Medicine and Health Sciences Commons^™

Enhancer Reprogramming Confers Dependence On Glycolysis And Igf Signaling In Kmt2d Mutant Melanoma., Mayinuer Maitituoheti, Emily Z Keung, Ming Tang, Liang Yan, Hunain Alam, Guangchun Han, Anand K Singh, Ayush T Raman, Christopher Terranova, Sharmistha Sarkar, Elias Orouji, Samir B Amin, Sneha Sharma, Maura Williams, Neha S Samant, Mayura Dhamdhere, Norman Zheng, Tara Shah, Amiksha Shah, Jacob B Axelrad, Nazanin E Anvar, Yu-Hsi Lin, Shan Jiang, Edward Q Chang, Davis R Ingram, Wei-Lien Wang, Alexander Lazar, Min Gyu Lee, Florian Muller, Linghua Wang, Haoqiang Ying, Kunal Rai

Faculty Research 2020

Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on conditional and melanocyte-specific deletion of KMT2D. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways, including glycolysis. KMT2D deficiency aberrantly upregulates glycolysis enzymes, intermediate metabolites, and glucose consumption rates. Mechanistically, KMT2D loss causes genome-wide reduction of H3K4me1-marked active enhancer chromatin states. Enhancer loss and subsequent repression of IGFBP5 activates IGF1R-AKT to increase …

Gli3 Utilizes Hand2 To Synergistically Regulate Tissue-Specific Transcriptional Networks., Kelsey H Elliott, Xiaoting Chen, Joseph Salomone, Praneet Chaturvedi, Preston A Schultz, Sai K Balchand, Jeffrey D Servetas, Aimée Zuniga, Rolf Zeller, Brian Gebelein, Matthew T Weirauch, Kevin A Peterson, Samantha A Brugmann

Faculty Research 2020

Despite a common understanding that Gli TFs are utilized to convey a Hh morphogen gradient, genetic analyses suggest craniofacial development does not completely fit this paradigm. Using the mouse model (Mus musculus), we demonstrated that rather than being driven by a Hh threshold, robust Gli3 transcriptional activity during skeletal and glossal development required interaction with the basic helix-loop-helix TF Hand2. Not only did genetic and expression data support a co-factorial relationship, but genomic analysis revealed that Gli3 and Hand2 were enriched at regulatory elements for genes essential for mandibular patterning and development. Interestingly, motif analysis at sites co-occupied …

Sexual Dimorphism In The Meiotic Requirement For Prdm9: A Mammalian Evolutionary Safeguard., Natalie Powers, Beth L Dumont, Chihiro Emori, Raman Akinyanju Lawal, Catherine Brunton, Kenneth Paigen, Mary Ann Handel, Ewelina Bolcun-Filas, Petko M. Petkov, Tanmoy Bhattacharyya

Faculty Research 2020

In many mammals, genomic sites for recombination are determined by the histone methyltransferase PRMD9. Some mouse strains lacking PRDM9 are infertile, but instances of fertility or semifertility in the absence of PRDM9 have been reported in mice, canines, and a human female. Such findings raise the question of how the loss of PRDM9 is circumvented to maintain fertility. We show that genetic background and sex-specific modifiers can obviate the requirement for PRDM9 in mice. Specifically, the meiotic DNA damage checkpoint protein CHK2 acts as a modifier allowing female-specific fertility in the absence of PRDM9. We also report that, in the …

Age And Genetic Background Modify Hybrid Male Sterility In House Mice., Samuel J Widmayer, Mary Ann Handel, David L Aylor

Faculty Research 2020

Hybrid male sterility (HMS) contributes to reproductive isolation commonly observed among house mouse (Mus musculus) subspecies, both in the wild and in laboratory crosses. Incompatibilities involving specific Prdm9 alleles and certain Chromosome (Chr) X genotypes are known determinants of fertility and HMS, and previous work in the field has demonstrated that genetic background modifies these two major loci. We constructed hybrids that have identical genotypes at Prdm9 and identical X chromosomes, but differ widely across the rest of the genome. In each case, we crossed female PWK/PhJ mice representative of the M. m. musculus subspecies to males from …

