Medical Specialties Commons^™

Mechanisms Underlying Atrial Fibrillation In Chronic Kidney Disease, Jose Alberto Navarro-Garcia, Joshua A Keefe, Jia Song, Na Li, Xander H T Wehrens

Faculty, Staff and Students Publications

Chronic kidney disease (CKD) is a serious and progressive worldwide health problem affecting 15 % of the global population. CKD is associated with higher mortality rates due to secondary complications such as cardiovascular disease. Common cardiovascular complications found in CKD patients include left ventricular hypertrophy, heart failure, and cardiac arrhythmias. The most common type of cardiac arrhythmia in CKD patients is atrial fibrillation (AF). Proper management of AF is important due to its high risk of cardiovascular complications and stroke. The incidence of AF remains higher in CKD patients than in the healthy population, highlighting the need to improve our …

The 2024 Think Tank On Prevention Of Sudden Cardiac Death In The Young: Pathway To Survival A Report From The Cardiac Safety Research Consortium, Jordan E Ezekian, Charles C Anderson, Peter F Aziz, Samia Baluch, Stuart Berger, Martha Lopez-Anderson, Vincent Miller, Yoshihide Mitani, Silvana Molossi, Valarie Morrow, Victoria L Vetter, Elizabeth Vickers Saarel, Bhavya Trivedi, Salim F Idriss, 2024 Think Tank Participants

Faculty, Staff and Students Publications

Sudden cardiac arrest and death in the young is a critical public health issue. It occurs in children of any age, sex, racial or ethnic demographic, or socioeconomic status. Importantly, it can affect any individual-athlete and nonathlete alike. Prevention of sudden death in the young is of high importance not only because of the loss of a young life but also because of the substantial impact to families and to society at large. This White Paper summarizes the proceedings of a third national Think Tank on prevention of sudden cardiac death in the young. The Think Tank, which convened on …

Characterization Of Visual Field Loss Over 4 Years In The Rate Of Progression In Ush2a-Related Retinal Degeneration (Rush2a) Study, Jacque L Duncan, Maureen G Maguire, Lee S Mcdaniel, Nicole R Doucet, Isabelle Audo, Allison R Ayala, Janet K Cheetham, Peiyao Cheng, Todd A Durham, Rachel M Huckfeldt, Robert B Hufnagel, K Thiran Jayasundera, Naheed Khan, Brett Malbin, Ramiro S Maldonado, Michel Michaelides, Mark E Pennesi, Christina Y Weng, Alex Zmejkoski, Shobana Aravind, Hiroshi Ishikawa, David G Birch

Faculty, Staff and Students Publications

Purpose: To report visual field loss using static perimetry (SP) and kinetic perimetry (KP) over 4 years in the Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A) study.

Design: Prospective, observational cohort study.

Subjects, participants, and/or controls: Participants had USH2A-related rod-cone degeneration, visual acuity ≥20/80, and KP III4e ≥10° at baseline in the study eye. Preserved cohorts with baseline visual fields sufficient to detect progression were identified.

Methods: Participants were examined annually through 4 years. Mixed-effects models were used to estimate the annual, standardized rate, and percentage rates of change.

Main outcome measures: SP measures included hill of vision (total: …

Diagnostic Value Of Cell-Free Dna Fetal Fraction In Patients With Prenatally Suspected Placenta Accreta Spectrum Disorder, Danielle Chirumbole, Christian M Parobek, Alex Tai, Haleh Sangi-Haghpeykar, Yamely H Mendez, Spoorthi Kamepalli, Christina C Reed, Arthur Ladron De Guevara, Keneshia Lane, Claire Hoppenot, Amir A Shamshirsaz, Michael A Belfort, Jessian L Munoz, Hendrik A Lombaard

Faculty, Staff and Students Publications

Objective: The purpose of this study was to investigate the relationship between fetal fraction (FF) and placenta accreta spectrum (PAS) pathology in patients with prenatally suspected PAS.

