Digital Commons Network^™

Neurodevelopmental Deficits And Cell-Type-Specific Transcriptomic Perturbations In A Mouse Model Of Hnrnpu Haploinsufficiency, Sarah A Dugger, Ryan S Dhindsa, Gabriela De Almeida Sampaio, Andrew K Ressler, Elizabeth E Rafikian, Sabrina Petri, Verity A Letts, Jiajie Teoh, Junqiang Ye, Sophie Colombo, Yueqing Peng, Mu Yang, Michael J Boland, Wayne N Frankel, David B Goldstein

Faculty, Staff and Students Publications

Heterozygous de novo loss-of-function mutations in the gene expression regulator HNRNPU cause an early-onset developmental and epileptic encephalopathy. To gain insight into pathological mechanisms and lay the potential groundwork for developing targeted therapies, we characterized the neurophysiologic and cell-type-specific transcriptomic consequences of a mouse model of HNRNPU haploinsufficiency. Heterozygous mutants demonstrated global developmental delay, impaired ultrasonic vocalizations, cognitive dysfunction and increased seizure susceptibility, thus modeling aspects of the human disease. Single-cell RNA-sequencing of hippocampal and neocortical cells revealed widespread, yet modest, dysregulation of gene expression across mutant neuronal subtypes. We observed an increased burden of differentially-expressed genes in mutant excitatory …

Purification And Characterization Of Mitochondrial Mg2+-Independent Sphingomyelinase From Rat Brain, Jong Min Choi, Yongwei Piao, Kyong Hoon Ahn, Seok Kyun Kim, Jong Hoon Won, Jae Hong Lee, Ji Min Jang, In Chul Shin, Zhicheng Fu, Sung Yun Jung, Eui Man Jeong, Dae Kyong Kim

Faculty, Staff and Students Publications

Sphingomyelinase (SMase) catalyzes ceramide production from sphingomyelin. Ceramides are critical in cellular responses such as apoptosis. They enhance mitochondrial outer membrane permeabilization (MOMP) through self-assembly in the mitochondrial outer membrane to form channels that release cytochrome c from intermembrane space (IMS) into the cytosol, triggering caspase-9 activation. However, the SMase involved in MOMP is yet to be identified. Here, we identified a mitochondrial Mg

Existing Evidence For Influenza B Virus Adaptations To Drive Replication In Humans As The Primary Host, Matthew J. Pekarek, Eric A. Weaver

Nebraska Center for Virology: Faculty Publications

Influenza B virus (IBV) is one of the two major types of influenza viruses that circulate each year. Unlike influenza A viruses, IBV does not harbor pandemic potential due to its lack of historical circulation in non-human hosts. Many studies and reviews have highlighted important factors for host determination of influenza A viruses. However, much less is known about the factors driving IBV replication in humans. We hypothesize that similar factors influence the host restriction of IBV. Here, we compile and review the current understanding of host factors crucial for the various stages of the IBV viral replication cycle. While …

A Ck2 And Sumo-Dependent, Pml Nb-Involved Regulatory Mechanism Controlling Blm Ubiquitination And G-Quadruplex Resolution, Shichang Liu, Erin Atkinson, Adriana Paulucci-Holthauzen, Bin Wang

Faculty, Staff and Student Publications

The Boom syndrome helicase (BLM) unwinds a variety of DNA structures such as Guanine (G)-quadruplex. Here we reveal a role of RNF111/Arkadia and its paralog ARKL1, as well as Promyelocytic Leukemia Nuclear Bodies (PML NBs), in the regulation of ubiquitination and control of BLM protein levels. RNF111 exhibits a non-canonical SUMO targeted E3 ligase (STUBL) activity targeting BLM ubiquitination in PML NBs. ARKL1 promotes RNF111 localization to PML NBs through SUMO-interacting motif (SIM) interaction with SUMOylated RNF111, which is regulated by casein kinase 2 (CK2) phosphorylation of ARKL1 at a serine residue near the ARKL1 SIM domain. Upregulated BLM in …

Updates On The Immune Cell Basis Of Hepatic Ischemia-Reperfusion Injury, Mi Jeong Heo, Ji Ho Suh, Kyle L Poulsen, Cynthia Ju, Kang Ho Kim

