Digital Commons Network^™

Dna Methylation Epitypes Of Burkitt Lymphoma With Distinct Molecular And Clinical Features, Nicole Thomas, Nancy L Bartlett, Et Al.

2020-Current year OA Pubs

UNLABELLED: The genetic subtypes of Burkitt lymphoma have been defined, but the role of epigenetics remains to be comprehensively characterized. We searched genomic DNA from 218 patients across four continents for recurrent DNA methylation patterns and their associations with clinical and molecular features. We identified DNA methylation patterns that were not fully explained by the Epstein-Barr virus status or mutation status, leading to two epitypes described here as HypoBL and HyperBL. Each is characterized by distinct genomic and clinical features including global methylation, mutation burden, aberrant somatic hypermutation, and survival outcomes. Methylation, gene expression, and mutational differences between the epitypes …

High-Frequency, At-Home Monitoring Of Drug Safety And Tolerability In Clinical Trials: Results From Studies Of Fluvoxamine For Covid-19 Treatment, Eric J Lenze, Madeline Nykamp, J Philip Miller, Angela Stevens, Julia Schweiger, Torie Gettinger, Michael Yingling, Yi Zhang, Ginger E Nicol, Charles F Zorumski, Angela M Reiersen

2020-Current year OA Pubs

Clinical trials are increasingly using remote monitoring techniques at the patient's home. We conducted a secondary analysis of remote safety and tolerability monitoring from two fully-remote clinical trials that tested fluvoxamine for the acute treatment of COVID-19. Both trials assessed pulse and blood pressure daily, and one study assessed symptoms daily via Ecological Momentary Assessment. On average, patients provided data on vital signs on 93% of the study days and provided data on side effects on 81% of the study days. With respect to safety, patients taking fluvoxamine had reduced pulse rate compared to placebo, with the greatest difference-5 points-at …

Clinical Evaluation Of The Healgen Rapid Covid-19 Antigen Test As A Point-Of-Care Diagnostic Tool, Stephen A Young, Hua Zhang, Jose Rodriguez, David Mishkin, Ward Paine, Li Seyfried, Latisha Hargrove, Dennis L Broyles, Chermaen Lindberg, Anurag Purushothaman, Stacey House

2020-Current year OA Pubs

BACKGROUND: Development of readily available Rapid COVID-19 Antigen tests essential for promptly identifying SARS-CoV2 infection and preventing its spread.

METHODS: This study evaluated the clinical performance of the Healgen Rapid COVID-19 antigen test as a point-of-care diagnostic tool with 806 evaluable subjects who were within 6 days post-symptom onset. The results from the Healgen test were compared to the results from Emergency Use Authorization (EUA) approved SARS-CoV-2 RT-PCR tests.

RESULTS: Out of the 806 evaluable subjects, 140 tested positive and 640 tested negative for SARS-CoV-2 with the Healgen COVID-19 test, showing good agreement with the EUA RT-PCR results. There were …

Individualized Functional And Structural Language Lateralities In Temporal Lobe Epilepsy And Their Impact On Memory, Ankeeta Ankeeta, Qirui Zhang, Sam Sharifzadeh Javidi, Shilpi Modi, Michael R. Sperling, Joseph I. Tracy

Department of Neurology Faculty Papers

The basis and impact of functional asymmetries in the brain, particularly language lateralization, are not fully understood, and the relationship between functional and structural asymmetries remains largely untested. This study investigated the degree to which asymmetries in hemispheric language laterality are concordant with asymmetries in gray matter (GM) structure and whether the hemispheric organization of memory is influenced by functional language asymmetries. Structural and functional MR data was acquired from 261 individuals, including those with unilateral temporal lobe epilepsy (LTLE = 96, RTLE = 69) and matched with healthy participants (HPs = 96). Functional language laterality indices (LIs) were calculated …

Phase Ii Basket Trial Of Dual Anti-Ctla-4 And Anti-Pd-1 Blockade In Rare Tumors (Dart) Swog S1609: Pancreatic Neuroendocrine Neoplasm (Pnen) Cohort, Sandip Pravin Patel, Jillian Fisher, Young Kwang Chae, Luisa Solis Soto, Anup Kasi, Bhavana Konda, Mark Walshauser, Edwin Parra, Jiexin Zhang, Caroline Duault, Edgar Gonzalez-Kozlova, Ganiraju Manyam, Jianhua Zhang, Hong Chen, Dzifa Yawa Duose, Caddie Laberiano Fernandez, Raja Luthra, Gheath Al-Atrash, Seunghee Kim-Schulze, Holden T Maecker, Ignacio I Wistuba, Sacha Gnjatic, J Jack Lee, Jianjun Zhang, Christine M Magner, Helen X Chen, Elad Sharon, Megan Othus, Christopher W Ryan, Charles Blanke, Cara L Haymaker, Razelle Kurzrock

Faculty, Staff and Student Publications

Purpose: SWOG S1609 Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) studied the efficacy of ipilimumab combined with nivolumab across multiple rare tumor types. We report the results of the pancreatic neuroendocrine neoplasm (PNEN) cohort.

