Digital Commons Network^™

Genomic Analysis Of Intracranial And Subcortical Brain Volumes Yields Polygenic Scores Accounting For Variation Across Ancestries, Luis M García-Marín, Adrian I Campos, Santiago Diaz-Torres, Jill A Rabinowitz, Zuriel Ceja, Brittany L Mitchell, Katrina L Grasby, Jackson G Thorp, Ingrid Agartz, Saud Alhusaini, David Ames, Philippe Amouyel, Ole A Andreassen, Konstantinos Arfanakis, Alejandro Arias-Vasquez, Nicola J Armstrong, Lavinia Athanasiu, Mark E Bastin, Alexa S Beiser, David A Bennett, Joshua C Bis, Marco P M Boks, Dorret I Boomsma, Henry Brodaty, Rachel M Brouwer, Jan K Buitelaar, Ralph Burkhardt, Wiepke Cahn, Vince D Calhoun, Owen T Carmichael, Mallar Chakravarty, Qiang Chen, Christopher R K Ching, Sven Cichon, Benedicto Crespo-Facorro, Fabrice Crivello, Anders M Dale, George Davey Smith, Eco J C De Geus, Philip L De Jager, Greig I De Zubicaray, Stéphanie Debette, Charles Decarli, Chantal Depondt, Sylvane Desrivières, Srdjan Djurovic, Stefan Ehrlich, Susanne Erk, Thomas Espeseth, Guillén Fernández, Irina Filippi, Simon E Fisher, Debra A Fleischman, Evan Fletcher, Myriam Fornage, Andreas J Forstner, Clyde Francks, Barbara Franke, Tian Ge, Aaron L Goldman, Hans J Grabe, Robert C Green, Oliver Grimm, Nynke A Groenewold, Oliver Gruber, Vilmundur Gudnason, Asta K Håberg, Unn K Haukvik, Andreas Heinz, Derrek P Hibar, Saima Hilal, Jayandra J Himali, Beng-Choon Ho, David F Hoehn, Pieter J Hoekstra, Edith Hofer, Wolfgang Hoffmann, Avram J Holmes, Georg Homuth, Norbert Hosten, M Kamran Ikram, Jonathan C Ipser, Clifford R Jack, Neda Jahanshad, Erik G Jönsson, Rene S Kahn, Ryota Kanai, Marieke Klein, Maria J Knol, Lenore J Launer, Stephen M Lawrie, Stephanie Le Hellard, Phil H Lee, Hervé Lemaître, Shuo Li, David C M Liewald, Honghuang Lin, W T Longstreth, Oscar L Lopez, Michelle Luciano, Pauline Maillard, Andre F Marquand, Nicholas G Martin, Jean-Luc Martinot, Karen A Mather, Venkata S Mattay, Katie L Mcmahon, Patrizia Mecocci, Ingrid Melle, Andreas Meyer-Lindenberg, Nazanin Mirza-Schreiber, Yuri Milaneschi, Thomas H Mosley, Thomas W Mühleisen, Bertram Müller-Myhsok, Susana Muñoz Maniega, Matthias Nauck, Kwangsik Nho, Wiro J Niessen, Markus M Nöthen, Paul A Nyquist, Jaap Oosterlaan, Massimo Pandolfo, Tomas Paus, Zdenka Pausova, Brenda W J H Penninx, G Bruce Pike, Bruce M Psaty, Benno Pütz, Simone Reppermund, Marcella D Rietschel, Shannon L Risacher, Nina Romanczuk-Seiferth, Rafael Romero-Garcia, Gennady V Roshchupkin, Jerome I Rotter, Perminder S Sachdev, Philipp G Sämann, Arvin Saremi, Muralidharan Sargurupremraj, Andrew J Saykin, Lianne Schmaal, Helena Schmidt, Reinhold Schmidt, Peter R Schofield, Markus Scholz, Gunter Schumann, Emanuel Schwarz, Li Shen, Jean Shin, Sanjay M Sisodiya, Albert V Smith, Jordan W Smoller, Hilkka S Soininen, Vidar M Steen, Dan J Stein, Jason L Stein, Sophia I Thomopoulos, Arthur W Toga, Diana Tordesillas-Gutiérrez, Julian N Trollor, Maria C Valdes-Hernandez, Dennis Van T Ent, Hans Van Bokhoven, Dennis Van Der Meer, Nic J A Van Der Wee, Javier Vázquez-Bourgon, Dick J Veltman, Meike W Vernooij, Arno Villringer, Louis N Vinke, Henry Völzke, Henrik Walter, Joanna M Wardlaw, Daniel R Weinberger, Michael W Weiner, Wei Wen, Lars T Westlye, Eric Westman, Tonya White, A Veronica Witte, Christiane Wolf, Jingyun Yang, Marcel P Zwiers, M Arfan Ikram, Sudha Seshadri, Paul M Thompson, Claudia L Satizabal, Sarah E Medland, Miguel E Rentería

Faculty, Staff and Student Publications

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse …

Sex Differences In Hypertension And Its Management Throughout Life, Wan-Jin Yeo, Rahul Abraham, Aditya L Surapaneni, Pascal Schlosser, Shoshana H Ballew, Bige Ozkan, Carina M Flaherty, Bing Yu, Joseph V Bonventre, Chirag R Parikh, Paul L Kimmel, Ramachandran S Vasan, Josef Coresh, Morgan E Grams

Faculty, Staff and Student Publications

Background: The prevalence of hypertension and uncontrolled hypertension may differ by age and sex.