Faculty, Staff and Student Publications

Liver ischemia-reperfusion injury (IRI) is the main cause of organ dysfunction and failure after liver surgeries including organ transplantation. The mechanism of liver IRI is complex and numerous signals are involved but cellular metabolic disturbances, oxidative stress, and inflammation are considered the major contributors to liver IRI. In addition, the activation of inflammatory signals exacerbates liver IRI by recruiting macrophages, dendritic cells, and neutrophils, and activating NK cells, NKT cells, and cytotoxic T cells. Technological advances enable us to understand the role of specific immune cells during liver IRI. Accordingly, therapeutic strategies to prevent or treat liver IRI have been …

The Role Of Zinc In Psd-95 Palmitoyl Modification, Luis F. Acosta, Lili Guerra, Safiya Syed, Ivonn Ruvalcaba, Yonghong Zhang, Xiaoqian Fang

Research Symposium

Postsynaptic density-95 (PSD-95) is a membrane-associated guanylate kinase that mediates localization of receptors in the excitatory postsynaptic density. It has been reported that PSD-95 mediates postsynaptic localization of NMDA receptors and anchors postsynaptic AMPAR receptors mainly through its postsynaptic membrane targeting by its N-terminal palmitoylation. Recent studies have shown that Ca2+/calmodulin blocks palmitoylation of PSD-95 by binding at the N-terminus of PSD-95, which promotes dissociation of PSD-95 from the postsynaptic membrane and causes loss of surface AMPARs in cultured neurons. Another metal ion zinc is found in various areas of the brain. As an endogenous neuromodulator, zinc plays a role …

Stem Cell Technology For Age Related Macular Degeneration Intervention, Laura Valdez

Research Symposium

Retinal pigmented epithelium (RPE) cells are located between the choroid and photoreceptors within the eye and are essential to provide nutrients from blood to rods and cones, as well retinoids of the visual cycle. Vision loss and various ocular diseases are attributable to the degeneration or dysfunction of the RPE cells, leading to blindness.One of the major ocular problem from RPE dysfunction is macular degeneration. Age-related macular degeneration (AMD) can be frequently diagnosed in patients over the age of 60. In the early stages of AMD, some symptoms may not be noticeable but will lead to vision loss in both …

Long Non-Coding Rna (Lncrna) As A New Biomarker For Hepatocellular Carcinoma (Hcc) Drug Resistance, Areeb Masood, Kyle Doxtater, Anupam Dhasmana, Subhash C. Chuahan, Sanjaya Satapathy, Manish Tripathi

Research Symposium

Background: Hepatocellular carcinoma (HCC) is the 4^th leading cause of cancer-related deaths worldwide and the 6^th most common cancer worldwide. When HCC progresses to advanced stages, drug resistance becomes a major hurdle and leaves clinicians with limited therapeutic options. Long non-coding RNAs (lncRNAs) have shown to promote drug resistance in various cancers. The goal of our research is to explain the molecular role of lncRNAs in HCC drug resistance and compile a comprehensive list of studied lncRNAs involved in HCC drug resistance.

Methods: To compile a list of lncRNA involved in HCC drug resistance we performed an advanced …

Vadadustat For Treatment Of Anemia In Patients With Dialysis-Dependent Chronic Kidney Disease Receiving Peritoneal Dialysis, Mark J Sarnak, Rajiv Agarwal, Neil Boudville, Pradip C P Chowdhury, Kai-Uwe Eckardt, Carlos R Gonzalez, Laura A Kooienga, Mark J Koury, Kwabena A Ntoso, Wenli Luo, Patrick S Parfrey, Dennis L Vargo, Wolfgang C Winkelmayer, Zhiqun Zhang, Glenn M Chertow

Faculty, Staff and Students Publications

BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear.

METHODS: We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular …

Heterogenous Lung Inflammation Ct Patterns Distinguish Pneumonia And Immune Checkpoint Inhibitor Pneumonitis And Complement Blood Biomarkers In Acute Myeloid Leukemia: Proof Of Concept, Muhammad Aminu, Naval Daver, Myrna C B Godoy, Girish Shroff, Carol Wu, Luis F Torre-Sada, Alberto Goizueta, Vickie R Shannon, Saadia A Faiz, Mehmet Altan, Guillermo Garcia-Manero, Hagop Kantarjian, Farhad Ravandi-Kashani, Tapan Kadia, Marina Konopleva, Courtney Dinardo, Sherry Pierce, Aung Naing, Sang T Kim, Dimitrios P Kontoyiannis, Fareed Khawaja, Caroline Chung, Jia Wu, Ajay Sheshadri

Faculty, Staff and Student Publications

BACKGROUND: Immune checkpoint inhibitors (ICI) may cause pneumonitis, resulting in potentially fatal lung inflammation. However, distinguishing pneumonitis from pneumonia is time-consuming and challenging. To fill this gap, we build an image-based tool, and further evaluate it clinically alongside relevant blood biomarkers.

