Digital Commons Network^™

Cfp1 Governs Uterine Epigenetic Landscapes To Intervene In Progesterone Responses For Uterine Physiology And Suppression Of Endometriosis, Seung Chel Yang, Mira Park, Kwon-Ho Hong, Hyeonwoo La, Chanhyeok Park, Peike Wang, Gaizhen Li, Qionghua Chen, Youngsok Choi, Francesco J Demayo, John P Lydon, David G Skalnik, Hyunjung J Lim, Seok-Ho Hong, So Hee Park, Yeon Sun Kim, Hye-Ryun Kim, Haengseok Song

Faculty, Staff and Students Publications

Progesterone (P4) is required for the preparation of the endometrium for a successful pregnancy. P4 resistance is a leading cause of the pathogenesis of endometrial disorders like endometriosis, often leading to infertility; however, the underlying epigenetic cause remains unclear. Here we demonstrate that CFP1, a regulator of H3K4me3, is required for maintaining epigenetic landscapes of P4-progesterone receptor (PGR) signaling networks in the mouse uterus. Cfp1f/f;Pgr-Cre (Cfp1d/d) mice showed impaired P4 responses, leading to complete failure of embryo implantation. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 regulates uterine mRNA profiles not only in H3K4me3-dependent …

The Landscape Of Tolerated Genetic Variation In Humans And Primates, Hong Gao, Tobias Hamp, Jeffrey Ede, Joshua G Schraiber, Jeremy Mcrae, Moriel Singer-Berk, Yanshen Yang, Anastasia S D Dietrich, Petko P Fiziev, Lukas F K Kuderna, Laksshman Sundaram, Yibing Wu, Aashish Adhikari, Yair Field, Chen Chen, Serafim Batzoglou, Francois Aguet, Gabrielle Lemire, Rebecca Reimers, Daniel Balick, Mareike C Janiak, Martin Kuhlwilm, Joseph D Orkin, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rousselle, Felipe Ennes Silva, Lidia Agueda, Julie Blanc, Marta Gut, Dorien De Vries, Ian Goodhead, R Alan Harris, Muthuswamy Raveendran, Axel Jensen, Idriss S Chuma, Julie E Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Fabiano R De Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, João Valsecchi Do Amaral, Mariluce Messias, Maria N F Da Silva, Mihir Trivedi, Rogerio Rossi, Tomas Hrbek, Nicole Andriaholinirina, Clément J Rabarivola, Alphonse Zaramody, Clifford J Jolly, Jane Phillips-Conroy, Gregory Wilkerson, Christian Abee, Joe H Simmons, Eduardo Fernandez-Duque, Sree Kanthaswamy, Fekadu Shiferaw, Dongdong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D Keyyu, Sascha Knauf, Minh D Le, Esther Lizano, Stefan Merker, Arcadi Navarro, Thomas Bataillon, Tilo Nadler, Chiea Chuen Khor, Jessica Lee, Patrick Tan, Weng Khong Lim, Andrew C Kitchener, Dietmar Zinner, Ivo Gut, Amanda Melin, Katerina Guschanski, Mikkel Heide Schierup, Robin M D Beck, Govindhaswamy Umapathy, Christian Roos, Jean P Boubli, Monkol Lek, Shamil Sunyaev, Anne O'Donnell-Luria, Heidi L Rehm, Jinbo Xu, Jeffrey Rogers, Tomas Marques-Bonet, Kyle Kai-How Farh

Faculty, Staff and Students Publications

INTRODUCTION:

Millions of people have received genome and exome sequencing to date, a collective effort that has illuminated for the first time the vast catalog of small genetic differences that distinguish us as individuals within our species. However, the effects of most of these genetic variants remain unknown, limiting their clinical utility and actionability. New approaches that can accurately discern disease-causing from benign mutations and interpret genetic variants on a genome-wide scale would constitute a meaningful initial step towards realizing the potential of personalized genomic medicine.

RATIONALE:

As a result of the short evolutionary distance between humans and nonhuman primates, …

Evaluating The Use Of Blood Pressure Polygenic Risk Scores Across Race/Ethnic Background Groups, Nuzulul Kurniansyah, Matthew O Goodman, Alyna T Khan, Jiongming Wang, Elena Feofanova, Joshua C Bis, Kerri L Wiggins, Jennifer E Huffman, Tanika Kelly, Tali Elfassy, Xiuqing Guo, Walter Palmas, Henry J Lin, Shih-Jen Hwang, Yan Gao, Kendra Young, Gregory L Kinney, Jennifer A Smith, Bing Yu, Simin Liu, Sylvia Wassertheil-Smoller, Joann E Manson, Xiaofeng Zhu, Yii-Der Ida Chen, I-Te Lee, C Charles Gu, Donald M Lloyd-Jones, Sebastian Zöllner, Myriam Fornage, Charles Kooperberg, Adolfo Correa, Bruce M Psaty, Donna K Arnett, Carmen R Isasi, Stephen S Rich, Robert C Kaplan, Susan Redline, Braxton D Mitchell, Nora Franceschini, Daniel Levy, Jerome I Rotter, Alanna C Morrison, Tamar Sofer