Genetic Variant Effects On Gene Expression In Human Pancreatic Islets And Their Implications For T2d., Ana Viñuela, Arushi Varshney, Martijn Van De Bunt, Rashmi B Prasad, Olof Asplund, Amanda Bennett, Michael Boehnke, Andrew A Brown, Michael R Erdos, João Fadista, Ola Hansson, Gad Hatem, Cédric Howald, Apoorva K Iyengar, Paul Johnson, Ulrika Krus, Patrick E Macdonald, Anubha Mahajan, Jocelyn E Manning Fox, Narisu Narisu, Vibe Nylander, Peter Orchard, Nikolay Oskolkov, Nikolaos I Panousis, Anthony Payne, Michael L. Stitzel, Swarooparani Vadlamudi, Ryan Welch, Francis S Collins, Karen L Mohlke, Anna L Gloyn, Laura J Scott, Emmanouil T Dermitzakis, Leif Groop, Stephen C J Parker, Mark I Mccarthy

Faculty Research 2020

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in …

Endothelin 1-Induced Retinal Ganglion Cell Death Is Largely Mediated By Jun Activation., Olivia J Marola, Stephanie B Syc-Mazurek, Gareth R Howell, Richard T Libby

Faculty Research 2020

Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells (RGCs), the output neurons of the retina. Multiple lines of evidence show the endothelin (EDN, also known as ET) system is important in glaucomatous neurodegeneration. To date, the molecular mechanisms within RGCs driving EDN-induced RGC death have not been clarified. The pro-apoptotic transcription factor JUN (the canonical target of JNK signaling) and the endoplasmic reticulum stress effector and transcription factor DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been shown to act downstream of EDN receptors. Previous studies demonstrated that JUN and DDIT3 were important …

Association Of Cnvs With Methylation Variation., Xinghua Shi, Saranya Radhakrishnan, Jia Wen, Jin Yun Chen, Junjie Chen, Brianna Ashlyn Lam, Ryan E Mills, Barbara E Stranger, Charles Lee, Sunita R Setlur

Faculty Research 2020

Germline copy number variants (CNVs) and single-nucleotide polymorphisms (SNPs) form the basis of inter-individual genetic variation. Although the phenotypic effects of SNPs have been extensively investigated, the effects of CNVs is relatively less understood. To better characterize mechanisms by which CNVs affect cellular phenotype, we tested their association with variable CpG methylation in a genome-wide manner. Using paired CNV and methylation data from the 1000 genomes and HapMap projects, we identified genome-wide associations by methylation quantitative trait locus (mQTL) analysis. We found individual CNVs being associated with methylation of multiple CpGs and vice versa. CNV-associated methylation changes were correlated with …

Protocol For Isolation Of Cardiac Interstitial Cells From Adult Murine Hearts For Unbiased Single Cell Profiling., Elvira Forte, Sandra Daigle, Nadia Rosenthal

Faculty Research 2020

Interstitial cells have a crucial role in cardiac fibrosis and repair of the mammalian heart. Single-cell profiling using droplet-based technology has revolutionized the investigation of cell states and identities. Here, we present a protocol for the efficient isolation of high-quality live nucleated non-cardiomyocytes from adult murine heart, for unbiased single-cell RNA sequencing using 10× Chromium technology. This protocol has been applied to homeostatic and injured hearts from different mouse strains. For complete details on the use and execution of this protocol, please refer to Forte et al. (2020).