MATERIALS AND METHODS: We studied CT images from 97 patients with pneumonia and 29 patients with pneumonitis from acute myeloid leukemia treated with ICIs. We developed a CT-derived signature using a habitat imaging algorithm, whereby infected lungs are segregated into clusters ("habitats"). We validated the model and compared it with a clinical-blood model to determine whether imaging can add …

New Jak3-Insl3 Fusion Transcript-An Oncogenic Event In Cutaneous T-Cell Lymphoma, Loka Reddy Velatooru, Cheng Hui Hu, Pedram Bijani, Xiaohong Wang, Pierr Bojaxhi, Hao Chen, Madeleine Duvic, Xiao Ni

Faculty, Staff and Student Publications

Constitutively activated tyrosine kinase JAK3 is implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCL). The mechanisms of constitutive JAK3 activation are unknown although a JAK3 mutation was reported in a small portion of CTCL patients. In this study, we assessed the oncogenic roles of a newly identified JAK3-INSL3 fusion transcript in CTCL. Total RNA from malignant T-cells in 33 patients with Sézary syndrome (SS), a leukemic form of CTCL, was examined for the new JAK3-INSL3 fusion transcript by RT-PCR followed by Sanger sequencing. The expression levels were assessed by qPCR and correlated with patient survivals. Knockdown and/or knockout assays …

Efficacy Of Scrambler Therapy In Patients With Painful Diabetic Peripheral Neuropathy: A Single-Arm, Prospective, Pilot Study, Seung Hee Yoo, Won-Joong Kim, Ji Seon Chae, Bo Kyung Kang, Min Jeong Kang, Min Hyouk Beak

Faculty, Staff and Student Publications

BACKGROUND: A variety of medications are available to manage painful diabetic peripheral neuropathy (DPN), but the proper treatment remains challenging. Accordingly, various neuromodulation modalities have been used. However, no prospective clinical trials have evaluated the use of scrambler therapy (ST) in painful DPN. This study aimed to explore the long-term effects of ST in managing painful DPN.

METHODS: The patients received 10 consecutive STs of 45 minutes every 1 to 2 days. The primary outcome was pain score. We measured the visual analog scale (VAS) pain scores at baseline, during ST, immediately after ST, and at 1, 2, 3, and …

Pediatric Hepatocellular Adenomas: What Is Known And What Is New?, Andres F Espinoza, Sanjeev A Vasudevan, Prakash M Masand, Dolores H Lòpez-Terrada, Kalyani R Patel

Faculty, Staff and Students Publications

Current understanding and classification of pediatric hepatocellular adenomas (HCA) are largely based on adult data. HCAs are rare in children and, unlike in adults, are often seen in the context of syndromes or abnormal background liver. Attempts to apply the adult classification to pediatric tumors have led to several "unclassifiable" lesions. Although typically considered benign, few can show atypical features and those with beta-catenin mutations have a risk for malignant transformation. Small lesions can be monitored while larger (>5.0 cm) lesions are excised due to symptoms or risk of bleeding/rupture, etc. Management depends on gender, age, underlying liver disease, …

Palmitoylation As A Regulator Of Maguk Proteins Postsynaptic Localization, Rozena Shirvani-Arani, Santiago Balderas, Yonghong Zhang, Xioaqian Fang

Research Symposium

Synaptic plasticity is the ability of the brain to make changes and the changes occur at synapses. To achieve the complicated functions, a good number of proteins are present at synapse and are called synaptic proteins. To stabilize these proteins at synapses, proteins are modified through posttranslational modifications (PTMs). The most studied PTMs include phosphorylation, acetylation, ubiquitination, glycosylation, palmitoylation, etc. Palmitoylation is a type of lipid modification and has received more attention recently for its contribution to protein trafficking, localization, and interaction in various synaptic plasticity. The membrane-associated guanylate kinase (MAGUK) family includes PSD-95, PSD-93 (also known as chapsyn-110), SAP102, …