Experimental design: Treatment consisted of ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR) (Response Evaluation Criteria In Solid TumorsRECIST V.1.1). Secondary endpoints include progression-free survival (PFS), overall survival (OS), and toxicity. Clinical benefit rate (includes ORR plus stable disease (SD)>6 months was examined. Correlative …

"Holy Cow, Where Do I Sign Up?" Attitudes Of Military Veterans Toward Epigenomic Biomarker Toxic Exposure Testing, Stacey Pereira, Calvin Apodaca, Kyle Slominski, Rachele K Lipsky, Cristian Coarfa, Cheryl L Walker, Amy L Mcguire, Lea Steele, Drew A Helmer

Center for Medical Ethics and Health Policy Staff Publications

Introduction: After the Sergeant First Class Heath Robinson Honoring Our Promise to Address Comprehensive Toxics Promise to Address Comprehensive Toxics (PACT) Act in 2022, there has been a great interest in studying toxic exposures encountered during military service. Development of epigenomic biomarkers for exposures could facilitate understanding of exposure-related health effects, but such testing could also provide unwanted information.

Materials and methods: We explored attitudes toward epigenomic biomarker research and the potential to test for past exposures using semistructured interviews with Veterans (n = 22) who experienced potentially harmful exposures.

Results: Twenty Veterans said they would hypothetically want to receive …

Encorafenib, Cetuximab, And Mfolfox6 In Braf-Mutated Colorectal Cancer, Elena Elez, Takayuki Yoshino, Lin Shen, Sara Lonardi, Eric Van Cutsem, Cathy Eng, Tae Won Kim, Harpreet Singh Wasan, Jayesh Desai, Fortunato Ciardiello, Rona Yaeger, Timothy S Maughan, Van K Morris, Christina Wu, Tiziana Usari, Robert Laliberte, Samuel S Dychter, Xiaosong Zhang, Josep Tabernero, Scott Kopetz, Breakwater Trial Investigators

Faculty, Staff and Student Publications

Background: First-line treatment with encorafenib plus cetuximab (EC) with or without chemotherapy (oxaliplatin, leucovorin, and fluorouracil [mFOLFOX6]) for BRAF V600E-mutated metastatic colorectal cancer, an aggressive subtype with a poor prognosis, was compared with standard care (chemotherapy with or without bevacizumab) in an open-label, phase 3 trial, which showed significance regarding one of the two primary end points, objective response according to blinded independent central review (odds ratio for EC+mFOLFOX6 vs. standard care, 2.44; one-sided P< 0.001). This result led to accelerated Food and Drug Administration approval of this investigational combination therapy for BRAF V600E-mutated metastatic colorectal cancer, including as first-line therapy. Data on progression-free survival (the second primary end point) and an updated interim analysis of overall …

Intratumoral Neutrophil-To-Lymphocyte Ratio Is Mirrored By Circulating Neutrophil-To-Lymphocyte Ratio In Non-Small Cell Lung Cancer, Kyle G Mitchell, Younghee Lee, Nathaniel Deboever, Marcelo V Negrao, Hai T Tran, Edwin Parra, Lauren Byers, Alexandre Reuben, Lorenzo Federico, Chantale Bernatchez, Jing Wang, Mara B Antonoff, Ara A Vaporciyan, Stephen G Swisher, Tina Cascone, Ignacio I Wistuba, John V Heymach, Don L Gibbons, Jianjun Zhang, Daniel J Mcgrail, Boris Sepesi, Cara L Haymaker

Faculty, Staff and Student Publications

Tumor-initiated emergency granulopoiesis results in expansion of the circulating neutrophil compartment and neutrophil recruitment into the tumor microenvironment (TME), which may in turn promote tumor progression. Although an elevated circulating neutrophil-to-lymphocyte ratio (cNLR) has repeatedly been demonstrated to be an adverse prognostic factor in patients with non-small cell lung cancer (NSCLC), whether this neutrophil expansion in circulation reflects a similar relative neutrophil abundance in the TME remains unclear. We sought to characterize the relationships between cNLR and the intratumoral neutrophil-to-lymphocyte ratio (tNLR), between tNLR and proteogenomic and immune features of NSCLC tumors, and between tNLR and prognosis.We analyzed tNLR (transcriptomic …

Do Female Patients Experience Worse Outcomes Than Male Patients After Inguinal Hernia Repair? An Analysis Of The Abdominal Core Health Quality Collaborative Database, Amrita Iyer, Sunjay Kumar, Martina Rama, Sourav Podder, Li-Ching Huang, Sami Tannouri, Talar Tatarian, Francesco Palazzo

Department of Surgery Faculty Papers

BACKGROUND: Inguinal hernia repair is one of the most common general surgery operations. Some evidence suggests that female patients are at greater risk of chronic postoperative pain and hernia recurrence. We investigated rates of chronic inguinal pain and recurrence after inguinal hernia repair in both male and female patients using the Abdominal Core Health Quality Collaborative database.

