunderlich, Scott A. Armstrong, Jessica A. Pollard, Soheil Meshinchi, Yana Pikman, Kimberly Stegmaier

Manuscripts, Articles, Book Chapters and Other Papers

KMT2A-rearranged (KMT2A-r) acute leukemias are especially prevalent in the pediatric population. KMT2A-fusion proteins drive leukemogenic gene expression through an interaction with a chromatin complex that includes the scaffold protein menin, giving rise to aggressive acute leukemias. RAS pathway mutations are also common in pediatric leukemia. In a cohort of 1750 patients enrolled on Children's Oncology Group (COG) trials, we identified RAS pathway mutations in 43% of acute myeloid leukemia (AML) cases. The presence of RAS pathway mutations in KMT2A-r AML was associated with a lower complete remission rate, poor event-free survival and overall survival (OS), and early relapses. Given the …

Multiple Event Segmentation Mechanisms In The Human Brain, Tan T Nguyen, Joset A Etzel, Matthew A Bezdek, Jeffrey M Zacks

2020-Current year OA Pubs

The human brain segments continuous experience into discrete events, with theoretical accounts proposing two distinct mechanisms: creating boundaries at points of high

Feasibility Evaluation Of Tumor Treating Fields For Brainstem Gliomas, Anthony Chen, Ryan Shah, William Shi, Noa Urman, Nadav Shapira, Nicholas Avgeropoulos, Patrick Conlon, Neil Mookerjee, Wenyin Shi

Department of Radiation Oncology Faculty Papers

PURPOSE: Tumor treating fields (TTFields) are FDA-approved for supratentorial glioblastoma, but feasibility in infratentorial tumors remains poorly defined. This simulation study evaluated TTFields dose in brainstem gliomas using patient-specific modeling with scalp-only transducer arrays.

METHODS: MRI and CT imaging from seven patients with brainstem gliomas were used for TTFields planning with MAXPOINT® (Novocure, Switzerland). Clinical target volume (CTV) was defined as enhancing tumor on T1 post-contrast MRI (Gross tumor volume, GTV) plus a 3 mm peritumoral expansion. The platform optimized scalp-only array layouts, and finite element calculations generated maps of local minimum field intensity (LMiFI, V/cm) and local minimum power …

Subunit Composition Of The Katp Channels That Modulate Contractility Of Skeletal Muscle During Fatigue, Rosa Scala, Yuezhou Chen, Berk Mizrak, Gretchen A Meyer, Colin G Nichols

2020-Current year OA Pubs

ATP-sensitive potassium (KATP) channels are among the most expressed ion channels in skeletal muscle sarcolemma. While all KATP subunits can be detected in skeletal muscles, transcripts are enriched for KCNJ11 and ABCC9, suggesting that noncanonical Kir6.2/SUR2A assembly may constitute the majority of sarcolemmal KATP channels, but there has been no systematic dissection of KATP makeup in skeletal muscles. Here, we used a unique collection of murine lines selectively lacking specific channel-forming subunits (knockout, KO), and combined a genetic and pharmacological approach to determine which subunits of KATP channels are functionally relevant for skeletal muscle contraction. Under fatiguing conditions, isometric tetanic …

Bi-Allelic Loss-Of-Function Variants In Tmem63b Cause Syndromic Surfactant Dysfunction Disorder, Sock Hoai Chan, Audra N Iness, Jill A Rosenfeld, Mir Reza Bekheirnia, Lindsay C Burrage, Matthew Hoi Kin Chau, Chaerish Eint Myet Chae Htoo, Eric C Kao, Shamika Ketkar, Wan Wan Lim, Xi Luo, Rifhan Mazlan, Elizabeth Mizerik, Kein Seong Mun, Kalyani R Patel, Lorraine Potocki, Christina K Rapp, Xavier Roca, Ana Saianda, Ignacio Iglesias-Serrano, Everlyn C Siew, Donald Yuhui Sim, David R Spielberg, Sok-Kun Tae, Jing Xian Teo, Julian Warfsmann, Fan Xia, Child-Eu Registry, Saumya S Jamuar, Ee Shien Tan, Matthias Griese, Weng Khong Lim, Meow-Keong Thong, Keren Machol