Nemf Mutations That Impair Ribosome-Associated Quality Control Are Associated With Neuromuscular Disease., Paige B Martin, Yu Kigoshi-Tansho, Roger B Sher, Gianina Ravenscroft, Jennifer E Stauffer, Rajesh Kumar, Ryo Yonashiro, Tina Müller, Christopher Griffith, William Allen, Davut Pehlivan, Tamar Haral, Martin Zenker, Denise Howting, Denny Schanze, Eissa A Faqeih, Naif A M Almontashiri, Reza Maroofian, Henry Houlden, Neda Mazaheri, Hamid Galehdari, Ganka Douglas, Jennifer E Posey, Monique Ryan, James R Lupski, Nigel G Laing, Claudio A P Joazeiro, Gregory A. Cox

Faculty Research 2020

A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway-Ribosome-associated Quality Control (RQC)-by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with …

Genetic Variation Regulates Opioid-Induced Respiratory Depression In Mice., Jason A. Bubier, Hao He, Vivek M. Philip, Tyler A. Roy, Christian Monroy Hernandez, Rebecca Bernat, Kevin D Donohue, Bruce F O'Hara, Elissa J Chesler

Faculty Research 2020

In the U.S., opioid prescription for treatment of pain nearly quadrupled from 1999 to 2014. The diversion and misuse of prescription opioids along with increased use of drugs like heroin and fentanyl, has led to an epidemic in addiction and overdose deaths. The most common cause of opioid overdose and death is opioid-induced respiratory depression (OIRD), a life-threatening depression in respiratory rate thought to be caused by stimulation of opioid receptors in the inspiratory-generating regions of the brain. Studies in mice have revealed that variation in opiate lethality is associated with strain differences, suggesting that sensitivity to OIRD is genetically …

Identifying Mechanisms Of Normal Cognitive Aging Using A Novel Mouse Genetic Reference Panel., Amy R Dunn, Niran Hadad, Sarah M Neuner, Ji-Gang Zhang, Vivek M. Philip, Logan Dumitrescu, Timothy J Hohman, Jeremy H Herskowitz, Kristen M S O'Connell, Catherine Kaczorowski

Faculty Research 2020

Developing strategies to maintain cognitive health is critical to quality of life during aging. The basis of healthy cognitive aging is poorly understood; thus, it is difficult to predict who will have normal cognition later in life. Individuals may have higher baseline functioning (cognitive reserve) and others may maintain or even improve with age (cognitive resilience). Understanding the mechanisms underlying cognitive reserve and resilience may hold the key to new therapeutic strategies for maintaining cognitive health. However, reserve and resilience have been inconsistently defined in human studies. Additionally, our understanding of the molecular and cellular bases of these phenomena is …

The Case For Open Science: Rare Diseases., Yaffa R Rubinstein, Peter N Robinson, William A Gahl, Paul Avillach, Gareth Baynam, Helene Cederroth, Rebecca M Goodwin, Stephen C Groft, Mats G Hansson, Nomi L Harris, Vojtech Huser, Deborah Mascalzoni, Julie A Mcmurry, Matthew Might, Christoffer Nellaker, Barend Mons, Dina N Paltoo, Jonathan Pevsner, Manuel Posada, Alison P Rockett-Frase, Marco Roos, Tamar B Rubinstein, Domenica Taruscio, Esther Van Enckevort, Melissa A Haendel

Faculty Research 2020

The premise of Open Science is that research and medical management will progress faster if data and knowledge are openly shared. The value of Open Science is nowhere more important and appreciated than in the rare disease (RD) community. Research into RDs has been limited by insufficient patient data and resources, a paucity of trained disease experts, and lack of therapeutics, leading to long delays in diagnosis and treatment. These issues can be ameliorated by following the principles and practices of sharing that are intrinsic to Open Science. Here, we describe how the RD community has adopted the core pillars …

A Novel Mouse Model Expressing Human Forms For Complement Receptors Cr1 And Cr2., Harriet M. Jackson, Kate E Foley, Rita O'Rourke, Timothy M Stearns, Dina Fathalla, B Paul Morgan, Gareth R Howell

Faculty Research 2020

BACKGROUND: The complement cascade is increasingly implicated in development of a variety of diseases with strong immune contributions such as Alzheimer's disease and Systemic Lupus Erythematosus. Mouse models have been used to determine function of central components of the complement cascade such as C1q and C3. However, species differences in their gene structures mean that mice do not adequately replicate human complement regulators, including CR1 and CR2. Genetic variation in CR1 and CR2 have been implicated in modifying disease states but the mechanisms are not known.