Faculty, Staff and Student Publications

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs …

A Global Catalog Of Whole-Genome Diversity From 233 Primate Species\, Lukas F K Kuderna, Hong Gao, Mareike C Janiak, Martin Kuhlwilm, Joseph D Orkin, Thomas Bataillon, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rousselle, Felipe Ennes Silva, Lidia Agueda, Julie Blanc, Marta Gut, Dorien De Vries, Ian Goodhead, R Alan Harris, Muthuswamy Raveendran, Axel Jensen, Idrissa S Chuma, Julie E Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Joshua G Schraiber, Fabiano R De Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, João Valsecchi, Malu Messias, Maria N F Da Silva, Mihir Trivedi, Rogerio Rossi, Tomas Hrbek, Nicole Andriaholinirina, Clément J Rabarivola, Alphonse Zaramody, Clifford J Jolly, Jane Phillips-Conroy, Gregory Wilkerson, Christian Abee, Joe H Simmons, Eduardo Fernandez-Duque, Sree Kanthaswamy, Fekadu Shiferaw, Dongdong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D Keyyu, Sascha Knauf, Minh D Le, Esther Lizano, Stefan Merker, Arcadi Navarro, Tilo Nadler, Chiea Chuen Khor, Jessica Lee, Patrick Tan, Weng Khong Lim, Andrew C Kitchener, Dietmar Zinner, Ivo Gut, Amanda D Melin, Katerina Guschanski, Mikkel Heide Schierup, Robin M D Beck, Govindhaswamy Umapathy, Christian Roos, Jean P Boubli, Jeffrey Rogers, Kyle Kai-How Farh, Tomas Marques Bonet

Faculty, Staff and Students Publications

The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology and is urgent given severe threats these species are facing. Here, we present high-coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families …

Curated And Harmonized Gut Microbiome 16s Rrna Amplicon Data From Dietary Fiber Intervention Studies In Humans, Cynthia I Rodriguez, Ali Keshavarzian, Bruce R Hamaker, Feitong Liu, Genelle R Lunken, Heather Rasmussen, Hongwei Zhou, Julien Tap, Kelly S Swanson, Maria Ukhanova, Marion Leclerc, Martin Gotteland, Paola Navarrete, Petia Kovatcheva-Datchary, Wendy J Dahl, Jennifer B H Martiny

Faculty, Staff and Student Publications

Next generation amplicon sequencing has created a plethora of data from human microbiomes. The accessibility to this scientific data and its corresponding metadata is important for its reuse, to allow for new discoveries, verification of published results, and serving as path for reproducibility. Dietary fiber consumption has been associated with a variety of health benefits that are thought to be mediated by gut microbiota. To enable direct comparisons of the response of the gut microbiome to fiber, we obtained 16S rRNA sequencing data and its corresponding metadata from 11 fiber intervention studies for a total of 2,368 samples. We provide …

An Epidemic Model With Time Delays Determined By The Infectivity And Disease Durations, Masoud Saade, Samiran Ghosh, Malay Banerjee, Vitaly Volpert

Faculty, Staff and Student Publications

We propose an epidemiological model with distributed recovery and death rates. It represents an integrodifferential system of equations for susceptible, exposed, infectious, recovered and dead compartments. This model can be reduced to the conventional ODE model under the assumption that recovery and death rates are uniformly distributed in time during disease duration. Another limiting case, where recovery and death rates are given by the delta-function, leads to a new point-wise delay model with two time delays corresponding to the infectivity period and disease duration. Existence and positiveness of solutions for the distributed delay model and point-wise delay model are proved. …

Long-Term Outcomes Of Bevacizumab And Chemoradiation For Locoregionally Advanced Nasopharyngeal Carcinoma: A Nonrandomized Controlled Trial, Nancy Y. Lee, Jonathan Harris, John Kim, Adam Garden, James Mechalakos, David G. Pfister, Anthony T.C. Chan, Kenneth Hu, A. Dimitrios Colevas, Steven Frank, George Shenouda, Voichita Bar-Ad, John N. Waldron, Paul M. Harari, Adam Raben, Pedro Torres-Saavedra, Quynh-Thu Le

Department of Radiation Oncology Faculty Papers

IMPORTANCE: The long-term outcomes associated with adding bevacizumab, a vascular endothelial growth factor inhibitor, to standard chemoradiation have continued to be favorable for a group of patients with locoregionally advanced nasopharyngeal carcinoma (NPC).