Methods: We included participants in the Atherosclerosis Risk in Communities study at seven study visits over 33 years (visit 1: 15 636 participants; mean age, 54 years; 55% women), estimating sex differences in prevalence of hypertension (systolic blood pressure ≥130 mm Hg; diastolic blood pressure ≥80 mm Hg; or self-reported antihypertension medication use) and uncontrolled hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) using unadjusted and comorbidity-adjusted models.

Results: The prevalence of hypertension increased with age from 40% (ages, 43-46 …

Single-Cell Integration Reveals Metaplasia In Inflammatory Gut Diseases, Amanda J Oliver, Ni Huang, Raquel Bartolome-Casado, Ruoyan Li, Simon Koplev, Hogne R Nilsen, Madelyn Moy, Batuhan Cakir, Krzysztof Polanski, Victoria Gudiño, Elisa Melón-Ardanaz, Dinithi Sumanaweera, Daniel Dimitrov, Lisa Marie Milchsack, Michael E B Fitzpatrick, Nicholas M Provine, Jacqueline M Boccacino, Emma Dann, Alexander V Predeus, Ken To, Martin Prete, Jonathan A Chapman, Andrea C Masi, Emily Stephenson, Justin Engelbert, Sebastian Lobentanzer, Shani Perera, Laura Richardson, Rakeshlal Kapuge, Anna Wilbrey-Clark, Claudia I Semprich, Sophie Ellams, Catherine Tudor, Philomeena Joseph, Alba Garrido-Trigo, Ana M Corraliza, Thomas R W Oliver, C Elizabeth Hook, Kylie R James, Krishnaa T Mahbubani, Kourosh Saeb-Parsy, Matthias Zilbauer, Julio Saez-Rodriguez, Marte Lie Høivik, Espen S Bækkevold, Christopher J Stewart, Janet E Berrington, Kerstin B Meyer, Paul Klenerman, Azucena Salas, Muzlifah Haniffa, Frode L Jahnsen, Rasa Elmentaite, Sarah A Teichmann

Faculty, Staff and Student Publications

The gastrointestinal tract is a multi-organ system crucial for efficient nutrient uptake and barrier immunity. Advances in genomics and a surge in gastrointestinal diseases1,2 has fuelled efforts to catalogue cells constituting gastrointestinal tissues in health and disease3. Here we present systematic integration of 25 single-cell RNA sequencing datasets spanning the entire healthy gastrointestinal tract in development and in adulthood. We uniformly processed 385 samples from 189 healthy controls using a newly developed automated quality control approach (scAutoQC), leading to a healthy reference atlas with approximately 1.1 million cells and 136 fine-grained cell states. We anchor 12 gastrointestinal disease datasets spanning …

Surgical Predictors Of Clinical Outcome 6 Years After Revision Acl Reconstruction, Rick W Wright, Laura J Huston, Amanda K Haas, Jacquelyn S Pennings, Christina R Allen, Daniel E Cooper, Thomas M Deberardino, Warren R Dunn, Brett Brick A Lantz, Kurt P Spindler, Michael J Stuart, Annunziato Ned Amendola, Christopher C Annunziata, Robert A Arciero, Bernard R Bach, Champ L Baker, Arthur R Bartolozzi, Keith M Baumgarten, Jeffrey H Berg, Geoffrey A Bernas, Stephen F Brockmeier, Robert H Brophy, Charles A Bush-Joseph, J Brad Butler, James L Carey, James E Carpenter, Brian J Cole, Jonathan M Cooper, Charles L Cox, R Alexander Creighton, Tal S David, David C Flanigan, Robert W Frederick, Theodore J Ganley, Charles J Gatt, Steven R Gecha, James Robert Giffin, Sharon L Hame, Jo A Hannafin, Christopher D Harner, Norman Lindsay Harris, Keith S Hechtman, Elliott B Hershman, Rudolf G Hoellrich, David C Johnson, Timothy S Johnson, Morgan H Jones, Christopher C Kaeding, Ganesh V Kamath, Thomas E Klootwyk, Bruce A Levy, C Benjamin Ma, G Peter Maiers, Robert G Marx, Matthew J Matava, Gregory M Mathien, David R Mcallister, Eric C Mccarty, Robert G Mccormack, Bruce S Miller, Carl W Nissen, Daniel F O'Neill, Brett D Owens, Richard D Parker, Mark L Purnell, Arun J Ramappa, Michael A Rauh, Arthur C Rettig, Jon K Sekiya, Kevin G Shea, Orrin H Sherman, James R Slauterbeck, Matthew V Smith, Jeffrey T Spang, Steven J Svoboda, Timothy N Taft, Joachim J Tenuta, Edwin M Tingstad, Armando F Vidal, Darius G Viskontas, Richard A White, James S Williams, Michelle L Wolcott, Brian R Wolf, James J York

Faculty, Staff and Student Publications

Background: Revision anterior cruciate ligament (ACL) reconstruction has been documented to have inferior outcomes compared with primary ACL reconstruction. The reasons why remain unknown.

