Digital Commons Network^™

Combined Crispri And Proteomics Screening Reveal A Cohesin-Ctcf-Bound Allele Contributing To Increased Expression Of Ruvbl1 And Prostate Cancer Progression, Yijun Tian, Dandan Dong, Zixian Wang, Lang Wu, Jong Y Park, Gong-Hong Wei, Liang Wang

Faculty, Staff and Student Publications

Genome-wide association studies along with expression quantitative trait locus (eQTL) mapping have identified hundreds of single-nucleotide polymorphisms (SNPs) and their target genes in prostate cancer (PCa), yet functional characterization of these risk loci remains challenging. To screen for potential regulatory SNPs, we designed a CRISPRi library containing 9,133 guide RNAs (gRNAs) to cover 2,166 candidate SNP loci implicated in PCa and identified 117 SNPs that could regulate 90 genes for PCa cell growth advantage. Among these, rs60464856 was covered by multiple gRNAs significantly depleted in screening (FDR < 0.05). Pooled SNP association analysis in the PRACTICAL and FinnGen cohorts showed significantly higher PCa risk for the rs60464856 G allele (p value = 1.2 × 10

Genotype Error Due To Low-Coverage Sequencing Induces Uncertainty In Polygenic Scoring, Ella Petter, Yi Ding, Kangcheng Hou, Arjun Bhattacharya, Alexander Gusev, Noah Zaitlen, Bogdan Pasaniuc

Faculty, Staff and Student Publications

Polygenic scores (PGSs) have emerged as a standard approach to predict phenotypes from genotype data in a wide array of applications from socio-genomics to personalized medicine. Traditional PGSs assume genotype data to be error-free, ignoring possible errors and uncertainties introduced from genotyping, sequencing, and/or imputation. In this work, we investigate the effects of genotyping error due to low coverage sequencing on PGS estimation. We leverage SNP array and low-coverage whole-genome sequencing data (lcWGS, median coverage 0.04×) of 802 individuals from the Dana-Farber PROFILE cohort to show that PGS error correlates with sequencing depth (p = 1.2 × 10

Moving The Pendulum For Glioblastoma Treatment: One Injection At A Time, Xizi Wu, Christopher Alvarez-Breckenridge

Faculty, Staff and Student Publications

Despite advances, glioblastoma is characterized by exceptionally high rates of recurrence and resistance to therapy. This commentary remarks on the recently published article by Maruyama et al, which reports the PMDA review of G47Δ injection for malignant glioma, in which the efficacy and safety results of G47Δ were evaluated and approval conditions clarified.

Facs-Based Genome-Wide Crispr Screens Define Key Regulators Of Dna Damage Signaling Pathways, Min Huang, Fuwen Yao, Litong Nie, Chao Wang, Dan Su, Huimin Zhang, Siting Li, Mengfan Tang, Xu Feng, Bin Yu, Zhen Chen, Shimin Wang, Ling Yin, Lisha Mou, Traver Hart, Junjie Chen

Faculty, Staff and Student Publications

DNA damage-activated signaling pathways are critical for coordinating multiple cellular processes, which must be tightly regulated to maintain genome stability. To provide a comprehensive and unbiased perspective of DNA damage response (DDR) signaling pathways, we performed 30 fluorescence-activated cell sorting (FACS)-based genome-wide CRISPR screens in human cell lines with antibodies recognizing distinct endogenous DNA damage signaling proteins to identify critical regulators involved in DDR. We discovered that proteasome-mediated processing is an early and prerequisite event for cells to trigger camptothecin- and etoposide-induced DDR signaling. Furthermore, we identified PRMT1 and PRMT5 as modulators that regulate ATM protein level. Moreover, we discovered …

Two Structurally Defined Aβ Polymorphs Promote Different Pathological Changes In Susceptible Mice, Ruben Gomez-Gutierrez, Ujjayini Ghosh, Wai-Ming Yau, Nazaret Gamez, Katherine Do, Carlos Kramm, Hamid Shirani, Laura Vegas-Gomez, Jonathan Schulz, Ines Moreno-Gonzalez, Antonia Gutierrez, K Peter R Nilsson, Robert Tycko, Claudio Soto, Rodrigo Morales

Faculty, Staff and Student Publications

Misfolded Aβ is involved in the progression of Alzheimer's disease (AD). However, the role of its polymorphic variants or conformational strains in AD pathogenesis is not fully understood. Here, we study the seeding properties of two structurally defined synthetic misfolded Aβ strains (termed 2F and 3F) using in vitro and in vivo assays. We show that 2F and 3F strains differ in their biochemical properties, including resistance to proteolysis, binding to strain-specific dyes, and in vitro seeding. Injection of these strains into a transgenic mouse model produces different pathological features, namely different rates of aggregation, formation of different plaque types, …

