Medicine and Health Sciences Commons^™

Acute Consumption Of A Sugar-Sweetened Beverage Impairs Microvascular Function In Midwestern Hispanic Males, Emma Hirshman, Anne R. Crecelius

Health and Sport Science Faculty Publications

Hispanic males are at risk for cardiovascular disease and consume high levels of sugar-sweetened beverages (SSB); yet, their acute vascular response to SSBs is unknown. Ten healthy Hispanic men (18-45 years old) consumed a SSB and reactive hyperemia was performed prior to, immediately following, and 1-hr post-consumption. Both peak and total (area under the curve) forearm blood flow were attenuated immediately following consumption but returned to at or above pre-consumption levels at the 1-hr test.

Spatial Concordance Of Dna Methylation Classification In Diffuse Glioma., Niels Verburg, Floris P Barthel, Kevin J Anderson, Kevin C Johnson, Thomas Koopman, Maqsood M Yaqub, Otto S Hoekstra, Adriaan A Lammertsma, Frederik Barkhof, Petra J W Pouwels, Jaap C Reijneveld, Annemieke J M Rozemuller, Jeroen A M Beliën, Ronald Boellaard, Michael D Taylor, Sunit Das, Joseph F Costello, William Peter Vandertop, Pieter Wesseling, Philip C De Witt Hamer, Roel G W Verhaak

Faculty Research 2021

BACKGROUND: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence.

METHODS: We used neuronavigation to acquire 133 image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast-enhanced T1-weighted and fluid-attenuated inversion …

Sedation And Acute Encephalopathy In A Pediatric Patient Following Ingestion Of Delta-8-Tetrahydrocannabinol Gummies, Peter Akpunonu, Regan A. Baum, Andrew Reckers, Blake Davidson, Ross Ellison, Matthew Riley, Jordan Trecki, Roy Gerona

Emergency Medicine Faculty Publications

BACKGROUND Delta-8 tetrahydrocannabinol (delta-8 THC) is an isomer of delta-9-tetrahydrocannabinol (delta-9 THC), the primary psychoactive cannabinoid in the marijuana plant. Typically found at lower concentrations in marijuana, delta-8 THC exhibits psychoactive properties similar to delta-9 THC. Products containing delta-8 THC are readily available across the US and currently there is a lack of available confirmatory testing specific to delta-8 THC as there is cross-reactivity to other naturally occurring cannabinoids in standard immunoassays. Pediatric exposures to this substance are on the rise.

CASE REPORT We present a case with laboratory confirmation of a previously healthy 2-year-old girl ingesting approximately 15 mg/kg …

Fusion And Beyond: Satellite Cell Contributions To Loading-Induced Skeletal Muscle Adaptation, Kevin A. Murach, Christopher S. Fry, Esther E. Dupont-Versteegden, John J. Mccarthy, Charlotte A. Peterson

Center for Muscle Biology Faculty Publications

Satellite cells support adult skeletal muscle fiber adaptations to loading in numerous ways. The fusion of satellite cells, driven by cell-autonomous and/or extrinsic factors, contributes new myonuclei to muscle fibers, associates with load-induced hypertrophy, and may support focal membrane damage repair and long-term myonuclear transcriptional output. Recent studies have also revealed that satellite cells communicate within their niche to mediate muscle remodeling in response to resistance exercise, regulating the activity of numerous cell types through various mechanisms such as secretory signaling and cell–cell contact. Muscular adaptation to resistance and endurance activity can be initiated and sustained for a period of …

Comprehensive Characterization Of Covid-19 Patients With Repeatedly Positive Sars-Cov-2 Tests Using A Large U.S. Electronic Health Record Database., Xiao Dong, Yujia Zhou, Xiao-Ou Shu, Elmer V Bernstam, Rebecca Stern, David M Aronoff, Hua Xu, Loren Lipworth

Journal Articles

In the absence of genome sequencing, two positive molecular tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) separated by negative tests, prolonged time, and symptom resolution remain the best surrogate measure of possible reinfection. Using a large electronic health record database, we characterized clinical and testing data for 23 patients with repeatedly positive SARS-CoV-2 PCR test results ≥60 days apart, separated by ≥2 consecutive negative test results. The prevalence of chronic medical conditions, symptoms, and severe outcomes related to coronavirus disease 19 (COVID-19) illness were ascertained. The median age of patients was 64.5 years, 40% were Black, and 39% …