Methods: This was a case-control study utilizing a database of pregnancies with suspected or proven PAS delivered between 6/2012 and 7/2024 at a single institution. Pregnancies were excluded if FF was not reported. The primary outcome was mean FF in pregnancies with a final clinical diagnosis of low FIGO grade (no PAS or FIGO1-2) versus high FIGO grade (FIGO3) placenta accreta. Results were reported as mean FF ± standard error of the mean. …

Data-Driven Approach To Dynamic Resting State Functional Connectivity In Post-Traumatic Stress Disorder: An Enigma-Pgc Ptsd Study, Carissa W Tomas, Jacklynn M Fitzgerald, C Lexi Baird, Courtney C Haswell, Chadi G Abdallah, Michael Angstadt, Justin T Baker, Hannah Berg, Jennifer U Blackford, Josh Cisler, Andrew S Cotton, Judith K Daniels, Nicholas D Davenport, Richard J Davidson, Terri A Deroon-Cassini, Seth G Disner, Wissam El Hage, Negar Fani, Jessie L Frijling, Evan M Gordon, Daniel W Grupe, Xiaofu He, Ryan Herringa, David Hofmann, Ashley A Huggins, Ahmed Hussain, Jonathan Ipser, Neda Jahanshad, Tanja Jovanovic, Milissa L Kaufman, Yoojean Kim, Anthony King, Saskia B J Koch, Sheri Koopowitz, Amit Lazarov, Lauren A M Lebois, Isreal Liberzon, Shmuel Lissek, Antje Manthey, Geoffrey May, Katie A Mclaughlin, Laura Nawijn, Steven M Nelson, Yuval Neria, Jack B Nitschke, Bunmi O Olatunji, Miranda Olff, Matthew Peverill, Yann Quidé, Orren Ravid, Kerry Ressler, Marisa Ross, Lauren E Salminen, Kelly Sambrook, Chiahao Shih, Anika Sierk, Scott R Sponheim, Dan J Stein, Jennifer Stevens, Thomas Straube, Benjamin Suarez-Jimenez, Paul M Thompson, Nic J A Van Der Wee, Steven J A Van Der Werff, Sanne J H Van Rooij, Mirjam Van Zuiden, Dick J Veltman, Robert R J M Vermeiren, Henrik Walter, Xin Wang, Hong Xie, Xi Zhu, Sigal Zilcha-Mano, Christine L Larson, Rajendra Morey

Faculty, Staff and Students Publications

Using functional magnetic resonance imaging (fMRI), symptoms of posttraumatic stress disorder (PTSD) have been associated with aberrations in brain networks in the absence of a given cognitive demand or task, called resting-state networks. Prior work has focused on disruption in the static functional connectivity (FC) among specific regions constrained by a priori hypotheses. However, dynamic FC, an approach that examines brain network characteristics over time, may provide a more sensitive measure to understand the network properties underlying dysfunction in PTSD. Further, using a data-driven analytic approach may reveal the contribution of other larger network disturbances beyond those revealed by hypothesis-driven …

Integrative Exome Sequencing And Machine Learning Identify Micb And Interferon Pathway Genes As Contributors To Ssc Risk, Shamika Ketkar, Hongzheng Dai, Lindsay Burrage, David Murdock, Brian Dawson, Marialbert Acosta-Herrera, Martin Kerick, Javier Martin, Kevin Wilhelm, Jennifer Kay Asmussen, Olivier Lichtarge, Regeneron Genetics Center, Shervin Assassi, Maureen D Mayes, Brendan H Lee

Faculty, Staff and Students Publications

Objectives: Systemic sclerosis (SSc) is a complex autoimmune disease with both known and unidentified genetic contributors. While genome-wide association studies (GWAS) have implicated multiple loci, many reside in noncoding regions. We aimed to identify novel protein-coding variants and pathogenic pathways using exome sequencing (ES) integrated with an Evolutionary Action-Machine Learning (EAML) framework, single-cell RNA sequencing (scRNA-seq), and expression quantitative trait locus (eQTL) analysis.

Methods: GWAS was conducted in 2,559 SSc cases and 893 controls of Caucasian ancestry, with replication in 9,846 cases and 18,333 controls of European ancestry. EAML prioritized genes with high-impact missense variants predictive of disease. Public scRNA-seq …

Genetic Diversity And Expanded Phenotypes In Dystonia: Insights From Large-Scale Exome Sequencing, Mirja Thomsen, Fabian Ott, Sebastian Loens, Gamze Kilic-Berkmen, Ai Huey Tan, Shen-Yang Lim, Ebba Lohmann, Kaja M Schröder, Lea Ipsen, Lena A Nothacker, Linn Welzel, Alexandra S Rudnik, Frauke Hinrichs, Thorsten Odorfer, Kirsten E Zeuner, Friederike Schumann, Andrea A Kühn, Simone Zittel, Marius Moeller, Robert Pfister, Christoph Kamm, Anthony E Lang, Yi Wen Tay, Ana Luísa De Almeida Marcelino, Marie Vidailhet, Emmanuel Roze, Joel S Perlmutter, Jeanne S Feuerstein, Victor S C Fung, Florence Chang, Richard L Barbano, Steven Bellows, Aparna A Wagle Shukla, Alberto J Espay, Mark S Ledoux, Brian D Berman, Stephen Reich, Andres Deik, Andre Franke, Michael Wittig, Sören Franzenburg, Jens Volkmann, Norbert Brüggemann, H A Jinnah, Tobias Bäumer, Christine Klein, Hauke Busch, Katja Lohmann

Faculty, Staff and Students Publications

Objective: Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (~25%), the etiology in most patients remains elusive. Moreover, understanding correlations between clinical manifestations and genetic variants has become increasingly complex.