Mavs Signaling Is Required For Preventing Persistent Chikungunya Heart Infection And Chronic Vascular Tissue Inflammation, Maria G Noval, Sophie N Spector, Eric Bartnicki, Franco Izzo, Navneet Narula, Stephen T Yeung, Payal Damani-Yokota, M Zahidunnabi Dewan, Valeria Mezzano, Bruno A Rodriguez-Rodriguez, Cynthia Loomis, Kamal M Khanna, Kenneth A Stapleford

Faculty, Staff and Student Publications

Chikungunya virus (CHIKV) infection has been associated with severe cardiac manifestations, yet, how CHIKV infection leads to heart disease remains unknown. Here, we leveraged both mouse models and human primary cardiac cells to define the mechanisms of CHIKV heart infection. Using an immunocompetent mouse model of CHIKV infection as well as human primary cardiac cells, we demonstrate that CHIKV directly infects and actively replicates in cardiac fibroblasts. In immunocompetent mice, CHIKV is cleared from cardiac tissue without significant damage through the induction of a local type I interferon response from both infected and non-infected cardiac cells. Using mice deficient in …

Spatial Distribution Of Mycobacterium Tuberculosis Mrna And Secreted Antigens In Acid-Fast Negative Human Antemortem And Resected Tissue, Job Dekker, Frank Alber, Sarah Aufmkolk, Brian J Beliveau, Benoit G Bruneau, Andrew S Belmont, Lacramioara Bintu, Alistair Boettiger, Riccardo Calandrelli, Christine M Disteche, David M Gilbert, Thomas Gregor, Anders S Hansen, Bo Huang, Danwei Huangfu, Reza Kalhor, Christina S Leslie, Wenbo Li, Yun Li, Jian Ma, William S Noble, Peter J Park, Jennifer E Phillips-Cremins, Katherine S Pollard, Susanne M Rafelski, Bing Ren, Yijun Ruan, Yaron Shav-Tal, Yin Shen, Jay Shendure, Xiaokun Shu, Caterina Strambio-De-Castillia, Anastassiia Vertii, Huaiying Zhang, Sheng Zhong

Faculty, Staff and Student Publications

The four-dimensional nucleome (4DN) consortium studies the architecture of the genome and the nucleus in space and time. We summarize progress by the consortium and highlight the development of technologies for (1) mapping genome folding and identifying roles of nuclear components and bodies, proteins, and RNA, (2) characterizing nuclear organization with time or single-cell resolution, and (3) imaging of nuclear organization. With these tools, the consortium has provided over 2,000 public datasets. Integrative computational models based on these data are starting to reveal connections between genome structure and function. We then present a forward-looking perspective and outline current aims to …

Novel Murine Glioblastoma Models That Reflect The Immunotherapy Resistance Profile Of A Human Disease, Chao-Hsien Chen, Renee L Chin, Genevieve P Hartley, Spencer T Lea, Brian J Engel, Cheng-En Hsieh, Rishika Prasad, Jason Roszik, Takashi Shingu, Gregory A Lizee, Amy B Heimberger, Steven W Millward, Jian Hu, David S Hong, Michael A Curran

Faculty, Staff and Student Publications

BACKGROUND: The lack of murine glioblastoma models that mimic the immunobiology of human disease has impeded basic and translational immunology research. We, therefore, developed murine glioblastoma stem cell lines derived from Nestin-CreERT2QkL/L; Trp53L/L; PtenL/L (QPP) mice driven by clinically relevant genetic mutations common in human glioblastoma. This study aims to determine the immune sensitivities of these QPP lines in immunocompetent hosts and their underlying mechanisms.

METHODS: The differential responsiveness of QPP lines was assessed in the brain and flank in untreated, anti-PD-1, or anti-CTLA-4 treated mice. The impact of genomic landscape on the responsiveness of each tumor was measured through …