Purpose: To determine whether surgical factors performed at the time of revision ACL reconstruction can influence a patient's outcome at 6-year follow-up.

Study design: Cohort study; Level of evidence, 2.

Methods: Patients who underwent revision ACL reconstruction were identified and prospectively enrolled between 2006 and 2011. Data collected included baseline patient characteristics, surgical technique and pathology, and a series of validated patient-reported outcome instruments: Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) …

Genetic Regulation Of Human Brain Proteome Reveals Proteins Implicated In Psychiatric Disorders, Jie Luo, Ling Li, Mingming Niu, Dehui Kong, Yi Jiang, Suresh Poudel, Annie W Shieh, Lijun Cheng, Gina Giase, Kay Grennan, Kevin P White, Chao Chen, Sidney H Wang, Dalila Pinto, Yue Wang, Chunyu Liu, Junmin Peng, Xusheng Wang

Faculty, Staff and Student Publications

Psychiatric disorders are highly heritable yet polygenic, potentially involving hundreds of risk genes. Genome-wide association studies have identified hundreds of genomic susceptibility loci with susceptibility to psychiatric disorders; however, the contribution of these loci to the underlying psychopathology and etiology remains elusive. Here we generated deep human brain proteomics data by quantifying 11,608 proteins across 268 subjects using 11-plex tandem mass tag coupled with two-dimensional liquid chromatography-tandem mass spectrometry. Our analysis revealed 788 cis-acting protein quantitative trait loci associated with the expression of 883 proteins at a genome-wide false discovery rate < 5%. In contrast to expression at the transcript level and complex diseases that are found to be mainly influenced by noncoding variants, we found protein expression level tends to be regulated by non-synonymous variants. We also provided evidence of 76 shared regulatory signals between gene expression and protein abundance. Mediation analysis revealed that for most (88%) of the colocalized genes, the expression levels of their corresponding proteins are regulated by cis-pQTLs via gene transcription. Using summary data-based Mendelian randomization analysis, we identified 4 proteins and 19 genes that are causally associated with schizophrenia. We further integrated multiple omics data with network analysis to prioritize candidate genes for schizophrenia risk loci. Collectively, our findings underscore the potential of proteome-wide linkage analysis in gaining mechanistic insights into the pathogenesis of psychiatric disorders.

Increased White Blood Cell In Young Adults With Family Histories Of Alcohol And Other Substance Use Disorders, Mustafa N Mithaiwala, Nikki S Phillips, Dylan H Nguyen, Melanie S Beehler, Harrison S Ballard, Andrea S Vincent, William R Lovallo, Peter Kochunov, L Elliot Hong, Jason C O'Connor, Steve Cole, Ashley Acheson

Faculty, Staff and Student Publications

Individuals with a family history of alcohol or other substance use disorders (FH+) are at increased risk for developing alcohol and other substance use disorders (AUD/SUD) compared to individuals with no such family histories (FH-). FH+ young adults have blunted stress reactivity, lower cognitive performance and altered frontal white matter microstructure compared to FH- controls. We hypothesized that family history of AUD/SUD disrupts neuroendocrine regulation of the immune system in FH+ individuals, resulting in altered blood immune cell composition, inflammation and neurocognitive alterations that, ultimately, increases risk for AUD/SUD and associated psychopathology. We examined white blood cell (WBC) parameters derived …

Epigenomic And Transcriptomic Profiling Of Solitary Fibrous Tumors Identifies Site-Specific Patterns And Candidate Genes Regulated By Dna Methylation, Hannah C Beird, Jeffrey M Cloutier, Nalan Gokgoz, Christopher Eeles, Anthony M Griffin, Davis R Ingram, Khalida M Wani, Rossana Lazcano Segura, Luca Cohen, Carl Ho, Jay S Wunder, Irene L Andrulis, P Andrew Futreal, Benjamin Haibe-Kains, Alexander J Lazar, Wei-Lien Wang, Joanna Przybyl, Elizabeth G Demicco

Faculty, Staff and Student Publications

A solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that can arise at any anatomical site and is characterized by recurrent NAB2::STAT6 fusions and metastatic progression in 10% to 30%. The cell of origin has not been identified. Despite some progress in understanding the contribution of heterogeneous fusion types and secondary mutations to SFT biology, epigenetic alterations in extrameningeal SFT remain largely unexplored, and most sarcoma research to date has focused on the use of methylation profiling for tumor classification. We interrogated genome-wide DNA methylation in 79 SFTs to identify informative epigenetic changes. RNA-seq data from targeted panels and …