Development Of A Xylose-Inducible Promoter And Riboswitch Combination System For Manipulating Gene Expression In Fusobacterium Nucleatum, Bibek G C, Peng Zhou, Arindam Naha, Jianhua Gu, Chenggang Wu

Faculty, Staff and Student Publications

Inducible gene expression systems are important for studying bacterial gene function, yet most exhibit leakage. In this study, we engineered a leakage-free hybrid system for precise gene expression controls in Fusobacterium nucleatum by integrating the xylose-inducible expression system with the theophylline-responsive riboswitch. This innovative method enables concurrent control of target gene expression at both transcription and translation initiation levels. Using luciferase and the indole-producing enzyme tryptophanase (TnaA) as reporters, we demonstrated that the hybrid system displays virtually no observable signal in the absence of inducers. We employed this system to express FtsX, a protein related to fusobacterial cytokinesis, in an …

Integrated Molecular And Multiparametric Mri Mapping Of High-Grade Glioma Identifies Regional Biologic Signatures, Leland S Hu, Fulvio D'Angelo, Taylor M Weiskittel, Francesca P Caruso, Shannon P Fortin Ensign, Mylan R Blomquist, Matthew J Flick, Lujia Wang, Christopher P Sereduk, Kevin Meng-Lin, Gustavo De Leon, Ashley Nespodzany, Javier C Urcuyo, Ashlyn C Gonzales, Lee Curtin, Erika M Lewis, Kyle W Singleton, Timothy Dondlinger, Aliya Anil, Natenael B Semmineh, Teresa Noviello, Reyna A Patel, Panwen Wang, Junwen Wang, Jennifer M Eschbacher, Andrea Hawkins-Daarud, Pamela R Jackson, Itamar S Grunfeld, Christian Elrod, Gina L Mazza, Sam C Mcgee, Lisa Paulson, Kamala Clark-Swanson, Yvette Lassiter-Morris, Kris A Smith, Peter Nakaji, Bernard R Bendok, Richard S Zimmerman, Chandan Krishna, Devi P Patra, Naresh P Patel, Mark Lyons, Matthew Neal, Kliment Donev, Maciej M Mrugala, Alyx B Porter, Scott C Beeman, Todd R Jensen, Kathleen M Schmainda, Yuxiang Zhou, Leslie C Baxter, Christopher L Plaisier, Jing Li, Hu Li, Anna Lasorella, C Chad Quarles, Kristin R Swanson, Michele Ceccarelli, Antonio Iavarone, Nhan L Tran

Faculty, Staff and Student Publications

Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate …

Insulin Resistance And Insulin Handling In Chronic Kidney Disease, Vishnu P Parvathareddy, Jiao Wu, Sandhya S Thomas

Faculty, Staff and Students Publications

Insulin regulates energy metabolism involving multiple organ systems. Insulin resistance (IR) occurs when organs exhibit reduced insulin sensitivity, leading to difficulties in maintaining glucose homeostasis. IR ensures decades prior to development of overt diabetes and can cause silent metabolic derangements. IR is typically seen very early in the course of chronic kidney disease (CKD) and is evident even when the estimated glomerular filtration rate (eGFR) is within the normal range and IR persists at various stages of kidney disease. In this article, we will discuss insulin handling by the kidneys, mechanisms responsible for IR in CKD, measurements and management of …

Lack Of Methylation Changes In Gjb2 And Rb1 Non-Coding Regions Of Cochlear Implant Patients With Sensorineural Hearing Loss, Angelo Augusto M Sumalde, Ivana V Yang, Talitha Karisse L Yarza, Celina Ann M Tobias-Grasso, Ma Leah C Tantoco, Elizabeth Davidson, Abner L Chan, Mahshid S Azamian, Teresa Luisa G Cruz, Seema R Lalani, Maria Rina T Reyes-Quintos, Eva Maria Cutiongco-De La Paz, Regie Lyn P Santos-Cortez, Charlotte M Chiong

Faculty, Staff and Students Publications

OBJECTIVE: Recent advances in epigenetic studies continue to reveal novel mechanisms of gene regulation and control, however little is known on the role of epigenetics in sensorineural hearing loss (SNHL) in humans. We aimed to investigate the methylation patterns of two regions, one in