Proteogenomic Analysis Of Chemo-Refractory High-Grade Serous Ovarian Cancer, Shrabanti Chowdhury, Jacob J Kennedy, Richard G Ivey, Oscar D Murillo, Noshad Hosseini, Xiaoyu Song, Francesca Petralia, Anna Calinawan, Sara R Savage, Anna B Berry, Boris Reva, Umut Ozbek, Azra Krek, Weiping Ma, Felipe Da Veiga Leprevost, Jiayi Ji, Seungyeul Yoo, Chenwei Lin, Uliana J Voytovich, Yajue Huang, Sun-Hee Lee, Lindsay Bergan, Travis D Lorentzen, Mehdi Mesri, Henry Rodriguez, Andrew N Hoofnagle, Zachary T Herbert, Alexey I Nesvizhskii, Bing Zhang, Jeffrey R Whiteaker, David Fenyo, Wilson Mckerrow, Joshua Wang, Stephan C Schürer, Vasileios Stathias, X Steven Chen, Mary Helen Barcellos-Hoff, Timothy K Starr, Boris J Winterhoff, Andrew C Nelson, Samuel C Mok, Scott H Kaufmann, Charles Drescher, Marcin Cieslik, Pei Wang, Michael J Birrer, Amanda G Paulovich

Faculty, Staff and Student Publications

To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) …

Genetic Insights Into Resting Heart Rate And Its Role In Cardiovascular Disease, Yordi J Van De Vegte, Ruben N Eppinga, M Yldau Van Der Ende, Yanick P Hagemeijer, Yuvaraj Mahendran, Elias Salfati, Albert V Smith, Vanessa Y Tan, Dan E Arking, Ioanna Ntalla, Emil V Appel, Claudia Schurmann, Jennifer A Brody, Rico Rueedi, Ozren Polasek, Gardar Sveinbjornsson, Cecile Lecoeur, Claes Ladenvall, Jing Hua Zhao, Aaron Isaacs, Lihua Wang, Jian'an Luan, Shih-Jen Hwang, Nina Mononen, Kirsi Auro, Anne U Jackson, Lawrence F Bielak, Linyao Zeng, Nabi Shah, Maria Nethander, Archie Campbell, Tuomo Rankinen, Sonali Pechlivanis, Lu Qi, Wei Zhao, Federica Rizzi, Toshiko Tanaka, Antonietta Robino, Massimiliano Cocca, Leslie Lange, Martina Müller-Nurasyid, Carolina Roselli, Weihua Zhang, Marcus E Kleber, Xiuqing Guo, Henry J Lin, Francesca Pavani, Tessel E Galesloot, Raymond Noordam, Yuri Milaneschi, Katharina E Schraut, Marcel Den Hoed, Frauke Degenhardt, Stella Trompet, Marten E Van Den Berg, Giorgio Pistis, Yih-Chung Tham, Stefan Weiss, Xueling S Sim, Hengtong L Li, Peter J Van Der Most, Ilja M Nolte, Leo-Pekka Lyytikäinen, M Abdullah Said, Daniel R Witte, Carlos Iribarren, Lenore Launer, Susan M Ring, Paul S De Vries, Peter Sever, Allan Linneberg, Erwin P Bottinger, Sandosh Padmanabhan, Bruce M Psaty, Nona Sotoodehnia, Ivana Kolcic, Dcct/Edic Research Group, David O Arnar, Daniel F Gudbjartsson, Hilma Holm, Beverley Balkau, Claudia T Silva, Christopher H Newton-Cheh, Kjell Nikus, Perttu Salo, Karen L Mohlke, Patricia A Peyser, Heribert Schunkert, Mattias Lorentzon, Jari Lahti, Dabeeru C Rao, Marilyn C Cornelis, Jessica D Faul, Jennifer A Smith, Katarzyna Stolarz-Skrzypek, Stefania Bandinelli, Maria Pina Concas, Gianfranco Sinagra, Thomas Meitinger, Melanie Waldenberger, Moritz F Sinner, Konstantin Strauch, Graciela E Delgado, Kent D Taylor, Jie Yao, Luisa Foco, Olle Melander, Jacqueline De Graaf, Renée De Mutsert, Eco J C De Geus, Åsa Johansson, Peter K Joshi, Lars Lind, Andre Franke, Peter W Macfarlane, Kirill V Tarasov, Nicholas Tan, Stephan B Felix, E-Shyong Tai, Debra Q Quek, Harold Snieder, Johan Ormel, Martin Ingelsson, Cecilia Lindgren, Andrew P Morris, Olli T Raitakari, Torben Hansen, Themistocles Assimes, Vilmundur Gudnason, Nicholas J Timpson, Alanna C Morrison, Patricia B Munroe, David P Strachan, Niels Grarup, Ruth J F Loos, Susan R Heckbert, Peter Vollenweider, Caroline Hayward, Kari Stefansson, Philippe Froguel, Leif Groop, Nicholas J Wareham, Cornelia M Van Duijn, Mary F Feitosa, Christopher J O'Donnell, Mika Kähönen, Markus Perola, Michael Boehnke, Sharon L R Kardia, Jeanette Erdmann, Colin N A Palmer, Claes Ohlsson, David J Porteous, Johan G Eriksson, Claude Bouchard, Susanne Moebus, Peter Kraft, David R Weir, Daniele Cusi, Luigi Ferrucci, Sheila Ulivi, Giorgia Girotto, Adolfo Correa, Stefan Kääb, Annette Peters, John C Chambers, Jaspal S Kooner, Winfried März, Jerome I Rotter, Andrew A Hicks, J Gustav Smith, Lambertus A L M Kiemeney, Dennis O Mook-Kanamori, Brenda W J H Penninx, Ulf Gyllensten, James F Wilson, Stephen Burgess, Johan Sundström, Wolfgang Lieb, J Wouter Jukema, Mark Eijgelsheim, Edward L M Lakatta, Ching-Yu Cheng, Marcus Dörr, Tien-Yin Wong, Charumathi Sabanayagam, Albertine J Oldehinkel, Harriette Riese, Terho Lehtimäki, Niek Verweij, Pim Van Der Harst