Methods: Exome sequencing was conducted on 1924 genetically unsolved, mainly late-onset isolated dystonia patients, recruited primarily from two dystonia registries (DysTract and the Dystonia Coalition). Rare variants in genes previously linked to dystonia (n = 406) were examined, confirmed via Sanger sequencing, and analyzed for segregation when possible.

Results: We identified 137 distinct likely pathogenic/pathogenic variants (according to ACMG …

Rest-Activity Rhythm Phenotypes In Adults With Epilepsy And Intellectual Disability, Nandani Adhyapak, Grace E Cardenas, Mark A Abboud, Vaishnav Krishnan

Faculty, Staff and Students Publications

Objective: Rest-activity rhythms (RARs) are perturbed in many forms of neuropsychiatric illness. In this study, we applied wrist actigraphy to describe RAR perturbations in intellectually disabled adults with epilepsy ("E + ID"), using a cross-sectional case-control design. We examined whether RAR phenotypes correlated with epilepsy severity, deficits in adaptive function, and/or comorbid psychopathology.

Methods: Caregivers of E + ID subjects provided informed consent during routine ambulatory clinic visits and were asked to complete standardized surveys of overall epilepsy severity (GASE, Global Assessment of Severity of Epilepsy), adaptive function (ABAS-3, Adaptive Behavior Assessment System-3) and psychopathology (ABCL, Adult Behavior Checklist). Caregivers …

Racial And Ethnic Disparity For Cancer Mortality In General And Single-Payer Healthcare Systems In The United States, Rock Bum Kim, Emily Zhou, Kaitlin N Swinnerton, Jennifer La, Shengling Ma, Mrinal Ranjan, Nhan V Do, Mary T Brophy, Nathanael R Fillmore, Ang Li

Faculty, Staff and Students Publications

Background: It remains unclear what factors significantly drive racial disparity in cancer survival in the United States (US). We compared adjusted mortality outcomes in cancer patients from different racial and ethnic groups on a population level in the US and a single-payer healthcare system.

Patients and methods: We selected adult patients with incident solid and hematologic malignancies from the Surveillance, Epidemiology, and End Results (SEER) 2011-2020 and Veteran Affairs national healthcare system (VA) 2011-2021. We classified the self-reported NIH race and ethnicity into non-Hispanic White (NHW), non-Hispanic Black (NHB), non-Hispanic Asian Pacific Islander (API), and Hispanic. Cox regression models for …

N-Acetylaspartate From Fat Cells Regulates Postprandial Body Temperature, Jessica B Felix, Pradip K Saha, Evelyn L De Groot, Lin Tan, Robert Sharp, Elizabeth S Anaya, Yafang Li, Holly Quang, Nooshin Saidi, Layla Abushamat, Christie M Ballantyne, Christopher I Amos, Philip L Lorenzi, Samuel Klein, Xia Gao, Sean M Hartig

Faculty, Staff and Students Publications

N-acetylaspartate (NAA), the brain’s second most abundant metabolite, provides essential substrates for myelination through its hydrolysis1. However, the physiological roles of NAA in other tissues remain unknown. Here, we show that aspartoacylase (ASPA) expression in white adipose tissue (WAT) governs blood NAA levels for postprandial body temperature regulation. Genetic ablation of Aspa in mice resulted in systemically elevated NAA levels, and the ensuing accumulation in WAT stimulated pyrimidine production. Stable isotope tracing confirmed higher incorporation of glucose-derived carbon into pyrimidine metabolites in Aspa knockout cells. Additionally, serum NAA levels positively correlated with the abundance of the pyrimidine …

Crispr-Cas9 Engineering Of Human T Regulatory Cells – Design And Optimization Of A Manufacturing Process, Ortal Shimon, Adam M Dean, Shoshana Cohen, Aiden L Moser, Clifford C Dacso, Yosi Gilad, David M Lonard, Bert W O'Malley