The Phenotypic And Genotypic Spectrum Of Individuals With Mono- Or Biallelic Ank3 Variants., Francesca Furia, Amanda M. Levy, Miel Theunis, Michael J. Bamshad, Meghan N. Bartos, Emilia K. Bijlsma, Francesco Brancati, Lucile Cejudo, Jessica X. Chong, Chiara De Luca, Sarah Joy Dean, Alena Egense, Himanshu Goel, Adam J. Guenzel, Ulrike Hüffmeier, Eric Legius, Grazia M S Mancini, Iñigo Marcos-Alcalde, Tanguy Niclass, Marc Planes, Sylvia Redon, David Ros-Pardo, Karen Rouault, Rachel Schot, Sarah Schuhmann, Joseph J. Shen, Alice M. Tao, Isabelle Thiffault, Hilde Van Esch, Ingrid M. Wentzensen, Tahsin Stefan Barakat, Rikke S. Møller, Paulino Gomez-Puertas, Wendy K. Chung, Elena Gardella, Zeynep Tümer

Manuscripts, Articles, Book Chapters and Other Papers

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism …

A Phase I Dose Escalation Study Of The Lrp5 Antagonist Bi 905681 In Patients With Advanced And Metastatic Solid Tumors, D. R. Spigel, J. S. Wang, L. Pronk, B. Muskens, M. Teufel, Babar Bashir, H. Burris

Department of Medical Oncology Faculty Papers

BACKGROUND: The Wnt pathway is involved in proliferation and tissue homeostasis. Aberrant activation promotes cancer cell proliferation and survival. Inhibition of the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) coreceptors that regulate Wnt signaling could prevent cancer cell proliferation. BI 905681 is a novel LRP5 antagonist that has demonstrated potent in vivo antitumor activity.

PATIENTS AND METHODS: This was a phase I, dose escalation study (NCT04147247) evaluating BI 905681 in patients with advanced solid tumors over two dosing schedules (schedule A: every 3 weeks, 3-week cycles and schedule B: every 2 weeks, 4-week cycles). The primary endpoint was the maximum tolerated …

Integration Across Biophysical Scales Identifies Molecular And Cellular Correlates Of Person-To-Person Variability In Human Brain Connectivity, Bernard Ng, Shinya Tasaki, Kelsey M Greathouse, Courtney K Walker, Ada Zhang, Sydney Covitz, Matt Cieslak, Audrey J Weber, Ashley B Adamson, Julia P Andrade, Emily H Poovey, Kendall A Curtis, Hamad M Muhammad, Jakob Seidlitz, Ted Satterthwaite, David A Bennett, Nicholas T Seyfried, Jacob Vogel, Chris Gaiteri, Jeremy H Herskowitz

Faculty, Staff and Student Publications

Brain connectivity arises from interactions across biophysical scales, ranging from molecular to cellular to anatomical to network level. To date, there has been little progress toward integrated analysis across these scales. To bridge this gap, from a unique cohort of 98 individuals, we collected antemortem neuroimaging and genetic data, as well as postmortem dendritic spine morphometric, proteomic and gene expression data from the superior frontal and inferior temporal gyri. Through the integration of the molecular and dendritic spine morphology data, we identified hundreds of proteins that explain interindividual differences in functional connectivity and structural covariation. These proteins are enriched for …

Outcomes And Genetic Dynamics Of Acute Myeloid Leukemia At First Relapse, Alex Bataller, Hagop Kantarjian, Alexandre Bazinet, Tapan Kadia, Naval Daver, Courtney D Dinardo, Gautam Borthakur, Sanam Loghavi, Keyur Patel, Guilin Tang, Koji Sasaki, Nicholas J Short, Musa Yilmaz, Ghayas C Issa, Yesid Alvarado, Guillermo Montalban-Bravo, Abhishek Maiti, Hussein A Abbas, Koichi Takahashi, Sherry Pierce, Elias Jabbour, Guillermo Garcia-Manero, Farhad Ravandi

Faculty, Staff and Student Publications

Patients with relapsed acute myeloid leukemia (AML) experience dismal outcomes. We performed a comprehensive analysis of patients with relapsed AML to determine the genetic dynamics and factors predicting survival. We analyzed 875 patients with newly diagnosed AML who received intensive treatment or low-intensity treatment. Of these patients, 197 subsequently relapsed. Data were available for 164 of these patients, with a median time from complete remission/complete remission with incomplete blood count recovery to relapse of 6.5 months. Thirty-five of the 164 patients (21%) experienced relapse after allogeneic hematopoietic stem cell transplantation. At relapse, mutations in genes involved in pathway signaling tended …