Functional Characterization Of T2d-Associated Snp Effects On Baseline And Er Stress-Responsive Β Cell Transcriptional Activation., Shubham Khetan, Susan Kales, Romy Kursawe, Alexandria Jillette, Jacob C Ulirsch, Steven K Reilly, Duygu Ucar, Ryan Tewhey, Michael L. Stitzel

Faculty Research 2021

Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at >250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 β cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions. We identify 1,982/6,621 (29.9%) SNP-containing elements that activate transcription in MIN6 and 879 SNP alleles that …

Comprehensive Characterization Of 536 Patient-Derived Xenograft Models Prioritizes Candidatesfor Targeted Treatment., Hua Sun, Song Cao, R Jay Mashl, Chia-Kuei Mo, Simone Zaccaria, Michael C Wendl, Sherri R Davies, Matthew H Bailey, Tina M Primeau, Jeremy Hoog, Jacqueline L Mudd, Dennis A Dean, Rajesh Patidar, Li Chen, Matthew A Wyczalkowski, Reyka G Jayasinghe, Fernanda Martins Rodrigues, Nadezhda V Terekhanova, Yize Li, Kian-Huat Lim, Andrea Wang-Gillam, Brian A Van Tine, Cynthia X Ma, Rebecca Aft, Katherine C Fuh, Julie K Schwarz, Jose P Zevallos, Sidharth V Puram, John F Dipersio, Nci Pdxnet Consortium, Brandi Davis-Dusenbery, Matthew J Ellis, Michael T Lewis, Michael A Davies, Meenhard Herlyn, Bingliang Fang, Jack A Roth, Alana L Welm, Bryan E Welm, Funda Meric-Bernstam, Feng Chen, Ryan C Fields, Shunqiang Li, Ramaswamy Govindan, James H Doroshow, Jeffrey A Moscow, Yvonne A Evrard, Jeffrey Chuang, Benjamin J Raphael, Li Ding, Carol J Bult, Peter N Robinson

Faculty Research 2021

Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications …

Tet2 Controls The Responses Of Β Cells To Inflammation In Autoimmune Diabetes., Jinxiu Rui, Songyan Deng, Ana Luisa Perdigoto, Gerald Ponath, Romy Kursawe, Nathan Lawlor, Tomokazu Sumida, Maya Levine-Ritterman, Michael L. Stitzel, David Pitt, Jun Lu, Kevan C Herold

Faculty Research 2021

β cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO β cells show reduced expression …

Glis1 Regulates Trabecular Meshwork Function And Intraocular Pressure And Is Associated With Glaucoma In Humans., K Saidas Nair, Chitrangda Srivastava, Robert V Brown, Swanand Koli, Hélène Choquet, Hong Soon Kang, Yien-Ming Kuo, Sara A Grimm, Caleb Sutherland, Alexandra Badea, G Allan Johnson, Yin Zhao, Jie Yin, Kyoko Okamoto, Graham Clark, Terete Borrás, Gulab Zode, Krishnakumar Kizhatil, Subhabrata Chakrabarti, Simon W M John, Eric Jorgenson, Anton M Jetten

Faculty Research 2021

Chronically elevated intraocular pressure (IOP) is the major risk factor of primary open-angle glaucoma, a leading cause of blindness. Dysfunction of the trabecular meshwork (TM), which controls the outflow of aqueous humor (AqH) from the anterior chamber, is the major cause of elevated IOP. Here, we demonstrate that mice deficient in the Krüppel-like zinc finger transcriptional factor GLI-similar-1 (GLIS1) develop chronically elevated IOP. Magnetic resonance imaging and histopathological analysis reveal that deficiency in GLIS1 expression induces progressive degeneration of the TM, leading to inefficient AqH drainage from the anterior chamber and elevated IOP. Transcriptome and cistrome analyses identified several glaucoma- …

