Medicine and Health Sciences Commons^™

“Stripe” Transcription Factors Provide Accessibility To Co-Binding Partners In Mammalian Genomes, Yongbing Zhao, Supriya V Vartak, Andrea Conte, Xiang Wang, David A Garcia, Evan Stevens, Seol Kyoung Jung, Kyong-Rim Kieffer-Kwon, Laura Vian, Timothy Stodola, Francisco Moris, Laura Chopp, Silvia Preite, Pamela L Schwartzberg, Joseph M Kulinski, Ana Olivera, Christelle Harly, Avinash Bhandoola, Elisabeth F Heuston, David M Bodine, Raul Urrutia, Arpita Upadhyaya, Matthew T Weirauch, Gordon Hager, Rafael Casellas

Faculty, Staff and Student Publications

Regulatory elements activate promoters by recruiting transcription factors (TFs) to specific motifs. Notably, TF-DNA interactions often depend on cooperativity with colocalized partners, suggesting an underlying cis-regulatory syntax. To explore TF cooperativity in mammals, we analyze ∼500 mouse and human primary cells by combining an atlas of TF motifs, footprints, ChIP-seq, transcriptomes, and accessibility. We uncover two TF groups that colocalize with most expressed factors, forming stripes in hierarchical clustering maps. The first group includes lineage-determining factors that occupy DNA elements broadly, consistent with their key role in tissue-specific transcription. The second one, dubbed universal stripe factors (USFs), comprises ∼30 SP, …

Remission Of Liquid Tumors And Sars-Cov-2 Infection: A Literature Review, Dong Ho Shin, Andrew Gillard, Arie Van Wieren, Candelaria Gomez-Manzano, Juan Fueyo

Faculty, Staff and Student Publications

The coronavirus disease 2019 (COVID-19) pandemic has produced a new global challenge for patients with cancer. The disease and the immunosuppression induced by cancer therapies have generated a perfect storm of conditions to increase the severity of the symptoms and worsen the prognosis. However, a few clinical reports showcased the power of viruses to induce remission in some patients suffering from liquid tumors. Here, we reviewed six cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that resulted in cancer remission, simultaneously highlighting the strengths and the unique challenges of oncolytic virotherapy. Virotherapy has become a special case of cancer …

International Consensus Classification Of Myeloid Neoplasms And Acute Leukemias: Integrating Morphologic, Clinical, And Genomic Data, Daniel A Arber, Attilio Orazi, Robert P Hasserjian, Michael J Borowitz, Katherine R Calvo, Hans-Michael Kvasnicka, Sa A Wang, Adam Bagg, Tiziano Barbui, Susan Branford, Carlos E Bueso-Ramos, Jorge E Cortes, Paola Dal Cin, Courtney D Dinardo, Hervé Dombret, Eric J Duncavage, Benjamin L Ebert, Elihu H Estey, Fabio Facchetti, Kathryn Foucar, Naseema Gangat, Umberto Gianelli, Lucy A Godley, Nicola Gökbuget, Jason Gotlib, Eva Hellström-Lindberg, Gabriela S Hobbs, Ronald Hoffman, Elias J Jabbour, Jean-Jacques Kiladjian, Richard A Larson, Michelle M Le Beau, Mignon L-C Loh, Bob Löwenberg, Elizabeth Macintyre, Luca Malcovati, Charles G Mullighan, Charlotte Niemeyer, Olatoyosi M Odenike, Seishi Ogawa, Alberto Orfao, Elli Papaemmanuil, Francesco Passamonti, Kimmo Porkka, Ching-Hon Pui, Jerald P Radich, Andreas Reiter, Maria Rozman, Martina Rudelius, Michael R Savona, Charles A Schiffer, Annette Schmitt-Graeff, Akiko Shimamura, Jorge Sierra, Wendy A Stock, Richard M Stone, Martin S Tallman, Jürgen Thiele, Hwei-Fang Tien, Alexandar Tzankov, Alessandro M Vannucchi, Paresh Vyas, Andrew H Wei, Olga K Weinberg, Agnieszka Wierzbowska, Mario Cazzola, Hartmut Döhner, Ayalew Tefferi