Faculty, Staff and Students Publications

Transmembrane protein 63B gene (TMEM63B) encodes a mechanosensitive ion channel expressed in alveolar type II epithelial cells, where it mediates stretch-induced surfactant secretion. While heterozygous gain-of-function variants in TMEM63B have been associated with developmental and epileptic encephalopathy, no human disorder has previously been linked to bi-allelic loss-of-function variants. Here, we report five individuals from four unrelated families with childhood interstitial lung disease and bi-allelic predicted loss-of-function variants in TMEM63B. Affected individuals presented with early-onset respiratory distress, chronic hypoxemia, and diffuse parenchymal lung abnormalities on chest imaging. One individual died in infancy, two underwent bilateral lung transplantation, and two require oxygen …

Association Between Thumb Hypoplasia, Radial Longitudinal Deficiency, And Radial Polydactyly, Emma Payne, Charles A Goldfarb, M Claire Manske, Apurva Shah, Andrea Bauer, Lindley B Wall, Could Study Group

2020-Current year OA Pubs

PURPOSE: The expression of the sonic hedgehog protein has been associated with induction of both radial longitudinal deficiency (RLD) and radial polydactyly in animal studies. We sought to investigate the co-occurrence of thumb hypoplasia/RLD and radial polydactyly in a large registry patient cohort and to investigate the clinical presentations of such patients.

METHODS: The Congenital Upper Limb Differences (CoULD) registry was queried for all patients with contralateral diagnoses of thumb hypoplasia/RLD and radial polydactyly, as defined by the Oberg-Manske-Tonkin classification system, between June 2014 and January 2026. The demographic information, medical and musculoskeletal comorbidities, radiographs, and clinical images were collected. …

Implementation And Evaluation Of The Owll Intervention To Improve The Quality And Safety Of Pediatric Dental Sedation: A Mixed-Methods Approach, Kawtar Zouaidi, Jan Yeager, Sayali Tungare, Suhasini Bangar, Janelle Urata, Alfa-Ibrahim Yansane, Jungsoo Kim, Emily Sedlock, Krishna K Kookal, Yan Xiao, Oluwabunmi Tokede, Heiko Spallek, Amy Franklin, Gregory Olson, Joel White, Elsbeth Kalenderian, Muhammad F Walji

Faculty, Staff and Student Publications

Background: The OWLL (Open-Wide Learning Lab) intervention was developed using Human-Centered Design to improve the quality and safety of pediatric dental sedation. The intervention includes a patient-facing informational sedation brochure and video, and an enhanced set of clinical sedation records. Here, we report on the process evaluation 6 months after implementation in daily clinical practice.

Methods: This study was conducted at the outpatient pediatric dental clinics of 2 large US academic dental institutions. We used a mixed-methods design to assess the fidelity, acceptability, appropriateness, and feasibility of the OWLL intervention. Quantitative data were gathered through chart reviews, while qualitative data …

A Nationwide Central Diagnosis For Pediatric Cns Tumors In Japan: The Jccg Brain Tumor And Pathology Committees, Yoshiko Nakano, Junko Hirato, Takako Yoshioka, Tetsuya Takimoto, Sumihito Nobusawa, Kaishi Satomi, Ran Tomomasa, Seiji Yamada, Taku Homma, Shoh Sasaki, Ayako Yamazaki, Maki Sakaguchi, Yasuhide Takeuchi, Nei Fukazawa, Kai Yamasaki, Kohei Fukuoka, Yui Shinohara Kimura, Yuki Nagayama, Yohei Inoue, Akira Miyahira, Ema Yoshioka, Asako Katsuma, Hayato Fukusumi, Tomoko Shofuda, Yuko Hibiya, Yuko Matsushita, Mai Honda Kitahara, Yuki Yomoda, Miho Kato, Michael D Taylor, Yasuhito Arai, Tatsuhiro Shibata, Hiroaki Sakamoto, Keita Terashima, Yoshiki Arakawa, Toshihiro Kumabe, Ryo Nishikawa, Junichi Hara, Yonehiro Kanemura, Koichi Ichimura