Predictive Biomarkers For 5-Fluorouracil And Oxaliplatin-Based Chemotherapy In Gastric Cancers Via Profiling Of Patient-Derived Xenografts., Deukchae Na, Jeesoo Chae, Sung-Yup Cho, Wonyoung Kang, Ahra Lee, Seoyeon Min, Jinjoo Kang, Min Jung Kim, Jaeyong Choi, Woochan Lee, Dongjin Shin, Ahrum Min, Yu-Jin Kim, Kyung-Hun Lee, Tae-Yong Kim, Yun-Suhk Suh, Seong-Ho Kong, Hyuk-Joon Lee, Woo-Ho Kim, Hansoo Park, Seock-Ah Im, Han-Kwang Yang, Charles Lee, Jong-Il Kim

Faculty Research 2021

Gastric cancer (GC) is commonly treated by chemotherapy using 5-fluorouracil (5-FU) derivatives and platinum combination, but predictive biomarker remains lacking. We develop patient-derived xenografts (PDXs) from 31 GC patients and treat with a combination of 5-FU and oxaliplatin, to determine biomarkers associated with responsiveness. When the PDXs are defined as either responders or non-responders according to tumor volume change after treatment, the responsiveness of PDXs is significantly consistent with the respective clinical outcomes of the patients. An integrative genomic and transcriptomic analysis of PDXs reveals that pathways associated with cell-to-cell and cell-to-extracellular matrix interactions enriched among the non-responders in both …

The Age Presents Introduction To Geroscience Video Lecture Series., Alessandro Bitto, Mitchell B Lee, Cristal M Hill, Ron Korstanje, Matt Kaeberlein

Faculty Research 2021

The AGE Presents Introduction to Geroscience video lecture series is a collection of high-quality didactic video lectures and associated teaching materials focused on foundational topics in aging biology. The videos are made freely available on YouTube and are targeted toward an audience familiar with concepts learned in the first year of a college undergraduate biology/biomedical major. Members of the American Aging Association also receive the original lecture slides and lecture notes, with additional course materials to be developed in the future. We expect that these lectures will enhance understanding of geroscience among the general public while also providing tools that …

In Situ Chromatin Interaction Analysis Using Paired-End Tag Sequencing., Ping Wang, Yuliang Feng, Kun Zhu, Haoxi Chai, Ya-Ting Chang, Xiaofei Yang, Xiyuan Liu, Chen Shen, Eva Gega, Byoungkoo Lee, Minji Kim, Xiaoan Ruan, Yijun Ruan

Faculty Research 2021

Chromatin Interaction Analysis Using Paired-End Tag Sequencing (ChIA-PET) is an established method to map protein-mediated chromatin interactions. A limitation, however, is that it requires a hundred million cells per experiment, which hampers its broad application in biomedical research, particularly in studies in which it is impractical to obtain a large number of cells from rare samples. To reduce the required input cell number while retaining high data quality, we developed an in situ ChIA-PET protocol, which requires as few as 1 million cells. Here, we describe detailed step-by-step procedures for performing in situ ChIA-PET from cultured cells, including both an …

Profiling Variable-Number Tandem Repeat Variation Across Populations Using Repeat-Pangenome Graphs., Tsung-Yu Lu, Human Genome Structural Variation Consortium, Mark J P Chaisson, Charles Lee, Qihui Zhu

Faculty Research 2021

Variable number tandem repeats (VNTRs) are composed of consecutive repetitive DNA with hypervariable repeat count and composition. They include protein coding sequences and associations with clinical disorders. It has been difficult to incorporate VNTR analysis in disease studies that use short-read sequencing because the traditional approach of mapping to the human reference is less effective for repetitive and divergent sequences. In this work, we solve VNTR mapping for short reads with a repeat-pangenome graph (RPGG), a data structure that encodes both the population diversity and repeat structure of VNTR loci from multiple haplotype-resolved assemblies. We develop software to build a …

Homozygous Mtap Deletion In Primary Human Glioblastoma Is Not Associated With Elevation Of Methylthioadenosine., Yasaman Barekatain, Jeffrey J Ackroyd, Victoria C Yan, Sunada Khadka, Lin Wang, Ko-Chien Chen, Anton H Poral, Theresa Tran, Dimitra K Georgiou, Kenisha Arthur, Yu-Hsi Lin, Nikunj Satani, Elliot S Ballato, Eliot I Behr, Ana C Decarvalho, Roel G W Verhaak, John De Groot, Jason T Huse, John M Asara, Raghu Kalluri, Florian L Muller

Faculty Research 2021

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP's substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate …

Long Non-Coding Rnas And Their Targets As Potential Biomarkers In Breast Cancer., Maryam Khalid, Rehan Zafar Paracha, Maryum Nisar, Sumaira Malik, Salma Tariq, Iqra Arshad, Amnah Siddiqa, Zamir Hussain, Jamil Ahmad, Amjad Ali

Faculty Research 2021

Breast cancer is among the lethal types of cancer with a high mortality rate, globally. Its high prevalence can be controlled through improved analysis and identification of disease-specific biomarkers. Recently, long non-coding RNAs (lncRNAs) have been reported as key contributors of carcinogenesis and regulate various cellular pathways through post-transcriptional regulatory mechanisms. The specific aim of this study was to identify the novel interactions of aberrantly expressed genetic components in breast cancer by applying integrative analysis of publicly available expression profiles of both lncRNAs and mRNAs. Differential expression patterns were identified by comparing the breast cancer expression profiles of samples with …

Reduced Mitochondrial Dna And Oxphos Protein Content In Skeletal Muscle Of Children With Cerebral Palsy, Ferdinand Von Walden, Ivan J. Vechetti Jr., Davis A. Englund, Vandré C. Figueiredo, Rodrigo Fernandez-Gonzalo, Kevin A. Murach, Jessica Pingel, John J. Mccarthy, Per Stål, Eva Pontén

Physiology Faculty Publications

AIM: To provide a detailed gene and protein expression analysis related to mitochondrial biogenesis and assess mitochondrial content in skeletal muscle of children with cerebral palsy (CP).

METHOD: Biceps brachii muscle samples were collected from 19 children with CP (mean [SD] age 15y 4mo [2y 6mo], range 9-18y, 16 males, three females) and 10 typically developing comparison children (mean [SD] age 15y [4y], range 7-21y, eight males, two females). Gene expression (quantitative reverse transcription polymerase chain reaction [PCR]), mitochondrial DNA (mtDNA) to genomic DNA ratio (quantitative PCR), and protein abundance (western blotting) were analyzed. Microarray data sets (CP/aging/bed rest) were …

Endometrial Receptivity And Implantation Require Uterine Bmp Signaling Through An Acvr2a-Smad1/Smad5 Axis., Diana Monsivais, Takashi Nagashima, Renata Prunskaite-Hyyryläinen, Kaori Nozawa, Keisuke Shimada, Suni Tang, Clark Hamor, Julio E Agno, Fengju Chen, Ramya P Masand, Steven L Young, Chad J Creighton, Francesco J Demayo, Masahito Ikawa, Se-Jin Lee, Martin M Matzuk

Faculty Research 2021

During early pregnancy in the mouse, nidatory estrogen (E2) stimulates endometrial receptivity by activating a network of signaling pathways that is not yet fully characterized. Here, we report that bone morphogenetic proteins (BMPs) control endometrial receptivity via a conserved activin receptor type 2 A (ACVR2A) and SMAD1/5 signaling pathway. Mice were generated to contain single or double conditional deletion of SMAD1/5 and ACVR2A/ACVR2B receptors using progesterone receptor (PR)-cre. Female mice with SMAD1/5 deletion display endometrial defects that result in the development of cystic endometrial glands, a hyperproliferative endometrial epithelium during the window of implantation, and impaired apicobasal transformation that prevents …

Discovery Of Widespread Transcription Initiation At Microsatellites Predictable By Sequence-Based Deep Neural Network., Mathys Grapotte, Manu Saraswat, Chloé Bessière, Christophe Menichelli, Jordan A Ramilowski, Jessica Severin, Yoshihide Hayashizaki, Masayoshi Itoh, Michihira Tagami, Mitsuyoshi Murata, Miki Kojima-Ishiyama, Shohei Noma, Shuhei Noguchi, Takeya Kasukawa, Akira Hasegawa, Harukazu Suzuki, Hiromi Nishiyori-Sueki, Martin C Frith, Fantom Consortium, Clément Chatelain, Piero Carninci, Michiel J L De Hoon, Wyeth W Wasserman, Laurent Bréhélin, Charles-Henri Lecellier, Judith A. Blake, Carol J Bult