RESULTS: To decipher the roles of human CR1 and CR2 in health and disease, …

Cd226 Deletion Reduces Type 1 Diabetes In The Nod Mouse By Impairing Thymocyte Development And Peripheral T Cell Activation., Melanie R Shapiro, Wen-I Yeh, Joshua R Longfield, John Gallagher, Caridad M Infante, Sarah Wellford, Amanda L Posgai, Mark A Atkinson, Martha Campbell-Thompson, Scott M Lieberman, David V. Serreze, Aron M Geurts, Yi-Guang Chen, Todd M Brusko

Faculty Research 2020

The costimulatory molecule CD226 is highly expressed on effector/memory T cells and natural killer cells. Costimulatory signals received by T cells can impact both central and peripheral tolerance mechanisms. Genetic polymorphisms in CD226 have been associated with susceptibility to type 1 diabetes and other autoimmune diseases. We hypothesized that genetic deletion of Cd226 in the non-obese diabetic (NOD) mouse would impact type 1 diabetes incidence by altering T cell activation. CD226 knockout (KO) NOD mice displayed decreased disease incidence and insulitis in comparison to wild-type (WT) controls. Although female CD226 KO mice had similar levels of sialoadenitis as WT controls, …

Naive Pluripotent Stem Cells Exhibit Phenotypic Variability That Is Driven By Genetic Variation., Daniel Ortmann, Stephanie Brown, Anne M Czechanski, Selcan Aydin, Daniele Muraro, Yuanhua Huang, Rute A Tomaz, Anna Osnato, Giovanni Canu, Brandon T Wesley, Daniel A Skelly, Oliver Stegle, Ted Choi, Gary A Churchill, Christopher L. Baker, Peter J Rugg-Gunn, Steven C. Munger, Laura G Reinholdt, Ludovic Vallier

Faculty Research 2020

Variability among pluripotent stem cell (PSC) lines is a prevailing issue that hampers not only experimental reproducibility but also large-scale applications and personalized cell-based therapy. This variability could result from epigenetic and genetic factors that influence stem cell behavior. Naive culture conditions minimize epigenetic fluctuation, potentially overcoming differences in PSC line differentiation potential. Here we derived PSCs from distinct mouse strains under naive conditions and show that lines from distinct genetic backgrounds have divergent differentiation capacity, confirming a major role for genetics in PSC phenotypic variability. This is explained in part through inconsistent activity of extra-cellular signaling, including the Wnt …

Identifying The Molecular Systems That Influence Cognitive Resilience To Alzheimer's Disease In Genetically Diverse Mice., Sarah E Heuer, Sarah M Neuner, Niran Hadad, Kristen M S O'Connell, Robert W Williams, Vivek M. Philip, Chris Gaiteri, Catherine Kaczorowski

Faculty Research 2020

Individual differences in cognitive decline during normal aging and Alzheimer's disease (AD) are common, but the molecular mechanisms underlying these distinct outcomes are not fully understood. We utilized a combination of genetic, molecular, and behavioral data from a mouse population designed to model human variation in cognitive outcomes to search for the molecular mechanisms behind this population-wide variation. Specifically, we used a systems genetics approach to relate gene expression to cognitive outcomes during AD and normal aging. Statistical causal-inference Bayesian modeling was used to model systematic genetic perturbations matched with cognitive data that identified astrocyte and microglia molecular networks as …

Cross-Species Analyses Identify Dlgap2 As A Regulator Of Age-Related Cognitive Decline And Alzheimer's Dementia., Andrew R Ouellette, Sarah M Neuner, Logan Dumitrescu, Laura C. Anderson, Daniel M. Gatti, Emily R Mahoney, Jason A. Bubier, Gary Churchill, Luanne L. Peters, Matthew J Huentelman, Jeremy H Herskowitz, Hyun-Sik Yang, Alexandra N Smith, Christiane Reitz, Brian W Kunkle, Charles C White, Philip L De Jager, Julie A Schneider, David A Bennett, Nicholas T Seyfried, Alzheimer's Disease Genetics Consortium, Elissa J Chesler, Niran Hadad, Timothy J Hohman, Catherine Kaczorowski