METHODS: The Abdominal Core Health Quality Collaborative database was queried for patients undergoing elective, unilateral inguinal hernia repair who completed 30-day clinical follow-up and baseline and 1-year European Registry for Abdominal Wall Hernias Survey surveys. Both open and minimally invasive cases were included. …

Cholesterol Metabolism Regulated By Camkk2-Creb Signaling Promotes Castration-Resistant Prostate Cancer, Chenchu Lin, Thomas L Pulliam, Jenny J Han, Jiaqian Xu, Carlos Vera Recio, Sandi R Wilkenfeld, Yan Shi, Manoj Kushwaha, Sarah Bench, Eduardo Ruiz, Sanjanaa Senthilkumar, Jayasurya Dileep, Peter D A Shepherd, Nora M Navone, Albert R Klekers, Elizabeth M Whitley, Michael M Ittmann, Livia S Eberlin, Wenyi Wang, Daniel E Frigo

Faculty, Staff and Student Publications

Castration-resistant prostate cancer (CRPC) remains an incurable disease in need of improved treatments. CAMKK2 is an emerging therapeutic target whose oncogenic effects in prostate cancer have, to date, been largely attributed to its activation of AMP-activated protein kinase (AMPK). Here, we demonstrate that CAMKK2 promotes prostate cancer growth through an alternative downstream pathway involving CAMKI and CREB. Unbiased transcriptomics identify CREB-mediated transcription as a CAMKK2-regulated process, findings that we validate using diverse molecular, genetic, and pharmacological approaches in vitro and in vivo. CAMKK2 promotes CREB phosphorylation/activation through CAMKIα independently of AMPK, CAMKIV, or other CAMKI isoforms. Functionally, the CREB family …

Exploring Predictors Of Treatment Response To Glp-1 Receptor Agonists For Smoking Cessation, Luba Yammine, Constanza De Dios, Robert Suchting, Charles E Green, David A Nielsen, Consuelo Walss-Bass, Joy M Schmitz

Faculty, Staff and Student Publications

Introduction: Understanding predictors of smoking cessation medication efficacy facilitates the ability to enhance treatment effectiveness. In our pilot trial, exenatide, a glucagon-like peptide-1 receptor agonist, adjunct to nicotine patch improved smoking abstinence compared to nicotine patch alone. This secondary analysis explores potential baseline characteristics associated with differential treatment response to exenatide.

Aims and methods: The parent trial randomized (1:1) 84 smokers with prediabetes and/or overweight to once-weekly placebo or exenatide, 2 mg, subcutaneously. All participants received nicotine patch (21 mg) and brief smoking cessation counseling, with biologically confirmed 7-day point prevalence abstinence at week 6 (end-of-treatment) deemed the primary outcome. …