Intra-Tumoral And Peripheral Blood Tigit And Pd-1 As Immune Biomarkers In Nodular Lymphocyte Predominant Hodgkin Lymphoma, Jay Gunawardana, Soi C Law, Muhammed B Sabdia, Éanna Fennell, Aoife Hennessy, Ciara I Leahy, Paul G Murray, Karolina Bednarska, Sandra Brosda, Judith Trotman, Leanne Berkahn, Andreea Zaharia, Simone Birch, Melinda Burgess, Dipti Talaulikar, Justina N Lee, Emily Jude, Eliza A Hawkes, Sanjiv Jain, Karthik Nath, Cameron Snell, Fiona Swain, Joshua W D Tobin, Colm Keane, Mohamed Shanavas, Emily Blyth, Christian Steidl, Kerry Savage, Pedro Farinha, Merrill Boyle, Barbara Meissner, Michael R Green, Francisco Vega, Maher K Gandhi

Faculty, Staff and Student Publications

In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or …

Trends And Disparities In Coronary Artery Disease And Obesity-Related Mortality In The United States From 1999-2022, Mushood Ahmed, Hira Javaid, Aimen Shafiq, Zain Ali Nadeem, Areeba Ahsan, Abdullah Nofal, Raheel Ahmed, Mahboob Alam, Marat Fudim, Gregg C Fonarow, Mamas A Mamas

Faculty, Staff and Students Publications

BACKGROUND: Almost half of the US adult population has obesity, which predisposes to atherosclerosis and can lead to poor prognosis in coronary artery disease (CAD). We aim to identify CAD and obesity-related mortality trends among adults in the United States stratified by age, sex, race and geographical location.

METHODS: The CDC-WONDER database was used to extract death certificate data for adults aged ≥ 25 years. Crude mortality rates (CMR) and age-adjusted mortality rates (AAMRs) per 100,000 persons were calculated, and temporal trends were described by calculating annual percent change (APC) and the average APC (AAPC) in the rates using Joinpoint …

Genetic Risk Factors In Isolated Dystonia Escape Genome-Wide Association Studies, Björn-Hergen Laabs, Katja Lohmann, Eva-Juliane Vollstedt, Tobias Reinberger, Lisa-Marie Nuxoll, Gamze Kilic-Berkmen, Joel S Perlmutter, Sebastian Loens, Carlos Cruchaga, Andre Franke, Valerija Dobricic, Frauke Hinrichs, Anne Grözinger, Eckart Altenmüller, Steven Bellows, Sylvia Boesch, Susan B Bressman, Kevin R Duque, Alberto J Espay, Andreas Ferbert, Jeanne S Feuerstein, Samuel Frank, Thomas Gasser, Bernhard Haslinger, Robert Jech, Frank Kaiser, Christoph Kamm, Katja Kollewe, Andrea A Kühn, Mark S Ledoux, Ebba Lohmann, Abhimanyu Mahajan, Alexander Münchau, Trisha Multhaupt-Buell, Alexander Pantelyat, Sarah E Pirio Richardson, Deborah Raymond, Stephen G Reich, Rachel Saunders Pullman, Barbara Schormair, Nutan Sharma, Azadeh Hamzehei Sichani, Kristina Simonyan, Jens Volkmann, Aparna Wagle Shukla, Juliane Winkelmann, Laura J Wright, Michael Zech, Kirsten E Zeuner, Simone Zittel, Meike Kasten, Yan V Sun, Tobias Bäumer, Norbert Brüggemann, Laurie J Ozelius, Hyder A Jinnah, Christine Klein, Inke R König

Faculty, Staff and Students Publications

Background: Despite considerable heritability, previous smaller genome-wide association studies (GWASs) have not identified any robust genetic risk factors for isolated dystonia.

Objective: The objective of this study was to perform a large-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk factors for isolated dystonia.

Methods: Array-based GWASs were performed on autosomes for 4303 dystonia participants and 2362 healthy control subjects of European ancestry with subgroup analysis based on age at onset, affected body regions, and a newly developed clinical score. Another 736 individuals were used for validation.

Results: This GWAS identified no common genome-wide significant …

Perivascular Epithelioid Cell-Family Tumors In Children, Adolescents, And Young Adults: Clinicopathologic Features In 70 Cases, Phoebe M Hammer, Angus Toland, Muhammad Shaheen, Archana Shenoy, Ashwini Esnakula, M John Hicks, Mikako Warran, Alyaa Al-Ibraheemi, Jessica L Davis, Serena Y Tan

Faculty, Staff and Students Publications

Context.—: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors of uncertain histogenesis expressing smooth muscle and melanocytic markers. The clinicopathologic spectrum in young patients is not well documented.

Objective.—: To describe a multi-institutional series of PEComas in children, adolescents, and young adults.

Design.—: PEComas, not otherwise specified (NOS); angiomyolipomas (AMLs); lymphangioleiomyomatosis; and clear cell sugar tumors were retrospectively identified from 6 institutions and the authors' files.