Faculty Research 2020

Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide association study (GWAS) of Alzheimer's dementia (AD), and GWAS results in African Americans. We find an association between Dlgap2 and AD phenotypes at the variant, gene and protein expression, and methylation levels. Lower cortical …

Prognostic Gene Expression Signature For High-Grade Serous Ovarian Cancer., J Millstein, T Budden, E L Goode, M S Anglesio, A Talhouk, M P Intermaggio, H S Leong, S Chen, W Elatre, B Gilks, T Nazeran, M Volchek, R C Bentley, C Wang, D S Chiu, S Kommoss, S C Y Leung, J Senz, A Lum, V Chow, H Sudderuddin, R Mackenzie, Joshy George, Aocs Group, S Fereday, J Hendley, N Traficante, H Steed, J M Koziak, M Köbel, I A Mcneish, T Goranova, D Ennis, G Macintyre, D Silva De Silva, T Ramón Y Cajal, J García-Donas, S Hernando Polo, G C Rodriguez, K L Cushing-Haugen, H R Harris, C S Greene, R A Zelaya, S Behrens, R T Fortner, P Sinn, E Herpel, J Lester, J Lubiński, O Oszurek, A Tołoczko, C Cybulski, J Menkiszak, C L Pearce, M C Pike, C Tseng, J Alsop, V Rhenius, H Song, M Jimenez-Linan, A M Piskorz, A Gentry-Maharaj, C Karpinskyj, M Widschwendter, N Singh, C J Kennedy, R Sharma, P R Harnett, B Gao, S E Johnatty, R Sayer, J Boros, S J Winham, G L Keeney, S H Kaufmann, M C Larson, H Luk, B Y Hernandez, P J Thompson, L R Wilkens, M E Carney, B Trabert, J Lissowska, L Brinton, M E Sherman, C Bodelon, S Hinsley, L A Lewsley, R Glasspool, S N Banerjee, E A Stronach, P Haluska, I Ray-Coquard, S Mahner, B Winterhoff, D Slamon, D A Levine, L E Kelemen, J Benitez, J Chang-Claude, J Gronwald, A H Wu, U Menon, M T Goodman, J M Schildkraut, N Wentzensen, R Brown, A Berchuck, G Chenevix-Trench, A Defazio, S A Gayther, M J García, M J Henderson, M A Rossing, A Beeghly-Fadiel, P A Fasching, S Orsulic, B Y Karlan, G E Konecny, D G Huntsman, D D Bowtell, J D Brenton, J A Doherty, P D P Pharoah, S J Ramus

Faculty Research 2020

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.

PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for …

Dual Roles Of Neutrophils In Metastatic Colonization Are Governed By The Host Nk Cell Status., Peishan Li, Mingyang Lu, Jiayuan Shi, Li Hua, Zheng Gong, Qing Li, Leonard D. Shultz, Guangwen Ren

Faculty Research 2020

The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell …

Term Matrix: A Novel Gene Ontology Annotation Quality Control System Based On Ontology Term Co-Annotation Patterns., Valerie Wood, Seth Carbon, Midori A Harris, Antonia Lock, Stacia R Engel, David P. Hill, Kimberly Van Auken, Helen Attrill, Marc Feuermann, Pascale Gaudet, Ruth C Lovering, Sylvain Poux, Kim M Rutherford, Christopher J Mungall

Faculty Research 2020

Biological processes are accomplished by the coordinated action of gene products. Gene products often participate in multiple processes, and can therefore be annotated to multiple Gene Ontology (GO) terms. Nevertheless, processes that are functionally, temporally and/or spatially distant may have few gene products in common, and co-annotation to unrelated processes probably reflects errors in literature curation, ontology structure or automated annotation pipelines. We have developed an annotation quality control workflow that uses rules based on mutually exclusive processes to detect annotation errors, based on and validated by case studies including the three we present here: fission yeast protein-coding gene annotations …