OBJECTIVE: To assess long-term toxic effects and clinical outcomes associated with chemotherapy, radiation therapy (RT), and bevacizumab for NPC.

DESIGN, SETTING, AND PARTICIPANTS: This single-arm phase II nonrandomized controlled trial was conducted by the National Cancer Trials Network group and NRG Oncology (formerly Radiation Therapy Oncology Group), with accrual from December 13, 2006, to February 5, 2009, and data analysis from June 26 to July 1, 2019. …

Association Of Circulating Markers With Cognitive Decline After Radiation Therapy For Brain Metastasis, Kristin Huntoon, S Keith Anderson, Karla V Ballman, Erin Twohy, Katharine Dooley, Wen Jiang, Yi An, Jing Li, Christina Von Roemeling, Yaqing Qie, Owen A Ross, Jane H Cerhan, Anthony C Whitton, Jeffrey N Greenspoon, Ian F Parney, Jonathan B Ashman, Jean-Paul Bahary, Constantinos Hadjipanayis, James J Urbanic, Elana Farace, Deepak Khuntia, Nadia N Laack, Paul D Brown, David Roberge, Betty Y S Kim

Faculty, Staff and Student Publications

BACKGROUND: A recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline.

METHODS: In this retrospective analysis of prospectively collected …

Evaluating The Use Of Blood Pressure Polygenic Risk Scores Across Race/Ethnic Background Groups, Nuzulul Kurniansyah, C Charles Gu, Et Al.

2020-Current year OA Pubs

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs …

Machine Learning Reveals Lipidome Remodeling Dynamics In A Mouse Model Of Ovarian Cancer, Olatomiwa O Bifarin, Samyukta Sah, David A Gaul, Samuel G Moore, Ruihong Chen, Murugesan Palaniappan, Jaeyeon Kim, Martin M Matzuk, Facundo M Fernández

Faculty, Staff and Students Publications

Ovarian cancer (OC) is one of the deadliest cancers affecting the female reproductive system. It may present little or no symptoms at the early stages and typically unspecific symptoms at later stages. High-grade serous ovarian cancer (HGSC) is the subtype responsible for most ovarian cancer deaths. However, very little is known about the metabolic course of this disease, particularly in its early stages. In this longitudinal study, we examined the temporal course of serum lipidome changes using a robust HGSC mouse model and machine learning data analysis. Early progression of HGSC was marked by increased levels of phosphatidylcholines and phosphatidylethanolamines. …

Rare Penetrant Mutations Confer Severe Risk Of Common Diseases, Petko P Fiziev, Jeremy Mcrae, Jacob C Ulirsch, Jacqueline S Dron, Tobias Hamp, Yanshen Yang, Pierrick Wainschtein, Zijian Ni, Joshua G Schraiber, Hong Gao, Dylan Cable, Yair Field, Francois Aguet, Marc Fasnacht, Ahmed Metwally, Jeffrey Rogers, Tomas Marques-Bonet, Heidi L Rehm, Anne O'Donnell-Luria, Amit V Khera, Kyle Kai-How Farh

Faculty, Staff and Students Publications

We examined 454,712 exomes for genes associated with a wide spectrum of complex traits and common diseases and observed that rare, penetrant mutations in genes implicated by genome-wide association studies confer ~10-fold larger effects than common variants in the same genes. Consequently, an individual at the phenotypic extreme and at the greatest risk for severe, early-onset disease is better identified by a few rare penetrant variants than by the collective action of many common variants with weak effects. By combining rare variants across phenotype-associated genes into a unified genetic risk model, we demonstrate superior portability across diverse global populations compared …

Phylogenomic Analyses Provide Insights Into Primate Evolution, Yong Shao, Long Zhou, Fang Li, Lan Zhao, Bao-Lin Zhang, Feng Shao, Jia-Wei Chen, Chun-Yan Chen, Xupeng Bi, Xiao-Lin Zhuang, Hong-Liang Zhu, Jiang Hu, Zongyi Sun, Xin Li, Depeng Wang, Iker Rivas-González, Sheng Wang, Yun-Mei Wang, Wu Chen, Gang Li, Hui-Meng Lu, Yang Liu, Lukas F K Kuderna, Kyle Kai-How Farh, Peng-Fei Fan, Li Yu, Ming Li, Zhi-Jin Liu, George P Tiley, Anne D Yoder, Christian Roos, Takashi Hayakawa, Tomas Marques-Bonet, Jeffrey Rogers, Peter D Stenson, David N Cooper, Mikkel Heide Schierup, Yong-Gang Yao, Ya-Ping Zhang, Wen Wang, Xiao-Guang Qi, Guojie Zhang, Dong-Dong Wu