Faculty, Staff and Students Publications

Regulatory T cells (Tregs) are a subset of CD4 + T cells that comprise 5-10 % of the total CD4 + T cell population. Tregs, which are critically important for the maintenance of immune tolerance and immune homeostasis, are distinguished from other subtypes of CD4 + T cells by the expression of the transcription factor FOXP3. Because of the centrality to immunoregulation, Tregs have gained increasing attention as promising targets for clinical applications in autoimmune diseases, transplant rejection and graft-versus-host disease (GvHD). However, the essential role of Tregs in the complex network of the immune system implies their targeting as …

An Electronic Trigger To Detect Telemedicine-Related Diagnostic Errors, Daniel R Murphy, Himabindu Kadiyala, Li Wei, Hardeep Singh

Faculty, Staff and Students Publications

Introduction

Methods

Developing Culturally Centered Outreach Materials For Rural Native Veterans, Alexandra B Caloudas, Kelley Arredondo, Gail Beauchamp, Sharon Anastas, Kathy Marchant-Miros, Kristen Frosio, Giselle Day, Katherine Bay, Stephanie Day, Jan Lindsay, Jay Shore

Faculty, Staff and Students Publications

Native Americans serve in the U.S. military at the highest rate per capita of any ethnoracial group and have elevated rates of mental health (MH) difficulties compared to other ethnoracial groups, including posttraumatic stress disorder, alcohol use disorders, and suicide. Almost half of Native Veterans live in rural areas; rurality is associated with significant barriers to MH services. Engaging in outreach with Native Veterans is an important pathway for connecting them with MH care, but the outreach process and educational materials must be culturally aligned to be more effective. We collaborated with partners at a rural Department of Veterans Affairs …

Changes In Post-Transplant Serum Testosterone Levels In Men Undergoing Lung Transplantation: A Pilot Study Using The Trinetx Research Network, Austin Thompson, Danly Omil-Lima, Jaime Abraham Perez, Erin Jesse, Mohit Khera, Kenneth Chavin, Nannan Thirumavalavan

Faculty, Staff and Students Publications

Hypogonadism is understudied in men requiring solid organ transplants, particularly among lung transplant recipients. Improvement in serum testosterone levels has been reported in kidney and liver transplantation. Using the TriNetX Research Network, we performed a retrospective cohort study to evaluate the incidence of peri-transplant hypogonadism and the natural course of serum testosterone following successful lung transplantation. Men aged ≥ 18 with a lung transplant and total testosterone drawn within one year pre- and post-transplant were included. Men with receipt of testosterone therapy were excluded. A low testosterone (< 300 ng/dL) and normal testosterone (≥300 ng/dL) cohort was created before employing descriptive and analytic statistics to investigate the incidence of peri-transplant hypogonadism and the change in serum testosterone levels following lung transplantation. In our entire cohort, lung transplantation was not associated with a significant increase in post-transplant serum testosterone (329.86 ± 162.56 ng/dL pre-transplant and 355.13 ± 216.11 ng/dL post-transplant, p = 0.483). The number of men with low testosterone decreased by 9.8% following lung transplantation but was not significant, p = 0.404. In this pilot study, no significant change in the number of hypogonadal men nor serum testosterone levels was observed among men undergoing lung transplantation.

Definitions Of Cardiogenic Shock And Indications For Temporary Mechanical Circulatory Support: Joint Consensus Report Of The Perioperative Quality Initiative And The Enhanced Recovery After Surgery Cardiac Society, Michael C Grant, Charles Scott Brudney, Jaime Hernandez-Montfort, Stephanie O Ibekwe, Amanda Rea, Christian Stoppe, Alexander Zarbock, Andrew D Shaw, Daniel T Engelman, Manreet K Kanwar, Perioperative Quality Initiative (Poqi) And The Enhanced Recovery After Surgery (Eras) Cardiac Society Workgroup

Faculty, Staff and Students Publications

Background: The management of patients with cardiogenic shock (CS) is complex and resource intensive, particularly given the recent surge in temporary mechanical circulatory support (tMCS) devices. This document was created to establish an approach to the assessment of CS to provide early and targeted therapies, including tMCS.

Methods: An interdisciplinary, international panel of experts, using a structured appraisal of the literature and a modified Delphi method, derived consensus regarding the assessment of CS based on pathophysiologic severity, etiology, and phenotypic clustering to guide escalation of care as well as identify those patients who might benefit from tMCS.