Multi-Ancestry Genome-Wide Association Analyses Incorporating Snp-By-Psychosocial Interactions Identify Novel Loci For Serum Lipids, Amy R Bentley, Michael R Brown, Solomon K Musani, Karen L Schwander, Thomas W Winkler, Mario Sims, Tuomas O Kilpeläinen, Hugues Aschard, Traci M Bartz, Lawrence F Bielak, Jin-Fang Chai, Kumaraswamy Naidu Chitrala, Nora Franceschini, Mariaelisa Graff, Xiuqing Guo, Fernando P Hartwig, Andrea R V R Horimoto, Elise Lim, Yongmei Liu, Alisa K Manning, Ilja M Nolte, Raymond Noordam, Melissa A Richard, Albert V Smith, Yun Ju Sung, Dina Vojinovic, Rujia Wang, Yujie Wang, Mary F Feitosa, Sarah E Harris, Leo-Pekka Lyytikäinen, Giorgio Pistis, Rainer Rauramaa, Peter J Van Der Most, Erin Ware, Stefan Weiss, Wanqing Wen, Lisa R Yanek, Dan E Arking, Donna K Arnett, Christie Ballantyne, Eric Boerwinkle, Yii-Der Ida Chen, Martha L Daviglus, Lisa De Las Fuentes, Paul S De Vries, Joseph A C Delaney, Amanda M Fretts, Lynette Ekunwe, Jessica D Faul, Linda C Gallo, Sami Heikkinen, Georg Homuth, M Arfan Ikram, Carmen R Isasi, Jost Bruno Jonas, Liisa Keltikangas-Järvinen, Pirjo Komulainen, Aldi T Kraja, Jose E Krieger, Lenore Launer, Lifelines Cohort Study, Jianjun Liu, Kurt Lohman, Annemarie I Luik, Ani W Manichaikul, Pedro Marques-Vidal, Yuri Milaneschi, Stanford E Mwasongwe, Jeffrey R O'Connell, Kenneth Rice, Stephen S Rich, Pamela J Schreiner, Lars Schwettmann, James M Shikany, Xiao-Ou Shu, Jennifer A Smith, Harold Snieder, Nona Sotoodehnia, E Shyong Tai, Kent D Taylor, Lesley Tinker, Michael Y Tsai, André G Uitterlinden, Cornelia M Van Duijn, Diana Van Heemst, Melanie Waldenberger, Robert B Wallace, Hwee-Lin Wee, David R Weir, Wen-Bin Wei, Ko Willems Van Dijk, Gregory Wilson, Jie Yao, Kristin L Young, Xiaoyu Zhang, Wei Zhao, Xiaofeng Zhu, Alan B Zonderman, Ian J Deary, Christian Gieger, Hans Jörgen Grabe, Timo A Lakka, Terho Lehtimäki, Albertine J Oldehinkel, Martin Preisig, Ya-Xing Wang, Wei Zheng, Michele K Evans, Michael Province, James Gauderman, Vilmundur Gudnason, Catharina A Hartman, Bernardo L Horta, Sharon L R Kardia, Charles Kooperberg, Ching-Ti Liu, Dennis O Mook-Kanamori, Brenda Wjh Penninx, Alexandre C Pereira, Patricia A Peyser, Bruce M Psaty, Jerome I Rotter, Xueling Sim, Kari E North, Dabeeru C Rao, Laura Bierut, Clint L Miller, Alanna C Morrison, Charles N Rotimi, Myriam Fornage, Ervin R Fox

Faculty, Staff and Student Publications

Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids. We conducted a genome-wide gene-by-psychosocial factor interaction (G×Psy) study in up to 133,157 individuals to evaluate if G×Psy influences serum lipid levels. We conducted a two-stage meta-analysis …

Risk Factors For Serious Bacterial Infections Among Young Infants With Hypothermia: Protocol For A Multicenter, Retrospective Case-Control Study, Sriram Ramgopal, Paul Aronson, Douglas Lorenz, Alexander Joseph Rogers, Andrea Tania Cruz

Faculty, Staff and Students Publications

Background: Hypothermia in young infants presenting to the emergency department (ED) may indicate a serious bacterial infection (SBI) such as a urinary tract infection, bacteremia, or bacterial meningitis. Improved understanding of the epidemiology of SBI in infants with hypothermia and the development of prediction models can help avoid unnecessary invasive procedures and antimicrobial exposure.

Objective: The aim of the study is to (1) describe the epidemiology of SBI and herpes simplex virus (HSV) among infants with hypothermia, (2) assess the role of biomarkers in predicting SBI, and (3) derive and internally validate a multivariable predictive model for SBI among infants …

Type I Interferon Protects Against Bone Loss In Periodontitis By Mitigating An Interleukin (Il)-17-Neutrophil Axis, Jinmei Zhang, Qiong Ding, Angela X Wang, Maoxuan Lin, Ning Yu, Kevin Moss, Megumi A Williamson, Di Miao, Julie T Marchesan, Erliang Zeng, Wei Shi, Hongli Sun, Yu Leo Lei, Shaoping Zhang

Faculty, Staff and Student Publications

Type I interferons (IFNs-I), a group of pleiotropic cytokines, critically modulate host response in various inflammatory diseases. However, the role of the IFN-I pathway in periodontitis remains largely unknown. In this report, we describe that the IFN-β levels in the gingival crevicular fluid of human subjects were negatively associated with periodontitis and clinical gingival inflammation. Disruption of IFN-I signaling worsened alveolar bone resorption in a ligature-induced periodontitis murine model. Deficiency of the IFN-I pathway resulted in an exaggerated inflammatory response in myeloid cells and drastically increased the interleukin-17 (IL-17)-mediated neutrophil recruitment in the gingiva. We further identified that the myeloid …

Asymmetric Cingulum Bundle Connectivity Is Modulated By Paracingulate Sulcus Morphology, Isabel A Danstrom, Joshua A Adkinson, Meghan E Robinson, Lu Lin, Atul Maheshwari, Ben Shofty, Garrett Banks, Mohammed Hasen, Sameer A Sheth, Alica M Goldman, Eleonora Bartoli, Sarah R Heilbronner, Kelly R Bijanki

Faculty, Staff and Students Publications

The cingulum bundle (CB) is a group of axons supporting connectivity among several functional brain networks relevant in healthy and diseased states. The paracingulate sulcus (PCS) is present in at least one cerebral hemisphere across 70% of the population. PCS presence versus absence is linked to differences in structure and function of the anterior cingulate cortex, though the influence of PCS on the white matter of the CB remains unknown. The objective of this work was to define the CB electrographic connectivity profile and determine the impact of PCS morphology on CB engagement. Single-pulse electrical stimulation in combination with stereo-electroencephalography …