Faculty, Staff and Students Publications

Comparative analysis of primate genomes within a phylogenetic context is essential for understanding the evolution of human genetic architecture and primate diversity. We present such a study of 50 primate species spanning 38 genera and 14 families, including 27 genomes first reported here, with many from previously less well represented groups, the New World monkeys and the Strepsirrhini. Our analyses reveal heterogeneous rates of genomic rearrangement and gene evolution across primate lineages. Thousands of genes under positive selection in different lineages play roles in the nervous, skeletal, and digestive systems and may have contributed to primate innovations and adaptations. Our …

Simultaneous Evaluation Of Treatment Efficacy And Toxicity For Bispecific T-Cell Engager Therapeutics In A Humanized Mouse Model., Jiwon Yang, Jing Jiao, Kyle Draheim, Guoxiang Yang, Hongyuan Yang, Li-Chin Yao, Leonard D. Shultz, Dale L Greiner, Deepa Rajagopal, Sandrine Vessillier, Curtis C Maier, Sunish Mohanan, Danying Cai, Mingshan Cheng, Michael A Brehm, James G. Keck

Faculty Research 2023

Immuno-oncology (IO)-based therapies such as checkpoint inhibitors, bi-specific antibodies, and CAR-T-cell therapies have shown significant success in the treat- ment of several cancer indications. However, these therapies can result in the de- velopment of severe adverse events, including cytokine release syndrome (CRS). Currently, there is a paucity of in vivo models that can evaluate dose-response relationships for both tumor control and CRS-related safety issues. We tested an in vivo PBMC humanized mouse model to assess both treatment efficacy against specific tumors and the concurrent cytokine release profiles for individual human donors after treatment with a CD19xCD3 bispecific T-cell engager (BiTE). …

Variation In Histone Configurations Correlates With Gene Expression Across Nine Inbred Strains Of Mice., Anna L. Tyler, Catrina Spruce, Romy Kursawe, Annat Haber, Robyn L Ball, Wendy A Pitman, Alexander D Fine, Narayanan Raghupathy, Michael Walker, Vivek M. Philip, Christopher L. Baker, J Matthew Mahoney, Gary Churchill, Jennifer J. Trowbridge, Michael L. Stitzel, Kenneth Paigen, Petko M. Petkov, Gregory W. Carter

Faculty Research 2023

The diversity outbred (DO) mice and their inbred founders are widely used models of human disease. However, although the genetic diversity of these mice has been well documented, their epigenetic diversity has not. Epigenetic modifications, such as histone modifications and DNA methylation, are important regulators of gene expression, and as such are a critical mechanistic link between genotype and phenotype. Therefore, creating a map of epigenetic modifications in the DO mice and their founders is an important step toward understanding mechanisms of gene regulation and the link to disease in this widely used resource. To this end, we performed a …

From Bridge To Destination? Ethical Considerations Related To Withdrawal Of Ecmo Support Over The Objections Of Capacitated Patients, Andrew Childress, Trevor Bibler, Bryanna Moore, Ryan H Nelson, Joelle Robertson-Preidler, Olivia Schuman, Janet Malek

Faculty and Staff Publications

Extracorporeal membrane oxygenation (ECMO) is typically viewed as a time-limited intervention-a bridge to recovery or transplant-not a destination therapy. However, some patients with decision-making capacity request continued ECMO support despite a poor prognosis for recovery and lack of viability as a transplant candidate. In response, critical care teams have asked for guidance regarding the ethical permissibility of unilateral withdrawal over the objections of a capacitated patient. In this article, we evaluate several ethical arguments that have been made in favor of withdrawal, including distributive justice, quality of life, patients' rights, professional integrity, and the Equivalence Thesis. We find that existing …