Results: Key principles …

Global Cardiac Anesthesia Workforce Assessment: A Cross-Sectional Observational Survey Study, Alexander J C Mittnacht, Carolina S Romero Garcia, Joshua B Cadwell, Jiapeng Huang, Iwan Sofjan, Mohamed R Eltahan, Hong Liu, Chirojit Mukherjee, Fabio Guarracino, Andrew Shaw, Pablo Motta, International Academy Of Cardiac Anaesthesiologists (Iaca) Global Survey Team

Faculty, Staff and Students Publications

Objective: The primary aim of this survey was to assess the demographics, training background, practice setting, and work environment of cardiac anesthesiologists globally.

Design: Cross-sectional study of the global cardiac anesthesia workforce. A multilingual web-based survey was conducted between June 1 and December 31, 2023.

Setting: The survey was distributed via cardiac anesthesia societies, special interest groups, and social media using a non-probabilistic sample and with snowballing techniques.

Participants: Anesthesiologists actively practicing cardiac anesthesia.

Interventions: None.

Measurements and main results: In total, 3,430 participants from 99 countries responded. Results were summarized as descriptive data comparing geographical regions, and noticeable differences …

Anaphylaxis Definition, Overview, And Clinical Support Tool: 2024 Consensus Report-A Ga2len Project, Timothy E Dribin, Antonella Muraro, Carlos A Camargo, Paul J Turner, Julie Wang, Graham Roberts, Aikaterini Anagnostou, Susanne Halken, Jay Liebermann, Margitta Worm, Torsten Zuberbier, Hugh A Sampson, Ga(2)Len Anaphylaxis Study Team

Faculty, Staff and Students Publications

Background: The 2006 National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network anaphylaxis criteria are widely used in clinical care and research. In 2020, the World Allergy Organization published modified criteria that have not been uniformly adopted. Different criteria contribute to inconsistent care and research outcomes.

Objective: We sought to develop a consensus anaphylaxis definition, overview, and clinical support tool.

Methods: A 12-member writing group developed draft outputs modified with input from a 46-member international expert panel, 31 medical stakeholder organizations, and 15 patient advocacy organizations. The expert panel participated in a modified Delphi process to seek consensus …

Biotechnology Research Incubator For Teachers (Brite) Pilot Program: Advancing Technology Research Education For Secondary School Teachers, Zhongcheng Shi, Katherine A Harris, Alana D Newell, Michael Nguyen, Yuan Yao, Joel Sederstrom, Cynthia C Hallmark, Sherita Love, Fred A Pereira, Shixia Huang

Faculty, Staff and Students Publications

Introduction: Advanced technologies have transformed diagnostics and therapeutics, improving disease management. Secondary school educators play a vital role in fostering critical thinking, problem-solving, and inspiring students in science, technology, engineering, math, and medicine (STEMM) innovations. Comprehensive teacher training enhances education delivery and ensures long-term advancements in science education, empowering future generations.

Materials and methods: We launched the Biotechnology Research Incubator for Teachers (BRITE) pilot program to train secondary school teachers. This 3-week program immerses teachers in Advanced Technology Core facilities, providing hands-on experience with cutting-edge technologies, such as protein array technology, next-generation sequencing, and flow cytometry. It also offers collaborative …

Role And Use Of Race In Artificial Intelligence And Machine Learning Models Related To Health, Martin C Were, Ang Li, Bradley A Malin, Zhijun Yin, Joseph R Coco, Benjamin X Collins, Ellen Wright Clayton, Laurie L Novak, Rachele Hendricks-Sturrup, Abiodun O Oluyomi, Shilo Anders, Chao Yan

Faculty, Staff and Students Publications

The role and use of race within health-related artificial intelligence (AI) and machine learning (ML) models have sparked increasing attention and controversy. Despite the complexity and breadth of related issues, a robust and holistic framework to guide stakeholders in their examination and resolution remains lacking. This perspective provides a broad-based, systematic, and crosscutting landscape analysis of race-related challenges, structured around the AI and ML life cycle and framed through "points to consider" to support inquiry and decision-making.