Faculty Research 2021

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep …

Functional Impact Of A Germline Ret Mutation In Alveolar Rhabdomyosarcoma., Noah E Berlow, Kenneth A Crawford, Carol J Bult, Christopher Noakes, Ido Sloma, Erin R Rudzinski, Charles Keller

Faculty Research 2021

Specific mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia type 2A, a hereditary syndrome characterized by tumorigenesis in multiple glandular elements. In rare instances, MEN2A-associated germline RET mutations have also occurred with non-MEN2A associated cancers. One such germline mutant RET mutation occurred concomitantly in a young adult diagnosed with alveolar rhabdomyosarcoma, a pediatric and young adult soft-tissue cancer with a generally poor prognosis. Although tumor tissue samples were initially unable to provide a viable cell culture for study, tumor tissues were sequenced for molecular characteristics. Through a hierarchical clustering approach, the index case sample was matched to …

Integrating Genomics And Metabolomics For Scalable Non-Ribosomal Peptide Discovery., Bahar Behsaz, Edna Bode, Alexey Gurevich, Yan-Ni Shi, Florian Grundmann, Deepa Acharya, Andrés Mauricio Caraballo-Rodríguez, Amina Bouslimani, Morgan Panitchpakdi, Annabell Linck, Changhui Guan, Julia Oh, Pieter C Dorrestein, Helge B Bode, Pavel A Pevzner, Hosein Mohimani

Faculty Research 2021

Non-Ribosomal Peptides (NRPs) represent a biomedically important class of natural products that include a multitude of antibiotics and other clinically used drugs. NRPs are not directly encoded in the genome but are instead produced by metabolic pathways encoded by biosynthetic gene clusters (BGCs). Since the existing genome mining tools predict many putative NRPs synthesized by a given BGC, it remains unclear which of these putative NRPs are correct and how to identify post-assembly modifications of amino acids in these NRPs in a blind mode, without knowing which modifications exist in the sample. To address this challenge, here we report NRPminer, …

Digital Technology Needs In Maternal Mental Health: A Qualitative Inquiry., Alexandra Zingg, Laura Carter, Deevakar Rogith, Amy Franklin, Sudhakar Selvaraj, Jerrie Refuerzo, Sahiti Myneni

Journal Articles

Digital technologies offer many opportunities to improve mental healthcare management for women seeking pre- and-postnatal care. They provide a discrete, practical medium that is well-suited for the sensitive nature of mental health. Women who are more prone to experiencing peripartum depression (PPD), such as those of low-socioeconomic background or in high-risk pregnancies, can benefit the most from such technologies. However, current digital interventions directed towards this population provide suboptimal support, and their responsiveness to end user needs is quite limited. Our objective is to understand the digital terrain of information needs for low-socioeconomic status women with high-risk pregnancies, specifically within …

User Testing Of A Diagnostic Decision Support System With Machine-Assisted Chart Review To Facilitate Clinical Genomic Diagnosis., Alanna Kulchak Rahm, Nephi A Walton, Lynn K Feldman, Conner Jenkins, Troy Jenkins, Thomas N Person, Joeseph Peterson, Jonathon C Reynolds, Peter N Robinson, Makenzie A Woltz, Marc S Williams, Michael M Segal

Faculty Research 2021

OBJECTIVES: There is a need in clinical genomics for systems that assist in clinical diagnosis, analysis of genomic information and periodic reanalysis of results, and can use information from the electronic health record to do so. Such systems should be built using the concepts of human-centred design, fit within clinical workflows and provide solutions to priority problems.

METHODS: We adapted a commercially available diagnostic decision support system (DDSS) to use extracted findings from a patient record and combine them with genomic variant information in the DDSS interface. Three representative patient cases were created in a simulated clinical environment for user …

Generalized And Transferable Patient Language Representation For Phenotyping With Limited Data., Yuqi Si, Elmer V Bernstam, Kirk Roberts

Journal Articles

The paradigm of representation learning through transfer learning has the potential to greatly enhance clinical natural language processing. In this work, we propose a multi-task pre-training and fine-tuning approach for learning generalized and transferable patient representations from medical language. The model is first pre-trained with different but related high-prevalence phenotypes and further fine-tuned on downstream target tasks. Our main contribution focuses on the impact this technique can have on low-prevalence phenotypes, a challenging task due to the dearth of data. We validate the representation from pre-training, and fine-tune the multi-task pre-trained models on low-prevalence phenotypes including 38 circulatory diseases, 23 …