A Guide To The Brain Initiative Cell Census Network Data Ecosystem, Michael Hawrylycz, Maryann E Martone, Giorgio A Ascoli, Jan G Bjaalie, Hong-Wei Dong, Satrajit S Ghosh, Jesse Gillis, Ronna Hertzano, David R Haynor, Patrick R Hof, Yongsoo Kim, Ed Lein, Yufeng Liu, Jeremy A Miller, Partha P Mitra, Eran Mukamel, Lydia Ng, David Osumi-Sutherland, Hanchuan Peng, Patrick L Ray, Raymond Sanchez, Aviv Regev, Alex Ropelewski, Richard H Scheuermann, Shawn Zheng Kai Tan, Carol L Thompson, Timothy Tickle, Hagen Tilgner, Merina Varghese, Brock Wester, Owen White, Hongkui Zeng, Brian Aevermann, David Allemang, Seth Ament, Thomas L Athey, Cody Baker, Katherine S Baker, Pamela M Baker, Anita Bandrowski, Samik Banerjee, Prajal Bishwakarma, Ambrose Carr, Min Chen, Roni Choudhury, Jonah Cool, Heather Creasy, Florence D'Orazi, Kylee Degatano, Benjamin Dichter, Song-Lin Ding, Tim Dolbeare, Joseph R Ecker, Rongxin Fang, Jean-Christophe Fillion-Robin, Timothy P Fliss, James Gee, Tom Gillespie, Nathan Gouwens, Guo-Qiang Zhang, Yaroslav O Halchenko, Nomi L Harris, Brian R Herb, Houri Hintiryan, Gregory Hood, Sam Horvath, Bingxing Huo, Dorota Jarecka, Shengdian Jiang, Farzaneh Khajouei, Elizabeth A Kiernan, Huseyin Kir, Lauren Kruse, Changkyu Lee, Boudewijn Lelieveldt, Yang Li, Hanqing Liu, Lijuan Liu, Anup Markuhar, James Mathews, Kaylee L Mathews, Chris Mezias, Michael I Miller, Tyler Mollenkopf, Shoaib Mufti, Christopher J Mungall, Joshua Orvis, Maja A Puchades, Lei Qu, Joseph P Receveur, Bing Ren, Nathan Sjoquist, Brian Staats, Daniel Tward, Cindy T J Van Velthoven, Quanxin Wang, Fangming Xie, Hua Xu, Zizhen Yao, Zhixi Yun, Yun Renee Zhang, W Jim Zheng, Brian Zingg

Faculty, Staff and Student Publications

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman …

The Management Of Hepatocellular Carcinoma. Current Expert Opinion And Recommendations Derived From The 24th Esmo/World Congress On Gastrointestinal Cancer, Barcelona, 2022, Michel Ducreux, Ghassan K. Abou-Alfa, Tanios S. Bekaii-Saab, Jordan D. Berlin, Andrés Cervantes, Thierry De Baere, Cathy Eng, Peter Galle, Sharlene Gill, Thomas Gruenberger, Karin Haustermans, Angela Lamarca, Pierre Laurent-Puig, Josep M. Llovet, Florian Lordick, Teresa Macarulla, Deborah Mukherji, Kei Muro, Radka Obermannova, Juan Manuel O'Connor, Eileen O'Reilly, Pia Österlund, Philip A. Philip, Gerald Prager, Erika Ruiz-Garcia, Bruno Sangro, Thomas Seufferlein, Josep Tabernero, Chris Verslype, Harpreet Wasan, Eric Van Cutsem

Hematology/Oncology Articles

This article summarises expert discussion on the management of patients with hepatocellular carcinoma (HCC), which took place during the 24th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, July 2022. A multidisciplinary approach is mandatory to ensure an optimal diagnosis and staging of HCC, planning of curative and therapeutic options, including surgical, embolisation, ablative strategies, or systemic therapy. Furthermore, in many patients with HCC, underlying liver cirrhosis represents a challenge and influences the therapeutic options.

Ift74 Variants Cause Skeletal Ciliopathy And Motile Cilia Defects In Mice And Humans., Zeineb Bakey, Oscar A. Cabrera, Julia Hoefele, Dinu Antony, Kaman Wu, Michael W. Stuck, Dimitra Micha, Thibaut Eguether, Abigail O. Smith, Nicole N. Van Der Wel, Matias Wagner, Lara Strittmatter, Philip L. Beales, Julie A. Jonassen, Isabelle Thiffault, Maxime Cadieux-Dion, Laura Boyes, Saba Sharif, Beyhan Tüysüz, Desiree Dunstheimer, Hans W M Niessen, William Devine, Cecilia W. Lo, Hannah M. Mitchison, Miriam Schmidts, Gregory J. Pazour

Manuscripts, Articles, Book Chapters and Other Papers

Motile and non-motile cilia play critical roles in mammalian development and health. These organelles are composed of a 1000 or more unique proteins, but their assembly depends entirely on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). In mammals, malfunction of non-motile cilia due to IFT dysfunction results in complex developmental phenotypes that affect most organs. In contrast, disruption of motile cilia function causes subfertility, disruption of the left-right body axis, and recurrent airway infections with progressive lung damage. In this work, we characterize allele specific phenotypes resulting from IFT74 dysfunction in human …

Climate Change Imperils Pediatric Health: Child Advocacy Through Fossil Fuel Divestment., Sandra H. Jee, Elizabeth Friedman, Ruth A. Etzel, Vi T. Nguyen, Todd L. Sack, Kathi J. Kemper