Genetic Identification And Drug-Resistance Characterization Of, Jorge Cervantes, Noemí Yokobori, Bo-Young Hong

Faculty Research 2020

Clinical management of tuberculosis (TB) in endemic areas is often challenged by a lack of resources including laboratories for Mycobacterium tuberculosis (Mtb) culture. Traditional phenotypic drug susceptibility testing for Mtb is costly and time consuming, while PCR-based methods are limited to selected target loci. We herein utilized a portable, USB-powered, long-read sequencing instrument (MinION), to investigate Mtb genomic DNA from clinical isolates to determine the presence of anti-TB drug-resistance conferring mutations. Data analysis platform EPI2ME and antibiotic-resistance analysis using the real time ARMA workflow, identified Mtb species as well as extensive resistance gene profiles. The approach was highly sensitive, being …

Transcriptional Regulatory Networks Of Tumor-Associated Macrophages That Drive Malignancy In Mesenchymal Glioblastoma., Jason K Sa, Nakho Chang, Hye Won Lee, Hee Jin Cho, Michele Ceccarelli, Luigi Cerulo, Jinlong Yin, Sung Soo Kim, Francesca P Caruso, Mijeong Lee, Donggeon Kim, Young Taek Oh, Yeri Lee, Nam-Gu Her, Byeongkwi Min, Hye-Jin Kim, Da Eun Jeong, Hye-Mi Kim, Hyunho Kim, Seok Chung, Hyun Goo Woo, Jeongwu Lee, Doo-Sik Kong, Ho Jun Seol, Jung-Il Lee, Jinho Kim, Woong-Yang Park, Qianghu Wang, Erik P Sulman, Amy B Heimberger, Michael Lim, Jong Bae Park, Antonio Iavarone, Roel G W Verhaak, Do-Hyun Nam

Faculty Research 2020

BACKGROUND: Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages.

RESULTS: We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCO

CONCLUSIONS: Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for …

Addressing The Batch Effect Issue For Lc/Ms Metabolomics Data In Data Preprocessing., Qin Liu, Douglas Walker, Karan Uppal, Zihe Liu, Chunyu Ma, Vilinh Tran, Shuzhao Li, Dean P Jones, Tianwei Yu

Faculty Research 2020

With the growth of metabolomics research, more and more studies are conducted on large numbers of samples. Due to technical limitations of the Liquid Chromatography-Mass Spectrometry (LC/MS) platform, samples often need to be processed in multiple batches. Across different batches, we often observe differences in data characteristics. In this work, we specifically focus on data generated in multiple batches on the same LC/MS machinery. Traditional preprocessing methods treat all samples as a single group. Such practice can result in errors in the alignment of peaks, which cannot be corrected by post hoc application of batch effect correction methods. In this …

Hemodynamics During The 10-Minute Nasa Lean Test: Evidence Of Circulatory Decompensation In A Subset Of Me/Cfs Patients., Jihyun Lee, Suzanne D Vernon, Patricia Jeys, Weam Ali, Andrea Campos, Derya Unutmaz, Brayden Yellman, Lucinda Bateman

Faculty Research 2020

BACKGROUND: Lightheadedness, fatigue, weakness, heart palpitations, cognitive dysfunction, muscle pain, and exercise intolerance are some of the symptoms of orthostatic intolerance (OI). There is substantial comorbidity of OI in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome). The 10-minute NASA Lean Test (NLT) is a simple, point-of-care method that can aid ME/CFS diagnosis and guide management and treatment of OI. The objective of this study was to understand the hemodynamic changes that occur in ME/CFS patients during the 10-minute NLT.