Results.—: Seventy PEComas in 64 patients (median age, 15 years) were identified. They were more common in females (45 of 64 patients), occurring predominantly in the kidney (53 of 70), followed by the …

Dna Methylation Classes Of Stage Ii And Iii Primary Melanomas And Their Clinical And Prognostic Significance, Kathleen Conway, Sharon N Edmiston, Amanda Vondras, Allison Reiner, David L Corcoran, Ronglai Shen, Eloise A Parrish, Honglin Hao, Lan Lin, Jessica M Kenney, Gbemisola Ilelaboye, Caroline E Kostrzewa, Pei Fen Kuan, Klaus J Busam, Cecilia Lezcano, Tim K Lee, Eva Hernando, Paul B Googe, David W Ollila, Stergios Moschos, Ivan Gorlov, Christopher I Amos, Marc S Ernstoff, Anne E Cust, James S Wilmott, Richard A Scolyer, Graham J Mann, Ismael A Vergara, Jennifer Ko, Judy R Rees, Shaofeng Yan, Eduardo Nagore, Marcus Bosenberg, Bonnie Gould Rothberg, Iman Osman, Jeffrey E Lee, Yvonne Saenger, Paul Bogner, Cheryl L Thompson, Meg Gerstenblith, Sheri L Holmen, Pauline Funchain, Elise Brunsgaard, Natalie D Depcik-Smith, Li Luo, Tawny Boyce, Irene Orlow, Colin B Begg, Marianne Berwick, Nancy E Thomas

Faculty, Staff and Students Publications

Purpose: Patients with stage II and III cutaneous primary melanoma vary considerably in their risk of melanoma-related death. We explore the ability of methylation profiling to distinguish primary melanoma methylation classes and their associations with clinicopathologic characteristics and survival.

Materials and methods: InterMEL is a retrospective case-control study that assembled primary cutaneous melanomas from American Joint Committee on Cancer (AJCC) 8th edition stage II and III patients diagnosed between 1998 and 2015 in the United States and Australia. Cases are patients who died of melanoma within 5 years from original diagnosis. Controls survived longer than 5 years without evidence of …

Covid-19 Breakthrough Infection After Vaccination And Substance Use Disorders: A Longitudinal Cohort Of People With And Without Hiv Receiving Care In The United States Veterans Health Administration, Elena M Soyer, Kathleen A Mcginnis, Amy C Justice, Evelyn Hsieh, Maria C Rodriguez-Barradas, Emily C Williams, Lesley S Park

Faculty, Staff and Students Publications

Research regarding HIV, substance use disorders (SUD), and SARS-CoV-2 infections after COVID-19 vaccination is limited. In the Veterans Aging Cohort Study (VACS)-HIV cohort, we followed vaccinated persons with HIV (PWH) and without HIV (PWoH) from 12/2020 to 3/2022 and linked SARS-CoV-2 test results for laboratory-confirmed breakthrough infection through 9/2022. We examined associations of substance use (alcohol use disorder [AUD], other SUD, smoking status) and HIV status and severity with breakthrough infections, using Cox proportional hazards regression hazard ratios (HR). To test for potential interactions between substance use and HIV, we fit survival models with a multiplicative interaction term. Among 24,253 …

Biallelic Loss-Of-Function Variants In Ubap1l And Nonsyndromic Retinal Dystrophies, Ehsan Ullah, Siying Lin, Jiaxiong Lu, Chelsea Bender, Andrew R Webster, Samantha Malka, Savita Madhusudhan, Emma Rees, Denise Williams, Aime R Agather, Catherine A Cukras, Robert B Hufnagel, Rui Chen, Laryssa A Huryn, Gavin Arno, Bin Guan

Faculty, Staff and Students Publications

Importance: Inherited retinal dystrophies (IRDs) present a challenge in clinical diagnostics due to their pronounced genetic heterogeneity. Despite advances in next-generation sequencing (NGS) technologies, a substantial portion of the genetic basis underlying IRDs remains elusive. Addressing this gap seems important for gaining insights into the genetic landscape of IRDs, which may help improve diagnosis and prognosis and develop targeted therapies in the future.

Objective: To provide a clinical and molecular characterization of 6 patients with IRDs with biallelic disease-causing variants in a novel candidate IRD disease gene.

Design, setting, and participants: This multicenter case series study included 6 patients with …

Prognostic Stratification In Dlbcl Patients With Aberrant Myc Gene, Jian-Rong Li, Vikram R Shaw, Abi Parthasarathy, Yong Li, Christopher I Amos, Chao Cheng

Faculty, Staff and Students Publications

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by a subset of patients who exhibit treatment resistance and poor prognoses. Genomic assays have been widely employed to identify high-risk individuals characterized by rearrangements in the MYC, BCL2 and BCL6 genes. These patients typically undergo more aggressive therapeutic treatments; however, there remains a significant variation in their treatment outcomes. This study introduces an MYC signature score (MYCSS) derived from gene expression profiles, specifically designed to evaluate MYC overactivation in DLBCL patients. MYCSS was validated across several independent cohorts to assess its ability to stratify patients based on MYC-related genetic …

Senescence Biomarkers And Trajectories Of Frailty And Physical Function After Kidney Transplantation, Elizabeth C Lorenz, Byron H Smith, Hani M Wadei, Girish Mour, Cassie C Kennedy, Carrie A Schinstock, Walter K Kremers, Andrea L Cheville, Latonya J Hickson, Elizabeth J Atkinson, Thomas A White, Andrew D Rule, Nathan K Lebrasseur