METHODS: We investigated an RB1 promoter region that was previously identified as differentially methylated in children with SNHL and lead exposure. Additionally, we investigated a sequence in an enhancer-like region within GJB2 that contains four CpGs in close proximity. Bisulfite conversion was performed on salivary DNA samples from 15 children with SNHL and 45 unrelated ethnically-matched …

Circulating Endocannabinoids And N-Acylethanolamines In Individuals With Cannabis Use Disorder-Preliminary Findings, Nadia Boachie, Erin Gaudette, Richard P. Bazinet, Lin Lin, Rachel F. Tyndale, Esmaeil Mansouri, Marilyn A. Huestis, Junchao Tong, Bernard Le Foll, Stephen J. Kish, Tony P. George, Isabelle Boileau

Institute of Emerging Health Professions Faculty Papers

BACKGROUND: Endocannabinoids and related N-acylethanolamines (NAEs) are bioactive lipids with important physiological functions and putative roles in mental health and addictions. Although chronic cannabis use is associated with endocannabinoid system changes, the status of circulating endocannabinoids and related NAEs in people with cannabis use disorder (CUD) is uncertain.

METHODS: Eleven individuals with CUD and 54 healthy non-cannabis using control participants (HC) provided plasma for measurement by high-performance liquid chromatography-mass spectrometry of endocannabinoids (2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)) and related NAE fatty acids (N-docosahexaenoylethanolamine (DHEA) and N-oleoylethanolamine (OEA)). Participants were genotyped for the functional gene variant of FAAH (rs324420, C385A) which …

Antibodies To Coagulase Of Staphylococcus Aureus Crossreact To Efb And Reveal Different Binding Of Shared Fibrinogen Binding Repeats, Federico Bertoglio, Ya-Ping Ko, Sheila Thomas, Liliana Giordano, Francesca Romana Scommegna, Doris Meier, Saskia Polten, Marlies Becker, Srishtee Arora, Michael Hust, Magnus Höök, Livia Visai

Faculty, Staff and Student Publications

Staphylococcus aureus pathology is caused by a plethora of virulence factors able to combat multiple host defence mechanisms. Fibrinogen (Fg), a critical component in the host coagulation cascade, plays an important role in the pathogenesis of this bacterium, as it is the target of numerous staphylococcal virulence proteins. Amongst its secreted virulence factors, coagulase (Coa) and Extracellular fibrinogen-binding protein (Efb) share common Fg binding motives and have been described to form a Fg shield around staphylococcal cells, thereby allowing efficient bacterial spreading, phagocytosis escape and evasion of host immune system responses. Targeting these proteins with monoclonal antibodies thus represents a …

Adjunctive Diagnostic Studies Completed Following Detection Of Candidemia In Children: Secondary Analysis Of Observed Practice From A Multicenter Cohort Study Conducted By The Pediatric Fungal Network, Rachel L Wattier, Robert F T Bucayu, Craig L K Boge, Rachael K Ross, Inci Yildirim, Theoklis E Zaoutis, Debra L Palazzi, Surabhi B Vora, Elio Castagnola, Martha Avilés-Robles, Lara Danziger-Isakov, Alison C Tribble, Tanvi S Sharma, Antonio C Arrieta, Gabriela Maron, David M Berman, Dwight E Yin, Lillian Sung, Michael Green, Emmanuel Roilides, Kiran Belani, José Romero, Pere Soler-Palacin, Eduardo López-Medina, Dawn Nolt, Ibrahim Zaid Bin Hussain, William J Muller, Sarmistha B Hauger, Natasha Halasa, Daniel Dulek, Alice Pong, Blanca E Gonzalez, Mark J Abzug, Fabianne Carlesse, Anna R Huppler, Sujatha Rajan, Catherine Aftandilian, Monica I Ardura, Arunaloke Chakrabarti, Benjamin Hanisch, Christine M Salvatore, Lena Klingspor, Elizabeth D Knackstedt, Irja Lutsar, Maria E Santolaya, Sydney Shuster, Sarah K Johnson, William J Steinbach, Brian T Fisher

Faculty, Staff and Students Publications

BACKGROUND: Adjunctive diagnostic studies (aDS) are recommended to identify occult dissemination in patients with candidemia. Patterns of evaluation with aDS across pediatric settings are unknown.