Transgenerational Obesity Modulation Of Gut Mucosal Immunity, Chen-Ting Hung, Justin Kern, Tihana Trsan, Santosh K Panda, Marie Laury, Umang Jain, Marco Colonna, Thaddeus S Stappenbeck, Ta-Chiang Liu

2020-Current year OA Pubs

The prevalence of obesity in the United States has continued to increase over the past several decades. A growing concern is that transgenerational effects of obesity negatively impact physiologic functions. We showed that consumption of a high fat, high sugar "Western" diet (WD) decreased the density of both gut innate (Paneth cells) and adaptive immune cells (intraepithelial lymphocytes; IEL). We asked whether consumption of WD impacts gut mucosal immunity in the offspring. WD-mediated Paneth cell loss was reversible, whereas IEL loss was not. However, the overall composition of the fecal microbiome and response to infection were defined by the diet …

Integrated Metabolomics And Spatial Transcriptomics Of Cystic Pancreatic Cancer Precursors Reveals Dysregulated Polyamine Metabolism As A Biomarker Of Progression, Ricardo A León-Letelier, Yihui Chen, Rongzhang Dou, Ehsan Irajizad, Michele T Yip-Schneider, Ranran Wu, Rahmah Ejaz, Hamid K Rudsari, Yaxi Li, Rachelle Spencer, Riccardo Ballarò, Jody Vykoukal, Mark Hurd, Jennifer B Dennison, Kim-Anh Do, Anirban Maitra, Jianjun Zhang, Samir Hanash, C Max Schmidt, Johannes F Fahrmann

Faculty, Staff and Student Publications

Purpose: We conducted metabolomics and spatial cell transcriptomics of intraductal papillary mucinous neoplasms (IPMN), recognized pancreatic cancer precursors, to identify oncometabolites that inform upon risk of malignancy of IPMNs.

Experimental design: Untargeted metabolomic analyses were performed on cystic fluid from 125 patients with low-grade (LG) dysplasia or high-grade (HG) dysplasia with/without concurrent pancreatic ductal adenocarcinoma (PDAC; IPMN/PDAC). Predictive performance of individual metabolites for identifying HG or PDAC/IPMN was determined and compared with CA19-9 performance. Data were intersected with metabolic profiles of resected IPMN tissues and murine Kras;Gnas IPMN cell lines as well as spatial and single-cell transcriptomics of IPMNs.

Results: …

Azacitidine, Venetoclax, And Magrolimab In Newly Diagnosed And Relapsed Refractory Acute Myeloid Leukemia: Phase Ib/Ii Study And Correlative Analysis, Naval Daver, Jayastu Senapati, Hagop M Kantarjian, Bofei Wang, Patrick K Reville, Sanam Loghavi, Musa Yilmaz, Courtney D Dinardo, Tapan M Kadia, Mhd Yousuf Yassouf, Abhishek Maiti, Sankalp Arora, Guillermo Montalban Bravo, Guilin Tang, Gautam Borthakur, Koji Sasaki, Naveen Pemmaraju, Joie Alvarez, Graciela M Nogueras Gonzalez, Jing Ning, Ghayas C Issa, Marina Konopleva, Michael Andreeff, Farhad Ravandi, Guillermo Garcia-Manero, Hussein A Abbas

Faculty, Staff and Student Publications

Purpose: Magrolimab is a monoclonal antibody directed against the macrophage checkpoint CD47 on myeloid leukemia cells that was preclinically synergistic with azacitidine-venetoclax, warranting further clinical evaluation.

Patients and methods: In this phase Ib/II study, the triplet combination of azacitidine, venetoclax, and magrolimab was evaluated in adult patients with first-line (ineligible for intensive chemotherapy) and relapsed/refractory acute myeloid leukemia. Azacitidine was dosed at 75 mg/m2 for 7 days, venetoclax at 400 mg/day for 28 days, and magrolimab (recommended phase II dose) as follows: 1 mg/kg dose on days 1 and 4, 15 mg/kg on day 8, and 30 mg/kg on days …

Olfaction And Plasma Biomarkers Of Alzheimer Disease And Neurodegeneration In The Atherosclerosis Risk In Communities Study, Srishti Shrestha, Xiaoqian Zhu, Michael E Griswold, Priya Palta, Kevin J Sullivan, Honglei Chen, Andrea Lauren Christman Schneider, Abhay Moghekar, Megan L Grove, Bharat Thyagarajan, James Russell Pike, Rebecca F Gottesman, B Gwen Windham, Thomas H Mosley, Jennifer A Deal, Vidyulata Kamath

Faculty, Staff and Student Publications

Background and objectives: Investigation of olfactory impairment, an early manifestation of Alzheimer disease (AD), in relation to plasma biomarkers of AD and neurodegeneration could provide insights into the disease's pathophysiology. Because few such studies based on large, diverse, community-based populations exist, we investigated associations of odor identification ability with plasma biomarkers of AD and other neurodegenerative pathologies in community-dwelling Black and White older adults.