Faculty, Staff and Student Publications

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample …

Alternative Splicing Of Ceacam1 By Hypoxia-Inducible Factor-1Α Enhances Tolerance To Hepatic Ischemia In Mice And Humans, Kenneth J Dery, Hidenobu Kojima, Shoichi Kageyama, Kentaro Kadono, Hirofumi Hirao, Brian Cheng, Yuan Zhai, Douglas G Farmer, Fady M Kaldas, Xiaoyi Yuan, Holger K Eltzschig, Jerzy W Kupiec-Weglinski

Faculty, Staff and Student Publications

Although alternative splicing (AS) drives transcriptional responses and cellular adaptation to environmental stresses, its contributions in organ transplantation have not been appreciated. We have shown that carcinoembryonic antigen-related cell adhesion molecule (Ceacam1; CD66a), a transmembrane biliary glycoprotein expressed in epithelial, endothelial, and immune cells, determines donor liver transplant quality. Here, we studied how AS of Ceacam1 affects ischemia-reperfusion injury (IRI) in mouse and human livers. We found that the short cytoplasmic isoform Ceacam1-S increased during early acute and late resolution phases of warm IRI injury in mice. Transfection of Ceacam1-deficient mouse hepatocytes with adenoviral Ceacam1-S mitigated hypoxia-induced loss of …

Superficial Thrombophlebitis In Ipsilateral Breast After Covid-19 Vaccination, Zhichao Zhou, Patricia Q Tran, Alyssa M Adams, Kristopher Kieft, John A Breier, Caroline S Fortunato, Cody S Sheik, Julie A Huber, Meng Li, Gregory J Dick, Karthik Anantharaman

Faculty, Staff and Student Publications

In globally distributed deep-sea hydrothermal vent plumes, microbiomes are shaped by the redox energy landscapes created by reduced hydrothermal vent fluids mixing with oxidized seawater. Plumes can disperse over thousands of kilometers and their characteristics are determined by geochemical sources from vents, e.g., hydrothermal inputs, nutrients, and trace metals. However, the impacts of plume biogeochemistry on the oceans are poorly constrained due to a lack of integrated understanding of microbiomes, population genetics, and geochemistry. Here, we use microbial genomes to understand links between biogeography, evolution, and metabolic connectivity, and elucidate their impacts on biogeochemical cycling in the deep sea. Using …

Radiotherapy Use And Incidence Of Locoregional Recurrence In Patients With Favorable-Risk, Node-Positive Breast Cancer Enrolled In The Swog S1007 Trial, Reshma Jagsi, William E Barlow, Wendy A Woodward, Eileen Connolly, Reshma Mahtani, Dean Shumway, Corey Speers, Shane R Stecklein, Youssef Zeidan, Hong Zhang, Priyanka Sharma, Lajos Pusztai, Gabriel N Hortobagyi, Kevin Kalinsky

Faculty, Staff and Student Publications

IMPORTANCE: Little is known about regional nodal irradiation (RNI) practice patterns or rates of locoregional recurrence (LRR) with and without RNI in patients with limited nodal disease and favorable biology treated with modern surgical and systemic therapy, including approaches that de-escalate those latter treatments.

OBJECTIVE: To investigate how often patients with low-recurrence score breast cancer with 1 to 3 nodes involved receive RNI, incidence and predictors of LRR, and associations between locoregional therapy and disease-free survival.