Faculty, Staff and Student Publications

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As …

A Review Of The Effectiveness, Feasibility, And Acceptability Of Art Therapy For Children And Adolescents During The Covid-19 Pandemic, Minh Ngoc Le Vu, Anh Linh Do, Laurent Boyer, Quy Chi Tran, Stefan Kohler, Syed Ishtiaque Ahmed, Andreea Molnar, Tung Son Vu, Nhan Trong Huynh Vo, Linh Mai Vu Nguyen, Linh Gia Vu, Vu Anh Trong Dam, Thomy Duong, Dan Linh Nguyen Do, Ngoc Minh Do, Roger S Mclntyre, Carl Latkin, Roger Chun Man Ho, Cyrus Su Hui Ho

Faculty, Staff and Student Publications

Art therapy has been widely offered to reduce symptoms of psychological disturbance. Pooled evidence about its effectiveness in epidemic contexts, particularly during the COVID-19 pandemic, has not been yet established. This study reviewed the effectiveness, feasibility, and acceptability of art therapy on children and adolescents during the COVID-19 pandemic and past epidemics. We searched PubMed/Medline, PsycINFO, CENTRAL (Cochrane Library), and CINAHL for articles on art therapy during COVID-19. Included studies reported improvements in measures of mental health, sleep quality, and psychological well-being in children with or without disabilities in the epidemic context. Results also showed that art therapy was highly …

Inhibition Of Uba6 By Inosine Augments Tumour Immunogenicity And Responses, Lei Zhang, Li Jiang, Liang Yu, Qin Li, Xiangjun Tian, Jingquan He, Ling Zeng, Yuqin Yang, Chaoran Wang, Yuhan Wei, Xiaoyue Jiang, Jing Li, Xiaolu Ge, Qisheng Gu, Jikun Li, Di Wu, Anthony J Sadler, Di Yu, Dakang Xu, Yue Gao, Xiangliang Yuan, Baokun He

Faculty, Staff and Student Publications

Anti-cancer immunity and response to immune therapy is influenced by the metabolic states of the tumours. Immune checkpoint blockade therapy (ICB) is known to involve metabolic adaptation, however, the mechanism is not fully known. Here we show, by metabolic profiling of plasma samples from melanoma-bearing mice undergoing anti-PD1 and anti-CTLA4 combination therapy, that higher levels of purine metabolites, including inosine, mark ICB sensitivity. Metabolic profiles of ICB-treated human cancers confirm the association between inosine levels and ICB sensitivity. In mouse models, inosine supplementation sensitizes tumours to ICB, even if they are intrinsically ICB resistant, by enhancing T cell-mediated cytotoxicity and …

Where Have All The Flowers Gone? A Multicenter Investigation Of Frequent Users Of Midwest Emergency Department Services During The Covid-19 Stay-At-Home Orders., Howard W Levitin, Bruce G Jones, Marie M Lockhart, Christopher M Lloyd, Meenal D Sharkey, Paul A Willette, Andrew F Kalnow

Ambulatory and Primary Care Articles

INTRODUCTION: In this study we aimed to determine the impact of the mandatory coronavirus disease 2019 (COVID-19) pandemic stay-at-home order on the proportional makeup of emergency department (ED) visits by frequent users and super users.

METHODS: We conducted a secondary analysis of existing data using a multisite review of the medical records of 280,053 patients to measure the impact of the COVID-19 pandemic stay-at-home order on ED visits. The primary outcomes included analysis before and during the lockdown in determining ED use and unique characteristics of non-frequent, frequent, and super users of emergency services.

RESULTS: During the mandatory COVID-19 stay-at-home …

Clinical Activity Of Checkpoint Inhibitors In Angiosarcoma: A Retrospective Cohort Study, Vinod Ravi, Aparna Subramaniam, Jing Zheng, Behrang Amini, Van A Trinh, Jocelyn Joseph, Robert G Mennel, Andrew J Bishop, Erich M Sturgis, Ryan P Goepfert, Sudha Yalamanchili, Gilberto Botello, Bettzy Stephen, Sarina A Piha-Paul, Anisha B Patel, Alexander J Lazar, Anthony P Conley, Robert S Benjamin, Shreyaskumar R Patel, Phillip A Futreal, Neeta Somaiah, Aung Naing

Faculty, Staff and Student Publications

Background: Systemic treatments for angiosarcoma remains an area of unmet clinical need. The authors conducted this retrospective study to assess the clinical activity of checkpoint inhibitors in patients with angiosarcoma. The primary objective was to assess the objective response rate, and the secondary objective was to assess the progression-free and overall survival durations and disease control rate.