Methods: This cross-sectional investigation included participants from the Atherosclerosis Risk in Communities study who attended visit 5 (2011-2013) and who completed olfactory testing and brain MRI examinations and had plasma biomarkers measured (namely, amyloid-beta [Aβ]42/Aβ40 ratio, …

Hematopoietic Stem Cell Transplantation Outcomes For High-Risk Aml: A Report From The Children's Oncology Group., Benjamin J. Huang, Lauren K. Meyer, Todd A. Alonzo, Yi-Cheng Wang, Adam J. Lamble, Rhonda E. Ries, Weijie Wang, Betsy Hirsch, Gordana Raca, Xiaotu Ma, Alan S. Gamis, Richard Aplenc, E Anders Kolb, Todd M. Cooper, Katherine Tarlock, Michael R. Loken, Soheil Meshinchi, Joseph H. Chewning, William G. Woods, John T. Horan

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: Hematopoietic stem cell transplantation (HSCT) is used as consolidation for pediatric patients with high-risk AML in first complete remission (CR1). The definition of high-risk AML has evolved considerably over the past two decades with the successive identification of new unfavorable risk factors. We conducted a cross-study analysis to determine whether HSCT improves the outcomes of patients with contemporarily defined high-risk AML.

METHODS: We combined data from AAML0531 and AAML1031, the last two phase III clinical trials completed by the Children's Oncology Group (COG). These two trials established the prognostic importance of measurable residual disease (MRD) and several high-risk cryptic …

Application Of Claims-Based Frailty Index To A Structured Electronic Health Record Data, Min Ji Kwak, Caroline Schaefer, Youngran Kim, Sunyang Fu, Chan Mi Park, Abhijeet Dhoble, Nahid Rianon, Holly M Holmes, Dae Hyun Kim

Faculty, Staff and Student Publications

Background: The Claims-based Frailty Index (CFI) has been developed and validated using Medicare claims data. However, whether CFI can be applied to structured electronic health record data has not been studied.

Methods: We applied the CFI to a structured electronic health record dataset (Explorys dataset) and a Medicare fee-for-service 5% sample data and compared the prevalence of frailty from each dataset, using the cohort of older adults. Then, we assessed the odds ratio and area under the curve of the frailty predicting adverse clinical outcomes, any hospital or emergency room visit, or any adverse drug events related encounter within 1 …

Real-World Outcomes For Young Adult Patients Receiving Cd19 Car T-Cell Therapy., Hannah Lust, Liora M. Schultz, Soyang Kwon, Gregory W. Roloff, Ibrahim Aldoss, Christina Baggott, Samuel John, Jenna E. Rossoff, Kevin O. Mcnerney, Vanessa A. Fabrizio, Julie-An Talano, Amy Moskop, Kevin J. Curran, Christine L. Phillips, Nicole Karras, Susanne H C Baumeister, Stacy L. Cooper, Michelle Hermiston, Prakash Satwani, Muna Qayed, Sunil S. Raikar, Margaret Macmillan, Erin Hall, Khanh Nguyen, Ryan D. Cassaday, Noam E. Kopmar, Vamsi K. Kota, John Mathews, Paul Shaughnessy, Marc S. Schwartz, Abdullah Ladha, George Yaghmour, Muthu V. Kumaran, Veronika Bachanova, Sean Tracy, Tamer Othman, Marlise R. Luskin, Evan C. Chen, Anjani S. Advani, Nikeshan Jeyakumar, Katharine Miller, Amy Zhang, Katherine C. Sutherland, Bijal D. Shah, Lori Muffly, Rawan Faramand

Manuscripts, Articles, Book Chapters and Other Papers

Tisagenlecleucel (tisa-cel) and brexucabtagene autoleucel (brexu-cel) are approved CD19 chimeric antigen receptor T-cell therapy (CAR T) products for young adults (YA) with relapsed/refractory B-cell acute lymphoblastic leukemia. A distinct analysis of YAs receiving commercial CD19 CAR T has not been reported. Using retrospective data from the Pediatric Real-World CAR T Consortium and the Real-World Outcomes of CAR T in Adult ALL collaboration, we describe the efficacy and safety of tisa-cel and brexu-cel in 70 YAs (18-26 years; tisa-cel, n = 50; brexu-cel, n = 20). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were observed more frequently …