DESIGN, SETTING, AND PARTICIPANTS: In this secondary analysis of the SWOG S1007 trial, patients with hormone receptor-positive, ERBB2-negative breast cancer, and a Oncotype DX …

Lipid Droplet Biogenesis And Functions In Health And Disease, Armella Zadoorian, Ximing Du, Hongyuan Yang

Faculty, Staff and Student Publications

Ubiquitous yet unique, lipid droplets are intracellular organelles that are increasingly being recognized for their versatility beyond energy storage. Advances uncovering the intricacies of their biogenesis and the diversity of their physiological and pathological roles have yielded new insights into lipid droplet biology. Despite these insights, the mechanisms governing the biogenesis and functions of lipid droplets remain incompletely understood. Moreover, the causal relationship between the biogenesis and function of lipid droplets and human diseases is poorly resolved. Here, we provide an update on the current understanding of the biogenesis and functions of lipid droplets in health and disease, highlighting a …

Knowledge Representation And Management 2022: Findings In Ontology Development And Applications, Jean Charlet, Licong Cui, Section Editors For The Imia Yearbook Section On Knowledge Representation And Management

Faculty, Staff and Student Publications

OBJECTIVES: To select, present, and summarize the best papers in 2022 for the Knowledge Representation and Management (KRM) section of the International Medical Informatics Association (IMIA) Yearbook.

METHODS: We conducted PubMed queries and followed the IMIA Yearbook guidelines for performing biomedical informatics literature review to select the best papers in KRM published in 2022.

RESULTS: We retrieved 1,847 publications from PubMed. We nominated 15 candidate best papers, and two of them were finally selected as the best papers in the KRM section. The topics covered by the candidate papers include ontology and knowledge graph creation, ontology applications, ontology quality assurance, …

Fibroblast-Derived Pi16 Sustains Inflammatory Pain Via Regulation Of Cd206+ Myeloid Cells, Rachelle Garrity, Neha Arora, Md Areeful Haque, Drew Weis, Ronnie T Trinh, Sanjay V Neerukonda, Susmita Kumari, Ibdanelo Cortez, Eroboghene E Ubogu, Rajasekaran Mahalingam, Diana Tavares-Ferreira, Theodore J Price, Annemieke Kavelaars, Cobi J Heijnen, Andrew J Shepherd

Faculty, Staff and Student Publications

Originally identified in fibroblasts, Protease Inhibitor (PI)16 was recently shown to be crucial for the development of neuropathic pain via effects on blood-nerve barrier permeability and leukocyte infiltration, though its impact on inflammatory pain has not been established. Using the complete Freund’s Adjuvant inflammatory pain model, we show that Pi16-/- mice are protected against sustained inflammatory pain. Accordingly, intrathecal delivery of a PI16 neutralizing antibody in wild-type mice prevented sustained CFA pain. In contrast to neuropathic pain models, we did not observe any changes in blood-nerve barrier permeability due to PI16 deletion. Instead, Pi16-/- mice display reduced macrophage density …

Evaluation Of The Clinical And Radiographic Effectiveness Of Treating Peri-Implant Bone Defects With A New Biphasic Calcium Phosphate Bone Graft: A Prospective, Multicenter Randomized Controlled Trial, Jae-Hong Lee, Hyun-Wook An, Jae-Seung Im, Woo-Joo Kim, Dong-Won Lee, Jeong-Ho Yun

Faculty, Staff and Student Publications

PURPOSE: Biphasic calcium phosphate (BCP), a widely used biomaterial for bone regeneration, contains synthetic hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP), the ratio of which can be adjusted to modulate the rate of degradation. The aim of this study was to evaluate the clinical and radiographic benefits of reconstructing peri-implant bone defects with a newly developed BCP consisting of 40% β-TCP and 60% HA compared to demineralized bovine bone mineral (DBBM).

METHODS: This prospective, multicenter, parallel, single-blind randomized controlled trial was conducted at the periodontology departments of 3 different dental hospitals. Changes in clinical (defect width and height) and radiographic (augmented …

Diverse Clonal Fates Emerge Upon Drug Treatment Of Homogeneous Cancer Cells, Yogesh Goyal, Gianna T Busch, Maalavika Pillai, Jingxin Li, Ryan H Boe, Emanuelle I Grody, Manoj Chelvanambi, Ian P Dardani, Benjamin Emert, Nicholas Bodkin, Jonas Braun, Dylan Fingerman, Amanpreet Kaur, Naveen Jain, Pavithran T Ravindran, Ian A Mellis, Karun Kiani, Gretchen M Alicea, Mitchell E Fane, Syeda Subia Ahmed, Haiyin Li, Yeqing Chen, Cedric Chai, Jessica Kaster, Russell G Witt, Rossana Lazcano, Davis R Ingram, Sarah B Johnson, Khalida Wani, Margaret C Dunagin, Alexander J Lazar, Ashani T Weeraratna, Jennifer A Wargo, Meenhard Herlyn, Arjun Raj