Retrotransposon Methylation Profiles And Survival In Black Women With High-Grade Serous Ovarian Carcinoma, Christelle Colin-Leitzinger, Katherine A Lawson-Michod, Courtney E Johnson, Irma M Vlasac, Sean Yoder, Tania Mesa, Dana Roeber, Chad Huff, Michelle A T Hildebrandt, Kristin Haller, Anthony J Alberg, Elisa V Bandera, Melissa Bondy, Michele L Cote, Theresa Hastert, Edward S Peters, Paul D Terry, Andrew B Lawson, Andrew Berchuck, Brooke L Fridley, Jing-Yi Chern, Jennifer A Doherty, Jeffrey R Marks, Joellen M Schildkraut, Brock C Christensen, Lucas A Salas, Lauren C Peres

Faculty, Staff and Student Publications

Introduction: Retrotransposons (REs) constitute nearly half of the genome and include long terminal repeat (LTR) elements, Long INterspersed Elements (LINE), and Short INterspersed Elements (SINE). REs are typically silenced in somatic tissues via DNA methylation but can be reactivated through DNA hypomethylation, potentially impacting gene regulation. Here, we investigate genome-scale profiles of RE methylation in high-grade serous ovarian carcinoma (HGSOC) and associations with survival among Black women.

Methods: Methylation levels of LTR, LINE-1, and Alu (type of SINE) in 200 HGSOC tumors were predicted using a random forest approach and clustered using multiple consensus algorithms. Associations between RE methylation clusters …

Unveiling Spatial Heterogeneity In Medulloblastoma: A Multi-Omics Analysis Of Cellular State And Geographical Organization, Jiankang Li, Hailong Liu, Ziwei Wang, Jiao Zhang, Xuan Chen, Craig Daniels, Xiaochong Wu, Olivier Saulnier, Hiromichi Suzuki, Pasqualino De Antonellis, Alexandra Rasnitsyn, Winnie Ong, Evan Y Wang, Liam D Hendrikse, Yu Su, Yu Tian, Dongming Han, Ruohan Wang, Jialin Mo, Fei Liu, Kaiwen Deng, Dongyang Wang, Zhaoyang Feng, Yifei Jiang, Yanong Li, Yuting Ma, Zijia Liu, Meiyu Li, Peiyi Tian, Yanfeng Shi, Yong Jiang, Tao Yang, Shouwei Li, Jianfeng Liang, Jingchuan Wu, Ying Wang, Wanjing Zou, Yina Jiang, Lusheng Wang, Fang Chen, Xin Jin, Shuaicheng Li, Xiaoguang Qiu, Chunde Li, Ya Gao, Yujie Tang, Michael D Taylor, Tao Jiang

Faculty, Staff and Students Publications

Background: Despite numerous studies on medulloblastoma (MB) cell heterogeneity, the spatial characteristics of cellular states remain unclear.

Methods: We analyze single-nucleus and spatial transcriptomes and chromatin accessibility from human MB spanning four subgroups, to identify malignant cell populations and describe the spatial evolutionary trajectories. The spatial copy number variations (CNVs) patterns and niches were analyzed to investigate the cellular interactions.

Results: Three main malignant cell populations were identified, including progenitor-like, cycling, and differentiated populations. Gene signatures of cell populations strongly correlate to clinical outcomes. These tumor cell populations are geographically organized as stem-like and mature regions, highlighting their spatially heterogeneous …

Epigenomic Diagnosis And Prognosis Of Acute Myeloid Leukemia., Francisco Marchi, Vivek M. Shastri, Richard J. Marrero, Nam H K Nguyen, Antonella Öttl, Ann-Kathrin Schade, Marieke Landwehr, Olga Krali, Jessica Nordlund, Matin Ghavami, Fernando Sckaff, Vikash K. Mansinghka, Xueyuan Cao, William Slayton, Petr Starostik, Christopher R. Cogle, Raul C. Ribeiro, Jeffrey E. Rubnitz, Jeffery Klco, Abdelrahman Elsayed, Alan S. Gamis, Timothy J. Triche, Rhonda Ries, E Anders Kolb, Richard Aplenc, Todd Alonzo, Stanley Pounds, Soheil Meshinchi, Jatinder K. Lamba

Manuscripts, Articles, Book Chapters and Other Papers

Despite the critical role of DNA methylation, clinical implementations harnessing its promise have not been described in acute myeloid leukemia. Utilizing DNA methylation from 3314 leukemia patient samples across 11 harmonized cohorts, we describe the Acute Leukemia Methylome Atlas, which includes robust models capable of accurately predicting AML subtypes. A genome-wide prognostic model as well as a targeted panel of 38 CpGs significantly predict five-year survival in our pediatric and adult test cohorts. To accelerate rapid clinical utility, we develop a specimen-to-result protocol that uses long-read nanopore sequencing and machine learning to characterize patients' whole genomes and epigenomes. Clinical validation …