Manuscripts, Articles, Book Chapters and Other Papers

Climate change poses an existential threat to children's health. Divestment of ownership stakes in fossil fuel companies is one tool available to pediatricians to address climate change. Pediatricians are trusted messengers regarding children's health and therefore bear a unique responsibility to advocate for climate and health policies that affect children. Among the impacts of climate change on pediatric patients are allergic rhinitis and asthma; heat-related illnesses; premature birth; injuries from severe storms and fires; vector-borne diseases; and mental illnesses. Children are disproportionately affected as well by climate-related displacement of populations, drought, water shortages, and famine. The human-generated burning of fossil …

Long Noncoding Rna Expression Independently Predicts Outcome In Pediatric Acute Myeloid Leukemia., Jason E. Farrar, Jenny L. Smith, Megan Othus, Benjamin J. Huang, Yi-Cheng Wang, Rhonda Ries, Tiffany Hylkema, Era L. Pogosova-Agadjanyan, Sneha Challa, Amanda Leonti, Timothy I. Shaw, Timothy J. Triche, Alan S. Gamis, Richard Aplenc, E Anders Kolb, Xiaotu Ma, Derek L. Stirewalt, Todd A. Alonzo, Soheil Meshinchi

Manuscripts, Articles, Book Chapters and Other Papers

Purpose: Optimized strategies for risk classification are essential to tailor therapy for patients with biologically distinctive disease. Risk classification in pediatric acute myeloid leukemia (pAML) relies on detection of translocations and gene mutations. Long noncoding RNA (lncRNA) transcripts have been shown to associate with and mediate malignant phenotypes in acute myeloid leukemia (AML) but have not been comprehensively evaluated in pAML.

Methods: To identify lncRNA transcripts associated with outcomes, we evaluated the annotated lncRNA landscape by transcript sequencing of 1,298 pediatric and 96 adult AML specimens. Upregulated lncRNAs identified in the pAML training set were used to establish a regularized …

Irf7 And Unc93b1 Variants In An Infant With Recurrent Herpes Simplex Virus Infection., Megan H. Tucker, Wei Yu, Heather Menden, Sheng Xia, Carl F. Schreck, Margaret Gibson, Daniel A. Louiselle, T Pastinen, Nikita Raje, Venkatesh Sampath

Manuscripts, Articles, Book Chapters and Other Papers

Neonatal herpes simplex virus (HSV) infection is a devastating disease with substantial morbidity and mortality. The genetic basis of susceptibility to HSV in neonates remains undefined. We evaluated a male infant with neonatal skin/eye/mouth (SEM) HSV-1 disease, who had complete recovery after acyclovir but developed HSV-1 encephalitis at 1 year of age. An immune workup showed an anergic PBMC cytokine response to TLR3 stimulation but no other TLRs. Exome sequencing identified rare missense variants in IFN-regulatory factor 7 (IRF7) and UNC-93 homolog B1 (UNC93B1). PBMC single-cell RNA-Seq done during childhood revealed decreased expression of several innate immune genes and a …

5s Rrna Pseudogene Transcripts Are Associated With Interferon Production And Inflammatory Responses In Alcohol-Associated Hepatitis, Jianguo Wu, Adam Kim, Xiaoqin Wu, Semanti Ray, Daniela S Allende, Nicole Welch, Annette Bellar, Jaividhya Dasarathy, Srinivasan Dasarathy, Laura E Nagy

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Interferon (IFN) signaling is critical to the pathogenesis of alcohol-associated hepatitis (AH), yet the mechanisms for activation of this system are elusive. We hypothesize that host-derived 5S rRNA pseudogene (RNA5SP) transcripts regulate IFN production and modify immunity in AH.

APPROACH AND RESULTS: Mining of transcriptomic datasets revealed that in patients with severe alcohol-associated hepatitis (sAH), hepatic expression of genes regulated by IFNs was perturbed and gene sets involved in IFN production were enriched. RNA5SP transcripts were also increased and correlated with expression of type I IFNs. Interestingly, inflammatory mediators upregulated in sAH, but not in other liver …

Camonsertib In Dna Damage Response-Deficient Advanced Solid Tumors: Phase 1 Trial Results, Timothy A Yap, Elisa Fontana, Elizabeth K Lee, David R Spigel, Martin Højgaard, Stephanie Lheureux, Niharika B Mettu, Benedito A Carneiro, Louise Carter, Ruth Plummer, Gregory M Cote, Funda Meric-Bernstam, Joseph O'Connell, Joseph D Schonhoft, Marisa Wainszelbaum, Adrian J Fretland, Peter Manley, Yi Xu, Danielle Ulanet, Victoria Rimkunas, Mike Zinda, Maria Koehler, Ian M Silverman, Jorge S Reis-Filho, Ezra Rosen