Faculty, Staff and Student Publications

Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells1-7. Molecular differences in rare individual cells in the initial population enable certain cells to become resistant to therapy7-9; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically and …

Cell-Type-Specific Prediction Of 3d Chromatin Organization Enables High-Throughput In Silico Genetic Screening, Jimin Tan, Nina Shenker-Tauris, Javier Rodriguez-Hernaez, Eric Wang, Theodore Sakellaropoulos, Francesco Boccalatte, Palaniraja Thandapani, Jane Skok, Iannis Aifantis, David Fenyö, Bo Xia, Aristotelis Tsirigos

Faculty, Staff and Student Publications

Investigating how chromatin organization determines cell-type-specific gene expression remains challenging. Experimental methods for measuring three-dimensional chromatin organization, such as Hi-C, are costly and have technical limitations, restricting their broad application particularly in high-throughput genetic perturbations. We present C.Origami, a multimodal deep neural network that performs de novo prediction of cell-type-specific chromatin organization using DNA sequence and two cell-type-specific genomic features-CTCF binding and chromatin accessibility. C.Origami enables in silico experiments to examine the impact of genetic changes on chromatin interactions. We further developed an in silico genetic screening approach to assess how individual DNA elements may contribute to chromatin organization and …

Clinical, Endoscopic, And Histopathologic Gastrointestinal Disease In An American Cohort With Behçet's Disease, Bryan F Curtin, Kareen L Hill, Sumona Bhattacharya, Astin Powers, Aradhana Venkatesan, Preet Bagi, Elizabeth Joyal, Meghna Alimchandani, Raphaela Goldbach-Mansky, Peter Grayson, Martha Quezado, Cailin Sibley, Theo Heller

Faculty, Staff and Student Publications

INTRODUCTION: Behçet's disease (BD) is a chronic systemic vasculitis characterized by oral and genital ulcers, uveitis, and skin lesions. Patients with BD may develop gastrointestinal (GI) disease; however, characterization of GI disease in American cohorts is lacking. In this article, we present clinical, endoscopic, and histopathologic GI findings in an American cohort of patients with BD.

METHODS: Patients with established BD were evaluated prospectively at the National Institutes of Health. Demographic and clinical data were collected including BD manifestations and GI symptoms. Endoscopy with histopathologic sampling was performed for both clinical and research indications with written consent.

RESULTS: Eighty-three patients …

Prospective Evaluation Of In Vivo And Phantom Repeatability And Reproducibility Of Diffusion-Weighted Mri Sequences On 15 T Mri-Linear Accelerator (Mr-Linac) And Mr Simulator Devices For Head And Neck Cancers, Brigid A Mcdonald, Travis Salzillo, Samuel Mulder, Sara Ahmed, Alex Dresner, Kathryn Preston, Renjie He, John Christodouleas, Abdallah S R Mohamed, Marielle Philippens, Petra Van Houdt, Daniela Thorwarth, Jihong Wang, Amita Shukla Dave, Michael Boss, Clifton D Fuller

Faculty, Staff and Student Publications

INTRODUCTION: Diffusion-weighted imaging (DWI) on MRI-linear accelerator (MR-linac) systems can potentially be used for monitoring treatment response and adaptive radiotherapy in head and neck cancers (HNC) but requires extensive validation. We performed technical validation to compare six total DWI sequences on an MR-linac and MR simulator (MR sim) in patients, volunteers, and phantoms.

METHODS: Ten human papillomavirus-positive oropharyngeal cancer patients and ten healthy volunteers underwent DWI on a 1.5 T MR-linac with three DWI sequences: echo planar imaging (EPI), split acquisition of fast spin echo signals (SPLICE), and turbo spin echo (TSE). Volunteers were also imaged on a 1.5 T …

Multi-Parametric Mri For Radiotherapy Simulation, Tian Li, Jihong Wang, Yingli Yang, Carri K Glide-Hurst, Ning Wen, Jing Cai

Faculty, Staff and Student Publications

Magnetic resonance imaging (MRI) has become an important imaging modality in the field of radiotherapy (RT) in the past decade, especially with the development of various novel MRI and image-guidance techniques. In this review article, we will describe recent developments and discuss the applications of multi-parametric MRI (mpMRI) in RT simulation. In this review, mpMRI refers to a general and loose definition which includes various multi-contrast MRI techniques. Specifically, we will focus on the implementation, challenges, and future directions of mpMRI techniques for RT simulation.