Faculty, Staff and Students Publications

Cellular senescence is a biological mechanism of aging and age-related diseases. The aim of this study was to examine whether senescence biomarkers are associated with frailty and physical function trajectories in patients undergoing kidney transplantation (KT). We also discussed the relationship between senescence biomarkers and KT function. In this multicenter study, we prospectively assessed plasma levels of senescence biomarkers, frailty as measured by the Physical Frailty Phenotype, and physical function as measured by the Short Physical Performance Battery prior to KT. Frailty, physical function, and KT function were also measured 1 year after KT. Variable associations were assessed using Cox …

Pancreatitis Pain Quality Changes At Year 1 Follow-Up, But Gp130 Remains A Biomarker For Pain, Jami L Saloman, Kristofer Jennings, Kimberly Stello, Shuang Li, Anna Evans Phillips, Kristen Hall, Evan L Fogel, Santhi Swaroop Vege, Dana K Andersen, William E Fisher, Christopher E Forsmark, Phil A Hart, Stephen J Pandol, Walter G Park, Mark D Topazian, Stephen K Van Den Eeden, Jose Serrano, Darwin L Conwell, Liang Li, Dhiraj Yadav

Center for Medical Ethics and Health Policy Staff Publications

Background/objectives: Debilitating abdominal pain is a common symptom affecting patients with chronic pancreatitis (CP). CP pain is dynamic due to multiple underlying mechanisms. The objective of this study was to 1) evaluate changes in pain phenotype at one year follow-up and 2) validate putative pain biomarkers in a prospective cohort study.

Methods: The Neuropathic and Nociceptive PROMIS-PQ questionnaires were used to classify pain for participants with in the PROCEED study. Putative serum biomarkers were measured via immunoassay.

Results: At enrollment, 17.6 % (120/681) subjects with CP reported no pain in the previous year. Of those, 29 % experienced pain during …

Adjuvant Trastuzumab Emtansine Versus Paclitaxel Plus Trastuzumab For Stage I Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 5-Year Results And Correlative Analyses From Atempt, Paolo Tarantino, Ron Bose, Et Al.

2020-Current year OA Pubs

PURPOSE: Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need.

METHODS: In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. …

Tocilizumab Prophylaxis Following Axicabtagene Ciloleucel In Relapsed Or Refractory Large B-Cell Lymphoma, Frederick L Locke, Nancy L Bartlett, Et Al.

2020-Current year OA Pubs

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Most patients treated with axi-cel experience cytokine release syndrome (CRS) and/or adverse neurologic events (NEs). To explore potential approaches for reducing CAR T-cell-related toxicities with axi-cel, several safety expansion cohorts were added to the pivotal ZUMA-1 trial. ZUMA-1 Cohort 3 was an exploratory safety cohort that investigated the use of the IL-6 receptor-blocking antibody tocilizumab and anticonvulsant levetiracetam as prophylaxis against CRS and NEs in patients treated with axi-cel. Patients with R/R LBCL were enrolled in Cohort …

Risk-Stratified Treatment For Drug-Susceptible Pulmonary Tuberculosis, Vincent K Chang, Marjorie Z Imperial, Patrick P J Phillips, Gustavo E Velásquez, Payam Nahid, Andrew Vernon, Ekaterina V Kurbatova, Susan Swindells, Richard E Chaisson, Susan E Dorman, John L Johnson, Marc Weiner, Amina Jindani, Thomas Harrison, Erin E Sizemore, William Whitworth, Wendy Carr, Kia E Bryant, Deron Burton, Kelly E Dooley, Melissa Engle, Pheona Nsubuga, Andreas H Diacon, Nguyen Viet Nhung, Rodney Dawson, Radojka M Savic, Aids Clinical Trial Group, Tuberculosis Trials Consortium

Faculty, Staff and Student Publications

The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, …

Prenatal Opioid And Alcohol Exposures: Association With Altered Placental Serotonin Transporter Structure And/Or Expression, Nune Darbinian, Nana Merabova, Gabriel Tatevosian, Sandra Adele, Armine Darbinyan, Mary F Morrison, C Lindsay Devane, Sammanda Ramamoorthy, Laura Goetzl, Michael E Selzer

Faculty, Staff and Student Publications

Fetal exposures to many drugs of abuse, e.g., opioids and alcohol (EtOH), are associated with adverse neurodevelopmental problems in early childhood, including abnormalities in activity of the serotonin (5HT) transporter (SERT), which transports 5HT across the placenta. Little is known about the effects of these drugs on SERT expression. Pregnant women who used EtOH or opioids were compared to gestational age-matched controls using a structured questionnaire to determine prenatal substance exposure. Following elective pregnancy termination, placental membranous vesicles and exosomes were prepared from first and second trimester human placentas. Changes in EtOH- or opioid-exposed placental SERT expression and modifications were …