Cell Type-Specific Purifying Selection Of Synonymous Mitochondrial Dna Variation, Caleb A Lareau, Patrick Maschmeyer, Yajie Yin, Jacob C Gutierrez, Ryan S Dhindsa, Anne-Sophie Gribling-Burrer, Sebastian Zielinski, Yu-Hsin Hsieh, Lena Nitsch, Veronika Dimitrova, Benan Nalbant, Frank A Buquicchio, Tsion Abay, Robert R Stickels, Jacob C Ulirsch, Patrick Yan, Fangyi Wang, Zhuang Miao, Katalin Sandor, Bence Daniel, Vincent Liu, Paul L Mendez, Petra Knaus, Manpreet Meyer, William J Greenleaf, Anshul Kundaje, Redmond P Smyth, Mathias Munschauer, Leif S Ludwig, Ansuman T Satpathy

Duncan NRI Faculty and Staff Publications

While somatic variants are well-characterized drivers of tumor evolution, their influence on cellular fitness in nonmalignant contexts remains understudied. We identified a mosaic synonymous variant (m.7076A > G) in the mitochondrial DNA (mtDNA)-encoded cytochrome c-oxidase subunit 1 (MT-CO1, p.Gly391=), present at homoplasmy in 47% of immune cells from a healthy donor. Single-cell multiomics revealed strong, lineage-specific selection against the m.7076G allele in CD8+ effector memory T cells, but not other T cell subsets, mirroring patterns of purifying selection of pathogenic mtDNA alleles. The limited anticodon diversity of mitochondrial tRNAs forces m.7076G translation to rely on wobble pairing, unlike the Watson-Crick-Franklin pairing …

A Data Assimilation Framework For Predicting The Spatiotemporal Response Of High-Grade Gliomas To Chemoradiation, Hugo J M Miniere, David A Hormuth, Ernesto A B F Lima, Maguy Farhat, Bikash Panthi, Holly Langshaw, Mihir D Shanker, Wasif Talpur, Sara Thrower, Jodi Goldman, Sophia Ty, Caroline Chung, Thomas E Yankeelov

Faculty, Staff and Student Publications

Background: High-grade gliomas are highly invasive and respond variably to chemoradiation. Accurate, patient-specific predictions of tumor response could enhance treatment planning. We present a novel computational platform that assimilates MRI data to continually predict spatiotemporal tumor changes during chemoradiotherapy.

Methods: Tumor growth and response to chemoradiation was described using a two-species reaction-diffusion model of enhancing and non-enhancing regions of the tumor. Two evaluation scenarios were used to test the predictive accuracy of this model. In scenario 1, the model was calibrated on a patient-specific basis (n = 21) to weekly MRI data during the course of chemoradiotherapy. A data assimilation …

Structural Variants: Mechanisms, Mapping, And Interpretation In Human Genetics, Shruti Pande, Moez Dawood, Christopher M Grochowski

Faculty, Staff and Students Publications

Structural variations (SVs) represent genomic variations that involve breakage and rejoining of DNA segments. SVs can alter normal gene dosage, lead to rearrangements of genes and regulatory elements within a topologically associated domain, and potentially contribute to physical traits, genomic disorders, or complex traits. Recent advances in sequencing technologies and bioinformatics have greatly improved SV detection and interpretation at unprecedented resolution and scale. Despite these advances, the functional impact of SVs, the underlying SV mechanism(s) contributing to complex traits, and the technical challenges associated with SV detection and annotation remain active areas of research. This review aims to provide an …

Xpert Mtb/Rif Ultra Assay For Pulmonary Tuberculosis And Rifampicin Resistance In Adults And Adolescents, David J Horne, Jerry S Zifodya, Adrienne E Shapiro, Elizabeth Chandler Church, Jonah S Kreniske, Alexander W Kay, Katie Scandrett, Karen R Steingart, Yemisi Takwoingi

Faculty, Staff and Students Publications

Background: Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)-recommended rapid diagnostic test that simultaneously detects tuberculosis and rifampicin resistance. This review updates a comparative accuracy Cochrane review of Xpert MTB/RIF and Xpert Ultra as Xpert Ultra has replaced Xpert MTB/RIF.

Objectives: To determine the diagnostic accuracy of Xpert MTB/RIF Ultra (Xpert Ultra) for detecting pulmonary tuberculosis and rifampicin resistance in adults and adolescents with presumptive tuberculosis based on signs or symptoms or with an abnormal chest x-ray suggestive of tuberculosis.