Faculty, Staff and Students Publications

In 2016, the Japan Children's Cancer Group launched a nationwide research initiative to provide central diagnosis incorporating pathology review and molecular profiling for pediatric central nervous system (CNS) tumors. Over the first eight years, 2224 cases were registered. Non-next-generation sequencing analyzes, such as pyrosequencing and NanoString, were routinely performed, mainly for glioma, medulloblastoma, and ependymoma. Additional analyzes, including methylation profiling and RNA sequencing, were conducted for selected diagnostically challenging cases. The most common diagnoses were low-grade glioma (26%), medulloblastoma (18%), germ cell tumor (16%), high-grade glioma (12%), and ependymoma (11%). Diagnostic or targetable alterations were detected in nearly half of …

Adlm Guidance Document On Incorporating Gender Diversity In Pathology And Laboratory Medicine, Tiffany A Thomas, Gabrielle N Winston-Mcpherson, Ina Amarillo, Alisha D Berry, Caroline J Davidge-Pitts, Sridevi Devaraj, Zil Goldstein, Brad S Karon, Brooke M Katzman, Mahmoud A Khalifa, Hung S Luu, James H Nichols, Tracy L Stockley, Michelle R Stoffel, Dina N Greene, Matthew D Krasowski

Faculty, Staff and Students Publications

Background: The first international clinical standards of care for the gender-diverse population were formulated in the late 1970s. In the last 15 years, multiple subspecialty societies within the United States have developed clinical care guidelines for those with gender dysphoria, including gender-affirming hormone therapy (GAHT) and surgical treatments. To date, there are no pathology- and laboratory medicine-specific recommendations in the United States for the gender-diverse population.

Content: This document outlines pathology- and laboratory medicine-specific recommendations for providing optimal care to the gender-diverse population, with a predominant focus on the adult population. The scope of this document focuses on the following …

Helminth-Infected Mozambican Children With Malaria Have Increased Anaemia, Cytokines And Helminth-Specific Antibodies, Inocência Cuamba, Rebeca Santano, Berta Grau-Pujol, Marta Vidal, Anélsio Cossa, Chenjerai Jairoce, Rojelio Mejía, José Muñoz, Ruth Aguilar, Bin Zhan, Augusto Nhabomba, Gemma Moncunill, Carlota Dobaño

Faculty, Staff and Students Publications

Owing to their overlapping geographical distribution and the consequent occurrence of coinfections, several studies have evaluated the impact of helminth infections on malaria immune responses and clinical outcomes. However, little has been reported on how malaria coinfection affects anthelmintic responses in children harbouring worm infections. We therefore aimed to assess the impact of malaria coinfection on helminth-related clinical and immune outcomes in children. Here, we measured in plasma the levels of 30 cytokines, total IgE, and helminth-specific IgM, IgA, IgG, IgG1-4, and IgE antibodies to a panel of 11 helminth antigens by Luminex. Samples were obtained from 441 children aged …

Mapping Dna Methylation Signatures To Identify Epigenetic Variation Across Subcortical Regions Of The Human Posttraumatic Stress Disorder Brain, Hongyu Li, Yujing Liu, Yiming Shi, Jiawei Wang, Tuan P Nguyen, Yuhan Xie, Wangjie Zheng, Youshu Cheng, Dianne A Cruz, Jennifer L Modliszewski, Rosemarie Terwilliger, Alexa-Nicole Sliby, José Jaime Martínez-Magaña, Janitza L Montalvo-Ortiz, John D Roache, Lynnette A Averill, Stacey Young-Mccaughan, Paulo R Shiroma, Bertrand R Huber, David A Lewis, Jill Glausier, Paul Holtzheimer, Matthew J Friedman, Jing Zhang, Alan L Peterson, Chadi G Abdallah, Amir Valizadeh, Xinyu Zhang, Ke Xu, John H Krystal, Ronald S Duman, Hongyu Zhao, David L Corcoran, Douglas E Williamson, Matthew J Girgenti

Staff and Researcher Publications

Background: Posttraumatic stress disorder (PTSD) is a mental disorder that may occur in the aftermath of severe psychological trauma. Epigenetic changes in the brain may play a critical role in understanding the neurobiology of PTSD by linking environmental traumatic stress exposure to lasting alterations in gene expression that shape neuronal function.

Methods: We examined 1,065,750 DNA methylation (DNAm) sites from 171 donors including neurotypical controls and PTSD and major depressive disorder (MDD) cases across 6 regions implicated in the fear circuitry of the brain. We performed RNA sequencing (RNA-seq) to examine changes in gene expression and linked these changes to …