The Contribution Of Neutrophil Extracellular Traps To Coagulopathy In Patients With Covid-19-Related Thrombosis, Carolyn Enochs, Gabriela Delevati Colpo, Lucy Couture, Lynae Baskin, Ana E Cahuiche, Eunyoung Angela Lee, Shahid Nimjee, Louise D Mccullough

Faculty, Staff and Student Publications

COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is associated with hypercoagulability and increased incidence of thrombotic events. In this study, we investigated the levels of neutrophil extracellular trap biomarkers and von Willebrand factor to assess if these could predict the occurrence of a thrombotic event in COVID-19 patients. We enrolled 202 patients hospitalized with symptomatic COVID-19 infection. Of those, 104 patients did not experience any type of thrombotic events before or during their hospitalization. These patients were compared to the other cohort of 98, who experienced thrombotic events before or during their hospitalization. In total, …

Multiomic And Clinical Analysis Of Multiply Recurrent Meningiomas Reveals Risk Factors, Underlying Biology, And Insights Into Evolution, Sangami Pugazenthi, Bhuvic Patel, Collin W English, William A Leidig, Kyle P Mcgeehan, Colin R Mccornack, Shinghei Mok, Markus Anzaldua-Campos, Shervin Hosseingholi Nouri, Kaleigh Roberts, Ajay Chatrath, A Khan, Ron Gadot, Hiroko Yano, Tiemo J Klisch, Akdes S Harmanci, Akash J Patel, Albert H Kim

Faculty, Staff and Students Publications

An important subset of meningiomas behaves aggressively and is characterized by multiple recurrences. We identify clinical, genetic, and epigenetic predictors of multiply recurrent meningiomas (MRMs) and evaluate the evolution of these meningiomas in patient-matched samples. On multivariable binomial logistic regression, MRMs were significantly associated with male sex (P = 0.012), subtotal resection (P = 0.001), higher number of meningiomas on presentation (P = 0.017), and histopathological sheeting (P = 0.002). Multiomic analysis of primary meningiomas revealed that MRMs have greater copy number losses (P = 0.0313) and increased DNA methylation (P = 0.0155). In …

Association Of Deployment Characteristics And Exposures With Persistent Ill Health Among 1990–1991 Gulf War Veterans In The Va Million Veteran Program, Lea Steele, Rachel Quaden, Sarah T Ahmed, Kelly M Harrington, Linh M Duong, John Ko, Elizabeth J Gifford, Renato Polimanti, J Michael Gaziano, Mihaela Aslan, Drew A Helmer, Elizabeth R Hauser, Department Of Veterans Affairs Cooperative Studies Program #2006 And The Va Million Veteran Program

Center for Medical Ethics and Health Policy Staff Publications

Background: Veterans of the 1990-1991 Gulf War have experienced excess health problems, most prominently the multisymptom condition Gulf War illness (GWI). The Department of Veterans Affairs (VA) Cooperative Studies Program #2006 "Genomics of Gulf War Illness in Veterans" project was established to address important questions concerning pathobiological and genetic aspects of GWI. The current study evaluated patterns of chronic ill health/GWI in the VA Million Veteran Program (MVP) Gulf War veteran cohort in relation to wartime exposures and key features of deployment, 27-30 years after Gulf War service.

Methods: MVP participants who served in the 1990-1991 Gulf War completed the …

Multiomic And Clinical Analysis Of Multiply Recurrent Meningiomas Reveals Risk Factors, Underlying Biology, And Insights Into Evolution, Sangami Pugazenthi, Bhuvic Patel, William A Leidig, Kyle P Mcgeehan, Colin R Mccornack, Shinghei Mok, Markus Anzaldua-Campos, Kaleigh Roberts, Ajay Chatrath, Hiroko Yano, Akdes S Harmanci, Akash J Patel, Albert H Kim, Et Al.

2020-Current year OA Pubs

An important subset of meningiomas behaves aggressively and is characterized by multiple recurrences. We identify clinical, genetic, and epigenetic predictors of multiply recurrent meningiomas (MRMs) and evaluate the evolution of these meningiomas in patient-matched samples. On multivariable binomial logistic regression, MRMs were significantly associated with male sex (

Aromatase, Testosterone, Tmprss2: Determinants Of Covid-19 Severity, Eric C Mohan, Jude P J Savarraj, Gabriela D Colpo, Diego Morales, Carson E Finger, Alexis Mcalister, Hilda Ahnstedt, Huimahn Choi, Louise D Mccullough, Bharti Manwani

Faculty, Staff and Student Publications

Background: Male sex has been identified as a risk factor for worse COVID-19 outcomes. This sex difference has been mostly attributed to the complex role of sex hormones. Cell surface entry of SARS-CoV-2 is mediated by the transmembrane protease serine 2 (TMPRSS2) which is under transcriptional regulation by androgens. P450 aromatase enzyme converts androgens to estrogens. This study measured concentrations of aromatase enzyme, testosterone, estradiol, and TMPRSS-2 in plasma of hospitalized COVID-19 patients to elucidate the dynamics of sex-linked disparity in COVID-19 and correlate them with disease severity and mortality.

Methods: In this prospective cohort study, a total of 265 …