The National Covid Cohort Collaborative (N3c): Rationale, Design, Infrastructure, And Deployment., Melissa A Haendel, Christopher G Chute, Tellen D Bennett, David A Eichmann, Justin Guinney, Warren A Kibbe, Philip R O Payne, Emily R Pfaff, Peter N Robinson, Joel H Saltz, Heidi Spratt, Christine Suver, John Wilbanks, Adam B Wilcox, Andrew E Williams, Chunlei Wu, Clair Blacketer, Robert L Bradford, James J Cimino, Marshall Clark, Evan W Colmenares, Patricia A Francis, Davera Gabriel, Alexis Graves, Raju Hemadri, Stephanie S Hong, George Hripscak, Dazhi Jiao, Jeffrey G Klann, Kristin Kostka, Adam M Lee, Harold P Lehmann, Lora Lingrey, Robert T Miller, Michele Morris, Shawn N Murphy, Karthik Natarajan, Matvey B Palchuk, Usman Sheikh, Harold Solbrig, Shyam Visweswaran, Anita Walden, Kellie M Walters, Griffin M Weber, Xiaohan Tanner Zhang, Richard L Zhu, Benjamin Amor, Andrew T Girvin, Amin Manna, Nabeel Qureshi, Michael G Kurilla, Sam G Michael, Lili M Portilla, Joni L Rutter, Christopher P Austin, Ken R Gersing

Faculty Research 2021

OBJECTIVE: Coronavirus disease 2019 (COVID-19) poses societal challenges that require expeditious data and knowledge sharing. Though organizational clinical data are abundant, these are largely inaccessible to outside researchers. Statistical, machine learning, and causal analyses are most successful with large-scale data beyond what is available in any given organization. Here, we introduce the National COVID Cohort Collaborative (N3C), an open science community focused on analyzing patient-level data from many centers.

MATERIALS AND METHODS: The Clinical and Translational Science Award Program and scientific community created N3C to overcome technical, regulatory, policy, and governance barriers to sharing and harmonizing individual-level clinical data. We …

A Novel Cd4+ Ctl Subtype Characterized By Chemotaxis And Inflammation Is Involved In The Pathogenesis Of Graves' Orbitopathy., Yue Wang, Ziyi Chen, Tingjie Wang, Hui Guo, Yufeng Liu, Ningxin Dang, Shiqian Hu, Liping Wu, Chengsheng Zhang, Kai Ye, Bingyin Shi

Faculty Research 2021

Graves' orbitopathy (GO), the most severe manifestation of Graves' hyperthyroidism (GH), is an autoimmune-mediated inflammatory disorder, and treatments often exhibit a low efficacy. CD4+ T cells have been reported to play vital roles in GO progression. To explore the pathogenic CD4+ T cell types that drive GO progression, we applied single-cell RNA sequencing (scRNA-Seq), T cell receptor sequencing (TCR-Seq), flow cytometry, immunofluorescence and mixed lymphocyte reaction (MLR) assays to evaluate CD4+ T cells from GO and GH patients. scRNA-Seq revealed the novel GO-specific cell type CD4+ cytotoxic T lymphocytes (CTLs), which are characterized by chemotactic and inflammatory features. The clonal …

Neoadjuvant Anti-Ox40 (Medi6469) Therapy In Patients With Head And Neck Squamous Cell Carcinoma Activates And Expands Antigen-Specific Tumor-Infiltrating T Cells., Rebekka Duhen, Carmen Ballesteros-Merino, Alexandra K Frye, Eric Tran, Venkatesh Rajamanickam, Shu-Ching Chang, Yoshinobu Koguchi, Carlo Bifulco, Brady Bernard, Rom Leidner, Brendan Curti, Bernard A Fox, Walter Urba, Richard Bryan Bell, Andrew D Weinberg

Articles, Abstracts, and Reports

Despite the success of checkpoint blockade in some cancer patients, there is an unmet need to improve outcomes. Targeting alternative pathways, such as costimulatory molecules (e.g. OX40, GITR, and 4-1BB), can enhance T cell immunity in tumor-bearing hosts. Here we describe the results from a phase Ib clinical trial (NCT02274155) in which 17 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) received a murine anti-human OX40 agonist antibody (MEDI6469) prior to definitive surgical resection. The primary endpoint was to determine safety and feasibility of the anti-OX40 neoadjuvant treatment. The secondary objective was to assess the effect of …