METHODS: Candidemia episodes were included in a secondary analysis of a multicenter comparative effectiveness study that prospectively enrolled participants age 120 days to 17 years with invasive candidiasis (predominantly candidemia) from 2014 to 2017. Ophthalmologic examination (OE), abdominal imaging (AbdImg), echocardiogram, neuroimaging, and lumbar puncture (LP) were performed per clinician discretion. Adjunctive diagnostic studies performance and positive results were determined per episode, within 30 days from candidemia onset. Associations of aDS performance with episode characteristics …

Author Correction: Histone H2a Lys130 Acetylation Epigenetically Regulates Androgen Production In Prostate Cancer, Thanh Nguyen, Dhivya Sridaran, Surbhi Chouhan, Cody Weimholt, Audrey Wilson, Jingqin Luo, Tiandao Li, John Koomen, Bin Fang, Nagireddy Putluri, Arun Sreekumar, Felix Y Feng, Kiran Mahajan, Nupam P Mahajan

Faculty, Staff and Students Publications

No abstract provided.

Differential Effects Of Pancreatic Cancer-Derived Extracellular Vesicles Driving A Suppressive Environment, Anurag Purushothaman, Jacqueline Oliva-Ramírez, Warapen Treekitkarnmongkol, Deivendran Sankaran, Mark W Hurd, Nagireddy Putluri, Anirban Maitra, Cara Haymaker, Subrata Sen

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) cells display extensive crosstalk with their surrounding environment to regulate tumor growth, immune evasion, and metastasis. Recent advances have attributed many of these interactions to intercellular communication mediated by small extracellular vesicles (sEVs), involving cancer-associated fibroblasts (CAF). To explore the impact of sEVs on monocyte lineage transition as well as the expression of checkpoint receptors and activation markers, peripheral blood monocytes from healthy subjects were exposed to PDAC-derived sEVs. Additionally, to analyze the role of sEV-associated HA in immune regulation and tissue-resident fibroblasts, monocytes and pancreatic stellate cells were cultured in the presence of PDAC sEVs …

The Effects Of Resistance Training On Jumping And Selected Power Variables Of The Lower Limbs In Female Soccer Players, Tomasz Chamera, Magdalena Prończuk, Piotr Smok, Miłosz Drozd, Małgorzata Michalczyk, Adam Maszczyk

Baltic Journal of Health and Physical Activity

Introduction: The aim of the study was to compare the effects of a 6-week intervention of combined soccer training with resistance training on strength and power variables in highly trained female soccer players. It was hypothesized that 6 weeks is sufficient for a significant improvement in jumping ability and power to occur due to the intervention. The study involved 34 female soccer players of the top women’s league (22 ± 5 years old, body height 167 ± 5 cm, body weight 60 ± 8 kg). The players were divided into two groups of 17 participants. The control group performed 3 …

Tmem27 Suppresses Tumor Development By Promoting Ret Ubiquitination, Positioning, And Degradation, Qianjin Guo, Zi-Ming Cheng, Hector Gonzalez-Cantú, Matthew Rotondi, Gabriela Huelgas-Morales, Purushoth Ethiraj, Zhijun Qiu, Jonathan Lefkowitz, Wan Song, Bethany N Landry, Hector Lopez, Cynthia M Estrada-Zuniga, Shivi Goyal, Mohammad Aasif Khan, Timothy J Walker, Exing Wang, Faqian Li, Yanli Ding, Lois M Mulligan, Ricardo C T Aguiar, Patricia L M Dahia

Faculty, Staff and Student Publications

The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell …

Long-Term Outcomes Of Cardiac Sarcoid: Prognostic Implications Of Isolated Cardiac Involvement And Impact Of Diagnostic Delays, Joshua Sink, Cara Joyce, Max J. Liebo, David J. Wilber

Biostatistics Collaborative Core: Faculty Publications and Other Works

BACKGROUND: Isolated cardiac sarcoid (iCS) is reported to have more severe clinical presentation and greater risk of adverse events compared with cardiac sarcoid (CS) with extracardiac involvement (nonisolated CS). Delays in diagnosing specific organ involvement may play a role in these described differences.