METHODS: A total of 150 ME/CFS patients and 75 age, gender and race matched healthy controls (HCs) were enrolled. We recruited 75 ME/CFS …

Mechanisms Of T-Cell Exhaustion In Pancreatic Cancer., Didem Saka, Muazzez Gökalp, Betül Piyade, Nedim Can Cevik, Elif Arik Sever, Derya Unutmaz, Güralp O Ceyhan, Ihsan Ekin Demir, Hande Asimgil

Faculty Research 2020

T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to …

A Guide To Writing Systematic Reviews Of Rare Disease Treatments To Generate Fair-Compliant Datasets: Building A Treatabolome., Antonio Atalaia, Rachel Thompson, Alberto Corvo, Leigh Carmody, Davide Piscia, Leslie Matalonga, Alfons Macaya, Angela Lochmuller, Bertrand Fontaine, Birte Zurek, Carles Hernandez-Ferrer, Carola Rheinard, David Gómez-Andrés, Jean-François Desaphy, Katherine Schon, Katja Lohmann, Matthew J Jennings, Matthis Synofzik, Olaf Riess, Rabah Ben Yaou, Teresinha Evangelista, Thiloka Ratnaike, Virginie Bros-Facer, Gulcin Gumus, Rita Horvath, Patrick Chinnery, Steven Laurie, Holm Graessner, Peter N Robinson, Hanns Lochmuller, Sergi Beltran, Gisèle Bonne

Faculty Research 2020

BACKGROUND: Rare diseases are individually rare but globally affect around 6% of the population, and in over 70% of cases are genetically determined. Their rarity translates into a delayed diagnosis, with 25% of patients waiting 5 to 30 years for one. It is essential to raise awareness of patients and clinicians of existing gene and variant-specific therapeutics at the time of diagnosis to avoid that treatment delays add up to the diagnostic odyssey of rare diseases' patients and their families.

AIMS: This paper aims to provide guidance and give detailed instructions on how to write homogeneous systematic reviews of rare …

Tonic Tcr Signaling Inversely Regulates The Basal Metabolism Of Cd4, Ashley A Viehmann Milam, Juliet M Bartleson, Michael D Buck, Chih-Hao Chang, Alexey Sergushichev, David L Donermeyer, Wing Y Lam, Erika L Pearce, Maxim N Artyomov, Paul M Allen

Faculty Research 2020

The contribution of self-peptide-MHC signaling in CD4

Mediastinal Lymphadenopathy, Class-Switched Auto-Antibodies And Myocardial Immune-Complexes During Heart Failure In Rodents And Humans., Amalia Sintou, Catherine Mansfield, Alma Iacob, Rasheda A Chowdhury, Salomon Narodden, Stephen M Rothery, Robert Podovei, Jose L Sanchez-Alonso, Elisa Ferraro, Pamela Swiatlowska, Sian E Harding, Sanjay Prasad, Nadia Rosenthal, Julia Gorelik, Susanne Sattler

Faculty Research 2020

Mediastinal lymphadenopathy and auto-antibodies are clinical phenomena during ischemic heart failure pointing to an autoimmune response against the heart. T and B cells have been convincingly demonstrated to be activated after myocardial infarction, a prerequisite for the generation of mature auto-antibodies. Yet, little is known about the immunoglobulin isotype repertoire thus pathological potential of anti-heart auto-antibodies during heart failure. We obtained human myocardial tissue from ischemic heart failure patients and induced experimental MI in rats. We found that anti-heart autoimmunity persists during heart failure. Rat mediastinal lymph nodes are enlarged and contain active secondary follicles with mature isotype-switched IgG2a B …

Mgmt Genomic Rearrangements Contribute To Chemotherapy Resistance In Gliomas., Barbara Oldrini, Nuria Vaquero-Siguero, Quanhua Mu, Paula Kroon, Ying Zhang, Marcos Galán-Ganga, Zhaoshi Bao, Zheng Wang, Hanjie Liu, Jason K Sa, Junfei Zhao, Hoon Kim, Sandra Rodriguez-Perales, Do-Hyun Nam, Roel G W Verhaak, Raul Rabadan, Tao Jiang, Jiguang Wang, Massimo Squatrito

Faculty Research 2020

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in …

Ontologies, Knowledge Representation, And Machine Learning For Translational Research: Recent Contributions, Peter N Robinson, Melissa A. Haendel

Faculty Research 2020

No abstract provided.