Methods: Patient data were obtained using The University of Texas MD Anderson Cancer Center Tumor Registry database. The final study population was refined to only include patients who had undergone pembrolizumab monotherapy. The objective response rate was evaluated using RECIST/irRECIST version 1.1. Progression-free …

Economic Evaluation Of Ultrasound-Guided Central Venous Catheter Confirmation Vs Chest Radiography In Critically Ill Patients: A Labor Cost Model, Enyo A. Ablordeppey, Adam M. Koenig, Abigail R. Barker, Emily E. Hernandez, Suzanne M. Simkovich, James G. Krings, Derek S. Brown, Richard T. Griffey

2020-Current year OA Pubs

INTRODUCTION: Despite evidence suggesting that point-of-care ultrasound (POCUS) is faster and non-inferior for confirming position and excluding pneumothorax after central venous catheter (CVC) placement compared to traditional radiography, millions of chest radiographs (CXR) are performed annually for this purpose. Whether the use of POCUS results in cost savings compared to CXR is less clear but could represent a relative advantage in implementation efforts. Our objective in this study was to evaluate the labor cost difference for POCUS-guided vs CXR-guided CVC position confirmation practices.

METHODS: We developed a model to evaluate the per patient difference in labor cost between POCUS-guided vs …

Be The Change: Advancing Lung Health And Closing The Global Healthcare Gap, Gregory P Downey, M Patricia Rivera, Lynn Schnapp, Irina Petrache, Jesse Roman, Karen Collishaw

Department of Medicine Faculty Papers

No abstract provided.

Systemic Chemotherapies Retain Antitumor Activity In Desmoid Tumors Independent Of Specific Mutations In Ctnnb1 Or Apc: A Multi-Institutional Retrospective Study, Michael J Nathenson, Katharina Feister, Et Al

2020-Current year OA Pubs

PURPOSE: Determine whether specific CTNNB1 or APC mutations in patients with desmoid tumor were associated with differences in clinical responses to systemic treatments.

EXPERIMENTAL DESIGN: We established a multi-institutional dataset of previously treated patients with desmoid tumor across four U.S. sarcoma centers, including demographic and clinicopathologic characteristics, treatment regimens, and clinical and radiographic responses. CTNNB1 or APC mutation status was determined from prior pathology records, or archival tissue was requested and analyzed by Sanger sequencing and/or next-generation sequencing. Evaluable patients with mutation results were analyzed to determine clinical progression-free survival (cPFS), RECIST 1.1 PFS (rPFS), time to next treatment (TTNT), …

Risk And Incidence Of Head And Neck Cancers In Veterans Living With Hiv And Matched Hiv-Negative Veterans, Angela L Mazul, Christine M Hartman, Yvonne M Mowery, Jennifer R Kramer, Donna L White, Kathryn E Royse, Suchismita Raychaudhury, Vlad C Sandulache, Sarah T Ahmed, Jose P Zevallos, Peter A Richardson, Andrew G Sikora, Elizabeth Y Chiao

Faculty, Staff and Students Publications

BACKGROUND: Persons living with HIV/AIDS have a higher incidence of virus-related and tobacco/alcohol-related cancers. This study is the first to estimate the effect of HIV versus HIV-negative veterans on the risk of head and neck squamous cell carcinoma incidence in a large retrospective cohort study.

METHODS: The authors constructed a retrospective cohort study using patient data from 1999 to 2016 from the National Veterans Administration Corporate Data Warehouse and the VA Central Cancer Registry. This cohort study included 45,052 veterans living with HIV/AIDS and 162,486 HIV-negative patients matched by age, sex, and index visit (i.e., HIV diagnosis date or clinic …

How Did The Dietary Habits Of Patients With Chronic Medical Conditions Change During Covid-19?, Sahil K. Patel, Adarsh Gupta

Rowan-Virtua School of Osteopathic Medicine Departmental Research

CONTEXT: Previous studies have examined the changes in the dietary habits of general populations during the COVID-19 pandemic but have not focused on specific populations such as those with chronic medical conditions (CMCs). Prior to major vaccination efforts, 96.1% of deaths were attributed to patients with preexisting CMCs, thus it is important to examine how this population has endured changes.

OBJECTIVES: The purpose of this study was to identify differences in dietary habits, lifestyle habits, and food attitudes between those with CMCs compared to the populations without chronic medical conditions (non-CMCs) since the beginning of the COVID-19 pandemic.