METHODS AND RESULTS: A retrospective observational study of patients with CS over a 20-year period was conducted. Objective evidence of organ involvement and time of onset based on consensus criteria were identified. CS was confirmed by histology in all patients from myocardium only (iCS) or extracardiac tissue (nonisolated CS). The primary end point was a composite of …

Axl-Initiated Paracrine Activation Of Pstat3 Enhances Mesenchymal And Vasculogenic Supportive Features Of Tumor-Associated Macrophages, Chia-Nung Hung, Meizhen Chen, Daniel T Dearmond, Cheryl H-L Chiu, Catherine A Limboy, Xi Tan, Meena Kusi, Chih-Wei Chou, Li-Ling Lin, Zhao Zhang, Chiou-Miin Wang, Chun-Liang Chen, Kohzoh Mitsuya, Pawel A Osmulski, Maria E Gaczynska, Nameer B Kirma, Ratna K Vadlamudi, Don L Gibbons, Steve Warner, Andrew J Brenner, Daruka Mahadevan, Joel E Michalek, Tim H-M Huang, Josephine A Taverna

Faculty, Staff and Student Publications

Tumor-associated macrophages (TAMs) are integral to the development of complex tumor microenvironments (TMEs) and can execute disparate cellular programs in response to extracellular cues. However, upstream signaling processes underpinning this phenotypic plasticity remain to be elucidated. Here, we report that concordant AXL-STAT3 signaling in TAMs is triggered by lung cancer cells or cancer-associated fibroblasts in the cytokine milieu. This paracrine action drives TAM differentiation toward a tumor-promoting "M2-like" phenotype with upregulation of CD163 and putative mesenchymal markers, contributing to TAM heterogeneity and diverse cellular functions. One of the upregulated markers, CD44, mediated by AXL-IL-11-pSTAT3 signaling cascade, enhances macrophage ability to …

A Peptide-Binding Domain Shared With An Antarctic Bacterium Facilitates, Cameron J Lloyd, Shuaiqi Guo, Brett Kinrade, Hossein Zahiri, Robert Eves, Syed Khalid Ali, Fitnat Yildiz, Ilja K Voets, Peter L Davies, Karl E Klose

Faculty, Staff and Student Publications

No abstract provided.

Setd2 Safeguards The Genome Against Isochromosome Formation, Frank M Mason, Emily S Kounlavong, Anteneh T Tebeje, Rashmi Dahiya, Tiffany Guess, Abid Khan, Logan Vlach, Stephen R Norris, Courtney A Lovejoy, Ruhee Dere, Brian D Strahl, Ryoma Ohi, Peter Ly, Cheryl Lyn Walker, W Kimryn Rathmell

Faculty, Staff and Students Publications

Isochromosomes are mirror-imaged chromosomes with simultaneous duplication and deletion of genetic material which may contain two centromeres to create isodicentric chromosomes. Although isochromosomes commonly occur in cancer and developmental disorders and promote genome instability, mechanisms that prevent isochromosomes are not well understood. We show here that the tumor suppressor and methyltransferase SETD2 is essential to prevent these errors. Using cellular and cytogenetic approaches, we demonstrate that loss of SETD2 or its epigenetic mark, histone H3 lysine 36 trimethylation (H3K36me3), results in the formation of isochromosomes as well as isodicentric and acentric chromosomes. These defects arise during DNA replication and are …

In Vivo Crispr/Cas9 Screening Identifies Pbrm1 As A Regulator Of Myeloid Leukemia Development In Mice, Bin E Li, Grace Y Li, Wenqing Cai, Qian Zhu, Davide Seruggia, Yuko Fujiwara, Christopher R Vakoc, Stuart H Orkin

Faculty, Staff and Students Publications

CRISPR/Cas9 screening approaches are powerful tool for identifying in vivo cancer dependencies. Hematopoietic malignancies are genetically complex disorders in which the sequential acquisition of somatic mutations generates clonal diversity. Over time, additional cooperating mutations may drive disease progression. Using an in vivo pooled gene editing screen of epigenetic factors in primary murine hematopoietic stem and progenitor cells (HSPCs), we sought to uncover unrecognized genes that contribute to leukemia progression. We, first, modeled myeloid leukemia in mice by functionally abrogating both Tet2 and Tet3 in HSPCs, followed by transplantation. We, then, performed pooled CRISPR/Cas9 editing of genes encoding epigenetic factors and …