Outcomes Of Young Adults (Aged ≤ 40 Years) With Newly Diagnosed Multiple Myeloma After Up-Front Autologous Stem Cell Transplant, Oren Pasvolsky, Curtis Marcoux, Denái R Milton, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Hans C Lee, Krina K Patel, Partow Kebriaei, Priti Tewari, Lindsay Crawford-Suber, Sheeba K Thomas, Donna M Weber, Robert Z Orlowski, Elizabeth J Shpall, Richard E Champlin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Multiple myeloma (MM) primarily affects older patients. There are scarce data on the outcomes of young adults undergoing autologous transplantation (auto-HCT). In this single-centre analysis, we included 117 younger patients, with a median age of 37 years (range 22-40) at transplant. Seventeen (15%) patients had high-risk cytogenetics. Before transplant, 10% of patients achieved ≥CR and 44% achieved ≥VGPR. At best post-transplant response, 56% and 77% of patients achieved ≥CR and ≥VGPR respectively. With a median follow-up for survivors of 72.6 months (range 0.9-238.0), median PFS and OS were 43.1 months (95% CI 31.2-65.0) and 146.6 months (95% CI 100.0-208.1) respectively. …

A Review Of A Strategic Roadmapping Exercise To Advance Clinical Translation Of Photoacoustic Imaging: From Current Barriers To Future Adoption, Hisham Assi, Rui Cao, Madhura Castelino, Ben Cox, Fiona J Gilbert, Janek Gröhl, Kurinchi Gurusamy, Lina Hacker, Aoife M Ivory, James Joseph, Ferdinand Knieling, Martin J Leahy, Ledia Lilaj, Srirang Manohar, Igor Meglinski, Carmel Moran, Andrea Murray, Alexander A Oraevsky, Mark D Pagel, Manojit Pramanik, Jason Raymond, Mithun Kuniyil Ajith Singh, William C Vogt, Lihong Wang, Shufan Yang, Members Of Ipasc, Sarah E Bohndiek

Faculty, Staff and Student Publications

Photoacoustic imaging (PAI), also referred to as optoacoustic imaging, has shown promise in early-stage clinical trials in a range of applications from inflammatory diseases to cancer. While the first PAI systems have recently received regulatory approvals, successful adoption of PAI technology into healthcare systems for clinical decision making must still overcome a range of barriers, from education and training to data acquisition and interpretation. The International Photoacoustic Standardisation Consortium (IPASC) undertook an community exercise in 2022 to identify and understand these barriers, then develop a roadmap of strategic plans to address them. Here, we outline the nature and scope of …

Prame And Lef1 In Combined Deep Penetrating Nevus And Combined Blue Nevus: Utility And Pitfall, Kaitlin Vanderbeck, Aimi T Rothrock, Woo Cheal Cho, Priyadharsini Nagarajan, Phyu P Aung, Courtney Hudgens, Roland L Bassett, Doina Ivan, Victor G Prieto, Jonathan L Curry, Carlos A Torres-Cabala

Faculty, Staff and Student Publications

Deep penetrating nevi (DPN), particularly those showing combined features, or combined deep penetrating nevi (CDPN), may show histopathological resemblance to blue nevus (BN) and melanoma. Preferentially Expressed Antigen in MElanoma (PRAME) is a marker that helps distinguish melanoma from benign melanocytic lesions. Lymphoid enhancer-binding factor 1 (LEF1) has been proposed to be used in conjunction with β-catenin for diagnosis of DPN. The immunohistochemical expression of PRAME and LEF1 was evaluated in 10 DPN (including 6 CDPN and 2 DPN-like proliferations with atypical features), 16 BN (including combined and cellular BN), and 2 melanomas with features of DPN or BN. PRAME …

The Initial Age-Associated Decline In Early T-Cell Progenitors Reflects Fewer Pre-Thymic Progenitors And Altered Signals In The Bone Marrow And Thymus Microenvironments, Jayashree Srinivasan, Anusha Vasudev, Carolyn Shasha, Hilary J Selden, Encarnacion Perez, Bonnie Lafleur, Shripad A Sinari, Andreas Krueger, Ellen R Richie, Lauren I R Ehrlich

Faculty, Staff and Student Publications

Age-related thymus involution results in decreased T-cell production, contributing to increased susceptibility to pathogens and reduced vaccine responsiveness. Elucidating mechanisms underlying thymus involution will inform strategies to restore thymopoiesis with age. The thymus is colonized by circulating bone marrow (BM)-derived thymus seeding progenitors (TSPs) that differentiate into early T-cell progenitors (ETPs). We find that ETP cellularity declines as early as 3 months (3MO) of age in mice. This initial ETP reduction could reflect changes in thymic stromal niches and/or pre-thymic progenitors. Using a multicongenic progenitor transfer approach, we demonstrate that the number of functional TSP/ETP niches does not diminish with …