Faculty, Staff and Student Publications

Predictive biomarkers of response are essential to effectively guide targeted cancer treatment. Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) have been shown to be synthetic lethal with loss of function (LOF) of ataxia telangiectasia-mutated (ATM) kinase, and preclinical studies have identified ATRi-sensitizing alterations in other DNA damage response (DDR) genes. Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors harboring LOF alterations in DDR genes, predicted by chemogenomic CRISPR screens to sensitize tumors to ATRi. Primary objectives were to determine safety and propose …

Phase Ii Trial Of Nelipepimut-S Peptide Vaccine In Women With Ductal Carcinoma In Situ, Anne E O'Shea, Guy T Clifton, Na Qiao, Brandy M Heckman-Stoddard, Malgorzata Wojtowicz, Eileen Dimond, Isabelle Bedrosian, Diane Weber, Judy E Garber, Alexander Husband, Ricardo Pastorello, J Jack Lee, Mike Hernandez, Diane D Liu, Lana A Vornik, Powel H Brown, Gheath Alatrash, George E Peoples, Elizabeth A Mittendorf

Faculty, Staff and Student Publications

UNLABELLED: NeuVax is a vaccine comprised of the HER2-derived MHC class I peptide E75 (nelipepimut-S, NPS) combined with GM-CSF. We completed a randomized trial of preoperative vaccination with NeuVax versus GM-CSF alone in patients with ductal carcinoma in situ (DCIS). The primary objective was to evaluate for NPS-specific cytotoxic T lymphocyte (CTL) responses. Patients with human leukocyte antigen (HLA)-A2-positive DCIS were enrolled and randomized 2:1 to NeuVax versus GM-CSF alone and received two inoculations prior to surgery. The number of NPS-specific CTL was measured pre-vaccination, at surgery, and 1 and 3 to 6 months post-operation by dextramer assay. Differences in …

Representing And Utilizing Clinical Textual Data For Real World Studies: An Ohdsi Approach, Vipina K Keloth, Juan M Banda, Michael Gurley, Paul M Heider, Georgina Kennedy, Hongfang Liu, Feifan Liu, Timothy Miller, Karthik Natarajan, Olga V Patterson, Yifan Peng, Kalpana Raja, Ruth M Reeves, Masoud Rouhizadeh, Jianlin Shi, Xiaoyan Wang, Yanshan Wang, Wei-Qi Wei, Andrew E Williams, Rui Zhang, Rimma Belenkaya, Christian Reich, Clair Blacketer, Patrick Ryan, George Hripcsak, Noémie Elhadad, Hua Xu

Faculty, Staff and Student Publications

Clinical documentation in electronic health records contains crucial narratives and details about patients and their care. Natural language processing (NLP) can unlock the information conveyed in clinical notes and reports, and thus plays a critical role in real-world studies. The NLP Working Group at the Observational Health Data Sciences and Informatics (OHDSI) consortium was established to develop methods and tools to promote the use of textual data and NLP in real-world observational studies. In this paper, we describe a framework for representing and utilizing textual data in real-world evidence generation, including representations of information from clinical text in the Observational …

Maternal Embryonic Leucine Zipper Kinase Is Associated With Metastasis In Triple-Negative Breast Cancer, Xuemei Xie, Gaurav B Chauhan, Ramakrishna Edupuganti, Takahiro Kogawa, Jihyun Park, Moises Tacam, Alex W Tan, Mohd Mughees, Fnu Vidhu, Diane D Liu, Juliana M Taliaferro, Mary Kathryn Pitner, Luke S Browning, Ju-Hyeon Lee, Yu Shen, Jian Wang, Naoto T Ueno, Savitri Krishnamurthy, Gabriel N Hortobagyi, Debu Tripathy, Steven J Van Laere, Geoffrey Bartholomeusz, Kevin N Dalby, Chandra Bartholomeusz

Faculty, Staff and Student Publications

UNLABELLED: Triple-negative breast cancer (TNBC) has high relapse and metastasis rates and a high proportion of cancer stem-like cells (CSC), which possess self-renewal and tumor initiation capacity. MELK (maternal embryonic leucine zipper kinase), a protein kinase of the Snf1/AMPK kinase family, is known to promote CSC maintenance and malignant transformation. However, the role of MELK in TNBC metastasis is unknown; we sought to address this in the current study. We found that

SIGNIFICANCE: These findings indicate that MELK is a driver of aggressiveness and metastasis in TNBC.