Structure-Function Coupling In The First Month Of Life: Associations With Age And Attention, Ursula A Tooley, Jeanette K Kenley, M Catalina Camacho, Aidan Latham, Dimitrios Alexopoulos, Ashley N Nielsen, Tara A Smyser, Barbara B Warner, Joshua S Shimony, Jeffrey J Neil, Joan L Luby, Deanna M Barch, Cynthia E Rogers, Christopher D Smyser

2020-Current year OA Pubs

How brain structure relates to function is a critical and open question in neuroscience. Here, we characterize regional variation in structure-function coupling, capturing the degree to which a cortical region's structural connections relate to patterns of coordinated neural activity in healthy, term-born neonates (

Lrrc8 Channel Complexes Counterbalance Katp Channels To Mediate Swell-Secretion Coupling In Mouse Pancreatic Β Cells, Tarek Mohamed Abd El-Aziz, Chen Kang, Litao Xie, John D. Tranter, Sumit Patel, Rahul Chadda, Maria S. Remedi, Rajan Sah

2020-Current year OA Pubs

Insulin secretion from pancreatic β cells is initiated by membrane potential depolarization, followed by activation of voltage-gated Ca2+ channels to trigger Ca2+-mediated insulin vesicle fusion with the β cell plasma membrane. Here, we show that β cell swelling associated with glucose metabolism was sensed by LRRC8 channel complexes and contributed to insulin secretion. Hypertonic perfusate (360-380 mOsm) dose dependently impaired glucose-stimulated insulin secretion by counteracting β cell swelling. Hypotonic perfusate alone, independent of glucose stimulation or KATP channel closure, was sufficient to increase β cell intracellular Ca2+ and trigger insulin secretion. Inhibition of sodium-potassium-chloride cotransporter-1 with bumetanide, which diminished the …

Rewired M6a Of Promoter Antisense Rnas In Alzheimer’S Disease Regulates Neuronal Genes In 3d Nucleome, Benxia Hu, Yuqiang Shi, Feng Xiong, Yi-Ting Chen, Xiaoyu Zhu, Elisa Carrillo, Xingzhao Wen, Nathan Drolet, Chetan Singh Rajpurohit, Xiangmin Xu, Dung-Fang Lee, Claudio Soto, Sheng Zhong, Vasanthi Jayaraman, Hui Zheng, Wenbo Li

Faculty, Staff and Student Publications

N6-methyladenosine (m6A) is an abundant internal RNA modification that can impact gene expression at both post-transcriptional and transcriptional levels. However, the landscapes and functions of m6A in human brains and neurodegenerative diseases, including Alzheimer's disease (AD), are under-explored. Here, we examined RNA m6A methylome using total RNA-seq and meRIP-seq in middle frontal cortex of post-mortem brains from individuals with or without AD, which revealed m6A alteration on both mRNAs and various noncoding RNAs. Notably, many promoter-antisense RNAs (paRNAs) displayed cell-type-specific expression and changes in AD, including one produced adjacent to MAPT that encodes the Tau protein. MAPT-paRNA is highly expressed …

A Hormone-Dependent Trna Half Promotes Cell Cycle Progression Via Destabilization Of P21 Mrna, Takuya Kawamura, Megumi Shigematsu, Yohei Kirino

Department of Biochemistry and Molecular Biology Faculty Papers

tRNA halves are among the most abundant short non-coding RNAs in the cellular transcriptome. Here we report that in androgen receptor-positive LNCaP prostate cancer cells, the hormone-dependent 5'-tRNALysCUU half promoted cell proliferation by facilitating cell cycle progression. Global mRNA profiling upon the 5'-tRNALysCUU half depletion revealed that the mRNA of p21, a negative regulator of the cell cycle, is post-transcriptionally destabilized via a 5'-tRNALysCUU half-driven mechanism. YBX1, identified as a protein interacting with 5'-tRNALysCUU half in the cytosol, was shown to stabilize p21 mRNA. Specific sequences resembling the 5'-tRNALysCUU half, located in the 3'-UTR of p21 mRNA and termed LL588, …

Senescence Caused By Telomerase Inactivation In Myeloid, Mesenchymal, And Endothelial Cells Has Distinct Effects On Cancer Progression, Joseph Rupert, Zhanguo Gao, Yongmei Yu, Mikhail G Kolonin

Faculty, Staff and Student Publications

The effects of cell senescence in individual cell populations of the tumor microenvironment (TME) on cancer progression remain unclear. Here, we investigated the effects of cell senescence caused by inactivation of the catalytic subunit of telomerase (Tert) in distinct TME components. We generated genetic Tert knockout (KO) mice driven by the LysM promoter in myeloid cells, by the Pdgfra or Pdgfrb promoter in mesenchymal cells, and by the Tie2e promoter in endothelial cells. We compared the effect of the Tert KOs in syngeneic models of orthotopically grafted E0771 breast adenocarcinoma, RM1 prostate adenocarcinoma, and KPC pancreatic adenocarcinoma. Tumors in LysM-Tert …