Probiotic-Derived Ecto-5'-Nucleotidase Produces Anti-Inflammatory Adenosine Metabolites In Treg-Deficient Scurfy Mice, Yuying Liu, Shabba A Armbrister, Beanna Okeugo, Tingting W Mills, Rhea C Daniel, Jee-Hwan Oh, Jan-Peter Van Pijkeren, Evelyn S Park, Zeina M Saleh, Sharmistha Lahiri, Stefan Roos, Jmarc Rhoads

Faculty, Staff and Student Publications

Probiotic Limosilactobacillus reuteri DSM 17938 (DSM 17938) prolongs the survival of Treg-deficient scurfy (SF) mice and reduces multiorgan inflammation by a process requiring adenosine receptor 2A (A2A) on T cells. We hypothesized that L. reuteri-derived ecto-5'-nucleotidase (ecto-5'NT) activity acts to generate adenosine, which may be a central mediator for L. reuteri protection in SF mice. We evaluated DSM 17938-5'NT activity and the associated adenosine and inosine levels in plasma, gut, and liver of SF mice. We examined orally fed DSM 17938, DSM 17938Δ5NT (with a deleted 5'NT gene), and DSM 32846 (BG-R46) (a naturally selected strain derived from DSM 17938). …

Low-Grade Intestinal Inflammation Two Decades After Pelvic Radiotherapy, Sravani Devarakonda, Annika Thorsell, Per Hedenström, Azar Rezapour, Lisen Heden, Sanghita Banerjee, Malin E V Johansson, George Birchenough, Amelie Toft Morén, Karin Gustavsson, Viktor Skokic, Victor L Pettersson, Fei Sjöberg, Marie Kalm, Mohammad Al Masri, Michaela Ekh, Henrik Fagman, Mats Wolving, Rosie Perkins, Rodrigo A Morales, Francisca Castillo, Eduardo J Villablanca, Ulf Yrlid, Karin Bergmark, Gunnar Steineck, Cecilia Bull

Faculty, Staff and Student Publications

BACKGROUND: Radiotherapy is effective in the treatment of cancer but also causes damage to non-cancerous tissue. Pelvic radiotherapy may produce chronic and debilitating bowel symptoms, yet the underlying pathophysiology is still undefined. Most notably, although pelvic radiotherapy causes an acute intestinal inflammation there is no consensus on whether the late-phase pathophysiology contains an inflammatory component or not. To address this knowledge gap, we examined the potential presence of a chronic inflammation in mucosal biopsies from irradiated pelvic cancer survivors.

METHODS: We biopsied 24 cancer survivors two to 20 years after pelvic radiotherapy, and four non-irradiated controls. Using tandem mass tag …

Role Of Circulating Mitochondria In Venous Thrombosis In Glioblastoma, Ricardo Gonzalez-Delgado, Nina M Muñoz, Wendolyn Carlos-Alcalde, Min Soon Cho, Hani Lee, Jeff Jin, Victoria Serpas, Olga Gorlova, Rahul A Sheth, Vahid Afshar-Kharghan

Faculty, Staff and Student Publications

Background: Many patients with glioblastoma multiforme (GBM) develop deep venous thrombosis or pulmonary emboli. Cell-free circulating mitochondria increase after brain injury and are associated with coagulopathy.

Objectives: This study evaluated whether mitochondria play a role in the GBM-induced hypercoagulable state.

Methods: We examined the correlation between cell-free circulating mitochondria and venous thrombosis in patients with GBM and the impact of mitochondria on venous thrombosis in mice with inferior vena cava stenosis.

Results: Using plasma samples of 82 patients with GBM, we found that patients with GBM had a higher number of mitochondria in their plasma (GBM with venous thromboembolism [VTE],: …

T-Cell Receptor Beta Variable Gene Polymorphism Predicts Immune-Related Adverse Events During Checkpoint Blockade Immunotherapy, Bettzy Stephen, Joud Hajjar, Shrutii Sarda, Dzifa Yawa Duose, Jeffrey M Conroy, Carl Morrison, Anas Alshawa, Mingxuan Xu, Abdulrazzak Zarifa, Sapna P Patel, Ying Yuan, Evan Kwiatkowski, Linghua Wang, Jordi Rodon Ahnert, Siqing Fu, Funda Meric-Bernstam, Geoffrey M Lowman, Timothy Looney, Aung Naing

Faculty, Staff and Student Publications

BACKGROUND: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the …