A Novel Integrated Approach To Predicting Cancer Immunotherapy Efficacy, Ruihan Luo, Jacqueline Chyr, Jianguo Wen, Yanfei Wang, Weiling Zhao, Xiaobo Zhou

Faculty, Staff and Student Publications

Immunotherapies have revolutionized cancer treatment modalities; however, predicting clinical response accurately and reliably remains challenging. Neoantigen load is considered as a fundamental genetic determinant of therapeutic response. However, only a few predicted neoantigens are highly immunogenic, with little focus on intratumor heterogeneity (ITH) in the neoantigen landscape and its link with different features in the tumor microenvironment. To address this issue, we comprehensively characterized neoantigens arising from nonsynonymous mutations and gene fusions in lung cancer and melanoma. We developed a composite NEO2IS to characterize interplays between cancer and CD8+ T-cell populations. NEO2IS improved prediction accuracy of patient responses to immune-checkpoint …

Comparative Analyses Define Differences Between Bhd-Associated Renal Tumour And Sporadic Chromophobe Renal Cell Carcinoma, Ryosuke Jikuya, Todd A Johnson, Kazuhiro Maejima, Jisong An, Young-Seok Ju, Hwajin Lee, Kyungsik Ha, Woojeung Song, Youngwook Kim, Yuki Okawa, Shota Sasagawa, Yuki Kanazashi, Masashi Fujita, Seiya Imoto, Taku Mitome, Shinji Ohtake, Go Noguchi, Sachi Kawaura, Yasuhiro Iribe, Kota Aomori, Tomoyuki Tatenuma, Mitsuru Komeya, Hiroki Ito, Yusuke Ito, Kentaro Muraoka, Mitsuko Furuya, Ikuma Kato, Satoshi Fujii, Haruka Hamanoue, Tomohiko Tamura, Masaya Baba, Toshio Suda, Tatsuhiko Kodama, Kazuhide Makiyama, Masahiro Yao, Brian M Shuch, Christopher J Ricketts, Laura S Schmidt, W Marston Linehan, Hidewaki Nakagawa, Hisashi Hasumi

Faculty, Staff and Student Publications

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome, caused by germline alteration of folliculin (FLCN) gene, develops hybrid oncocytic/chromophobe tumour (HOCT) and chromophobe renal cell carcinoma (ChRCC), whereas sporadic ChRCC does not harbor FLCN alteration. To date, molecular characteristics of these similar histological types of tumours have been incompletely elucidated.

METHODS: To elucidate renal tumourigenesis of BHD-associated renal tumours and sporadic renal tumours, we conducted whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) of sixteen BHD-associated renal tumours from nine unrelated BHD patients, twenty-one sporadic ChRCCs and seven sporadic oncocytomas. We then compared somatic mutation profiles with FLCN variants and RNA expression profiles between BHD-associated …

The Integrative Studies On The Functional A-To-I Rna Editing Events In Human Cancers, Sijia Wu, Zhiwei Fan, Pora Kim, Liyu Huang, Xiaobo Zhou

Faculty, Staff and Student Publications

Adenosine-to-inosine (A-to-I) RNA editing, constituting nearly 90% of all RNA editing events in humans, has been reported to contribute to the tumorigenesis in diverse cancers. However, the comprehensive map for functional A-to-I RNA editing events in cancers is still insufficient. To fill this gap, we systematically and intensively analyzed multiple tumorigenic mechanisms of A-to-I RNA editing events in samples across 33 cancer types from The Cancer Genome Atlas. For individual candidate among ∼ 1,500,000 quantified RNA editing events, we performed diverse types of downstream functional annotations. Finally, we identified 24,236 potentially functional A-to-I RNA editing events, including the cases …

Efficacy Of Systemic Chemotherapy In Patients With Low-Grade Mucinous Appendiceal Adenocarcinoma: A Randomized Crossover Trial, John Paul Shen, Abdelrahman M Yousef, Fadl A Zeineddine, Mohammad A Zeineddine, Rebecca S Tidwell, Karen A Beaty, Lisa C Scofield, Safia Rafeeq, Nicholas Hornstein, Elizabeth Lano, Cathy Eng, Aurelio Matamoros, Wai Chin Foo, Abhineet Uppal, Christopher Scally, Paul Mansfield, Melissa Taggart, Kanwal P Raghav, Michael J Overman, Keith Fournier

Faculty, Staff and Student Publications

IMPORTANCE: Appendiceal adenocarcinoma is a rare tumor, and given the inherent difficulties in performing prospective trials in such a rare disease, there are currently minimal high-quality data to guide treatment decisions, highlighting the need for more preclinical and clinical investigation for this disease.

OBJECTIVE: To prospectively evaluate the effectiveness of fluoropyrimidine-based systemic chemotherapy in patients with inoperable low-grade mucinous appendiceal adenocarcinoma.

DESIGN, SETTING, AND PARTICIPANTS: This open-label randomized crossover trial recruited patients at a single tertiary care comprehensive cancer center from September 2013 to January 2021. The data collection cutoff was May 2022. Enrollment of up to 30 patients was …