Variants In Bsn, Encoding The Presynaptic Protein Bassoon, Result In A Distinct Neurodevelopmental Disorder With A Broad Phenotypic Range, Stacy G Guzman, Sarah M Ruggiero, Shiva Ganesan, Colin A Ellis, Alicia G Harrison, Katie R Sullivan, Zornitza Stark, Natasha J Brown, Sajel L Kana, Anabelle Tuttle, Jair Tenorio, Pablo Lapunzina, Julián Nevado, Marie T Mcdonald, Courtney Jensen, Patricia G Wheeler, Lila Stange, Jennifer Morrison, Boris Keren, Solveig Heide, Meg W Keating, Kameryn M Butler, Mike A Lyons, Shailly Jain, Mehdi Yeganeh, Michelle L Thompson, Molly Schroeder, Hoanh Nguyen, Jorge Granadillo, Kari M Johnston, Chaya N Murali, Katie Bosanko, T Andrew Burrow, Chop Birth Defects Biorepository, Penn Medicine Biobank, Syreeta Morgan, Deborah J Watson, Hakon Hakonarson, Ingo Helbig

Faculty, Staff and Students Publications

Disease-causing variants in synaptic function genes are a common cause of neurodevelopmental disorders (NDDs) and epilepsy. Here, we describe 14 individuals with de novo disruptive variants in BSN, which encodes the presynaptic protein Bassoon. To expand the phenotypic spectrum, we identified 15 additional individuals with protein-truncating variants (PTVs) from large biobanks. Clinical features were standardized using the Human Phenotype Ontology (HPO) across all 29 individuals, which revealed common clinical characteristics including epilepsy (13/29, 45%), febrile seizures (7/29, 25%), generalized tonic-clonic seizures (5/29, 17%), and focal-onset seizures (3/29, 10%). Behavioral phenotypes were present in almost half of all individuals (14/29, 48%), …

Loss Of Function Of The Zinc Finger Homeobox 4 Gene, Zfhx4, Underlies A Neurodevelopmental Disorder, María Del Rocío Pérez Baca, María Palomares-Bralo, Michiel Vanhooydonck, Lisa Hamerlinck, Eva D'Haene, Sebastian Leimbacher, Eva Z Jacobs, Laurenz De Cock, Erika D'Haenens, Annelies Dheedene, Zoë Malfait, Lies Vantomme, Ananilia Silva, Kathleen Rooney, Xiaonan Zhao, Amir Hossein Saeidian, Nichole Marie Owen, Fernando Santos-Simarro, Roser Lleuger-Pujol, Sixto García-Miñaúr, Itsaso Losantos-García, Björn Menten, Gaia Gestri, Nicola Ragge, Bekim Sadikovic, Elke Bogaert, Kris Vleminckx, Thomas Naert, Delfien Syx, Bert Callewaert, Sarah Vergult

Faculty, Staff and Students Publications

8q21.11 microdeletions involving ZFHX4 have previously been associated with a syndromic form of intellectual disability, hypotonia, unstable gait, and hearing loss. We report on 63 individuals-57 probands and 6 affected family members-with protein-truncating variants (n = 41), (micro)deletions (n = 21), or an inversion (n = 1) affecting ZFHX4. Probands display variable developmental delay and intellectual disability, distinctive facial characteristics, morphological abnormalities of the central nervous system, behavioral alterations, short stature, hypotonia, and occasionally cleft palate and anterior segment dysgenesis. The phenotypes associated with 8q21.11 microdeletions and ZFHX4 intragenic loss-of-function (LoF) variants largely overlap, although leukocyte-derived DNA shows a mild …

Cross-Sectional Analysis Of Wound-Associated Soluble Factors In Early, Established, And Chronic Wounds Of Recessive Dystrophic Epidermolysis Bullosa Patients, Vitali Alexeev, Leonie Huitema, Taylor Phillips, Paras Patel, Mauricio Garza, Franziska Ringpfeil, Julio Salas-Alanis, Olga Igoucheva

Department of Dermatology and Cutaneous Biology Faculty Papers

BACKGROUND: Poorly healing wounds represent the primary health-related burden for hereditary recessive dystrophic epidermolysis bullosa (RDEB) patients. Contribution of wound-associated soluble constituents to wound progression remains not well defined.

OBJECTIVE: To conduct cross-sectional analysis of cytokine, chemokine, and growth factor in exudates from RDEB wounds and define changes associated with wound progression.

METHODS: Concentrations of selected cytokines, chemokines, and growth factors were evaluated by multiplex ELISA in eight blister fluids and 66 exudates from early, established, and chronic RDEB and five chronic venous ulcers (VU). A cross-sectional analysis was performed.

RESULTS: Our data demonstrated that proinflammatory CXCL8 and IL-1β tend …