Disparities In Sars-Cov-2 Positivity Rates: Associations With Race And Ethnicity, Harvey W Kaufman, Justin K Niles, David B. Nash

College of Population Health Faculty Papers

Numerous reports indicate that African Americans and Latinos are being affected disproportionately by coronavirus disease 2019 (COVID-19). Positivity rates have not been analyzed on scale because only 4 states report race/ethnicity as part of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. Previous studies also have had little ability to control for many known risk factors to better identify the effects of COVID-19 on racial and ethnic communities. Using test results from a large national reference laboratory database that included patients from all 50 states and the District of Columbia, this study compared positivity rates for SARS-CoV-2 nucleic acid amplification …

The Circadian Cryptochrome, Cry1, Is A Pro-Tumorigenic Factor That Rhythmically Modulates Dna Repair., Ayesha A Shafi, Chris M Mcnair, Jennifer J Mccann, Mohammed Alshalalfa, Anton Shostak, Tesa M Severson, Yanyun Zhu, Andre Bergman, Nicolas Gordon, Amy C Mandigo, Saswati N Chand, Peter Gallagher, Emanuela Dylgjeri, Talya S Laufer, Irina A Vasilevskaya, Matthew J Schiewer, Michael Brunner, Felix Y Feng, Wilbert Zwart, Karen E Knudsen

Department of Cancer Biology Faculty Papers

Mechanisms regulating DNA repair processes remain incompletely defined. Here, the circadian factor CRY1, an evolutionally conserved transcriptional coregulator, is identified as a tumor specific regulator of DNA repair. Key findings demonstrate that CRY1 expression is androgen-responsive and associates with poor outcome in prostate cancer. Functional studies and first-in-field mapping of the CRY1 cistrome and transcriptome reveal that CRY1 regulates DNA repair and the G2/M transition. DNA damage stabilizes CRY1 in cancer (in vitro, in vivo, and human tumors ex vivo), which proves critical for efficient DNA repair. Further mechanistic investigation shows that stabilized CRY1 temporally regulates expression of genes required …

Multiwalled Carbon Nanotubes Co-Delivering Sorafenib And Epidermal Growth Factor Receptor Sirna Enhanced Tumor-Suppressing Effect On Liver Cancer., Zhili Wen, Yuliang Feng, Youwen Hu, Lingyan Lian, Hongyan Huang, Li Guo, Shanwen Chen, Qian Yang, Moran Zhang, Lijun Wan, Kedong Xu, Degejirifu, Xiaohua Yan

Faculty Research 2021

OBJECTIVE: This study aimed to investigate the effects of multiwalled carbon nanotubes (MWNTs) co-delivering sorafenib (Sor) and epidermal growth factor receptor (EGFR) siRNA (MWNT/Sor/siRNA) on tumor growth in liver cancer (LC).

RESULTS: MWNT/Sor/siRNA was proved to possess increased Sor release, high siRNA stability, and enhanced cellular uptake. In addition, MWNT treatment has few effects on cell proliferation and apoptosis in HepG2 cells; however, MWNT/Sor/siRNA treatment significantly inhibited clone number and induced cell apoptosis, which shows a more favorable antitumor effect than MWNT/Sor and free Sor and free siRNA in HepG2 cells. Moreover MWNT/Sor/siRNA treatment has the most significant antitumor effect …

The Gene Ontology Resource: Enriching A Gold Mine., Gene Ontology Consortium, Judith A. Blake, Mary E. Dolan, Harold J. Drabkin, David P. Hill

Faculty Research 2021

The Gene Ontology Consortium (GOC) provides the most comprehensive resource currently available for computable knowledge regarding the functions of genes and gene products. Here, we report the advances of the consortium over the past two years. The new GO-CAM annotation framework was notably improved, and we formalized the model with a computational schema to check and validate the rapidly increasing repository of 2838 GO-CAMs. In addition, we describe the impacts of several collaborations to refine GO and report a 10% increase in the number of GO annotations, a 25% increase in annotated gene products, and over 9,400 new scientific articles …