Search methods: We searched seven databases including CENTRAL, MEDLINE, and Embase, plus two trial registers (ClinicalTrials.gov …

A Novel Microdosimetry-Based Formalism For Cell Survival Modelling Applicable To Hypofractionated Radiotherapy, Oleg N Vassiliev, Radhe Mohan

Faculty, Staff and Student Publications

Objectives

Hypofractionated radiotherapy requires reliable cell survival models for doses much higher than the standard 2 Gy, for which the linear-quadratic (LQ) model is not applicable. We developed an alternative approach applicable to both low doses and high doses used in hypofractionated treatments and radiobiological experiments.

Approach.

We combined a standard microdosimetric technique with a recently introduced non-LQ cell survival model. Our formulation accounts for cell damage by multi-track events involving any number of particles. This is necessary for modelling cell survival at therapeutic doses. We characterise each cell type by the size �� of the sensitive volume (SV) and …

Use Of Cholic Acid In Smith-Lemli-Opitz Syndrome (Slos): Real-World Patient Outcomes, Edwin Ferren, Paul R Hillman, Amy Kritzer, Joseph Ray, Alvaro Serrano, Hope Northrup, Paige Roberts, Rana Dutta, Tiziano Pramparo, Pamela Vig, Robert D Steiner

Faculty, Staff and Student Publications

Background: Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by biallelic pathogenic variants in DHCR7, which encodes the enzyme 7-dehydrocholesterol reductase (DHCR7). SLOS is a multisystemic disorder affecting various aspects of health, including growth, development, behavior, and quality of life, underscoring the need for safe, efficacious interventions that limit disease burden. DHCR7 enzyme deficiency leads to a "metabolic block" resulting in decreased cholesterol production and accumulation of its precursor 7-dehydrocholesterol and the secondary isomer 8-dehydrocholesterol. Reduced cholesterol synthesis, in turn, leads to decreased levels of cholic acid (CA), an endogenous bile acid synthesized from cholesterol and …

Melanoma Antigens In Pediatric Medulloblastoma Contribute To Tumor Heterogeneity And Species-Specificity Of Group 3 Tumors, Rebecca R J Collins, Rebecca R Florke Gee, Sima Tozandehjani, Tara Bayat, Maria Camila Hoyos Sanchez, Juan Sebastian Solano Gutierrez, Barbara Breznik, Anna K Lee, Samuel T Peters, Jon P Connelly, Shondra M Pruett-Miller, Martine F Roussel, Dinesh Rakheja, Heather S Tillman, Patrick Ryan Potts, Klementina Fon Tacer

Faculty, Staff and Student Publications

Medulloblastoma (MB) is the most malignant childhood brain cancer. Group 3 MB (G3 MB) subtype accounts for about 25% of MB and is associated with the worst outcomes. Herein, we report that more than half of G3 MB tumors express melanoma antigens (MAGEs), which are potential prognostic and therapeutic markers. MAGEs are cancer-testis antigens, aberrantly expressed in several adult cancers, and associated with poorer prognosis and therapy resistance; however, their role in pediatric cancers is mostly unknown. This study aimed to determine whether MAGEs are activated and important in pediatric MB. We obtained formalin-fixed paraffin-embedded tumor samples of 34 patients, …

Human Ipsc-Based Breast Cancer Model Identifies S100p-Dependent Cancer Stemness Induced By Brca1 Mutation, Jingxin Liu, Cai Zhao, Jiahao Chen, Pengguihang Zeng, Qingjian Li, Ranran Dai, Xingqiang Lai, Wenqian Song, Jianing Chen, Xixi Zhu, Xinyi Liu, Jun Sun, Jia Wang, Peihang Fang, Tengfei Wang, Wenjie Chen, Diana Guallar, Nan Cao, Jianli Zhao, Shicheng Su, Andy Peng Xiang, Yi Arial Zeng, Jie Li, Junchao Cai, Dung-Fang Lee, Jinxin Bei, Yongliang Huo, Hai Hu, Shengbao Suo, Dong-Feng Huang, Jin Bai, Junjun Ding

Faculty, Staff and Student Publications

Breast cancer is the most common malignancy in females and remains the leading cause of cancer-related deaths for women worldwide. The cellular and molecular basis of breast tumorigenesis is not completely understood partly due to the lack of human research models which simulate the development of breast cancer. Here, we developed a method for generating functional mammary-like cells (MCs) from human-induced pluripotent stem cells (iPSCs). The iPSC-MCs closely resemble human primary MCs at cellular, transcriptional, and functional levels. Using this method, a breast cancer model was generated using patient-derived iPSCs harboring germline