METHODS: An …

Epigenetic Activation Of The Flt3 Gene By Znf384 Fusion Confers A Therapeutic Susceptibility In Acute Lymphoblastic Leukemia., Xujie Zhao, Ping Wang, Jonathan D Diedrich, Brandon Smart, Noemi Reyes, Satoshi Yoshimura, Jingliao Zhang, Wentao Yang, Kelly Barnett, Beisi Xu, Zhenhua Li, Xin Huang, Jiyang Yu, Kristine Crews, Allen Eng Juh Yeoh, Marina Konopleva, Chia-Lin Wei, Ching-Hon Pui, Daniel Savic, Jun J Yang

Faculty Research 2022

FLT3 is an attractive therapeutic target in acute lymphoblastic leukemia (ALL) but the mechanism for its activation in this cancer is incompletely understood. Profiling global gene expression in large ALL cohorts, we identify over-expression of FLT3 in ZNF384-rearranged ALL, consistently across cases harboring different fusion partners with ZNF384. Mechanistically, we discover an intergenic enhancer element at the FLT3 locus that is exclusively activated in ZNF384-rearranged ALL, with the enhancer-promoter looping directly mediated by the fusion protein. There is also a global enrichment of active enhancers within ZNF384 binding sites across the genome in ZNF384-rearranged ALL cells. Downregulation of ZNF384 blunts …

Bridging Thrombolysis In Atrial Fibrillation Stroke Is Associated With Increased Hemorrhagic Complications Without Improved Outcomes, Feras Akbik, Ali Alawieh, Laurie Dimisko, Brian M. Howard, C Michael Cawley, Frank C. Tong, Fadi Nahab, Owen B. Samuels, Ilko Maier, Wuwei Feng, Nitin Goyal, Robert M. Starke, Ansaar Rai, Kyle M. Fargen, Marios N. Psychogios, Pascal Jabbour, Reade De Leacy, Saleh G. Keyrouz, Travis M. Dumont, Peter Kan, Jan Liman, Adam S. Arthur, Stacey Q. Wolfe, J. Mocco, Roberto Javier Crosa, W Christopher Fox, Benjamin Gory, Alejandro M. Spiotta, Jonathan A. Grossberg

Department of Neurosurgery Faculty Papers

BACKGROUND: Atrial fibrillation (AF) associated ischemic stroke is associated with worse functional outcomes, less effective recanalization, and increased rates of hemorrhagic complications after intravenous thrombolysis (IVT). Conversely, AF is not associated with hemorrhagic complications or functional outcomes in patients undergoing mechanical thrombectomy (MT). This differential effect of MT and IVT in AF associated stroke raises the question of whether bridging thrombolysis increases hemorrhagic complications in AF patients undergoing MT.

METHODS: This international cohort study of 22 comprehensive stroke centers analyzed patients with large vessel occlusion (LVO) undergoing MT between June 1, 2015 and December 31, 2020. Patients were divided into …

Plasma Sars-Cov-2 Nucleocapsid Antigen Levels Are Associated With Progression To Severe Disease In Hospitalized Covid-19, Katherine D Wick, Pratik Sinha, Et Al.

2020-Current year OA Pubs

BACKGROUND: Studies quantifying SARS-CoV-2 have focused on upper respiratory tract or plasma viral RNA with inconsistent association with clinical outcomes. The association between plasma viral antigen levels and clinical outcomes has not been previously studied. Our aim was to investigate the relationship between plasma SARS-CoV-2 nucleocapsid antigen (N-antigen) concentration and both markers of host response and clinical outcomes.

METHODS: SARS-CoV-2 N-antigen concentrations were measured in the first study plasma sample (D0), collected within 72 h of hospital admission, from 256 subjects admitted between March 2020 and August 2021 in a prospective observational cohort of hospitalized patients with COVID-19. The rank …

The Effects On Gait Of 4-Wheeled Walker Use In People With Alzheimer's Disease Dementia And Gait Impairment: A Pilot Study, Humberto Omaña, Edward Madou, Susan W. Hunter

Physical Therapy Publications

In people with dementia, provision of mobility aids is standard treatment for those with impaired gait. However, mobility aid use is independently associated with increased falls risk. In this short communication, gait velocity and stride time variability were recorded in eleven adults with Alzheimer's disease dementia. Three conditions were tested: single-task (no aid), walking with a walker, and dual-task (walker use and counting backwards) under both a straight path and Figure-of-8 walking configuration. Gait velocity increased when using a walker compared to no aid in the Figure-of-8 walking configuration. Walker use improved gait in simple walking, but benefits diminished upon …

Defective Rab31-Mediated Megakaryocytic Early Endosomal Trafficking Of Vwf, Egfr, And M6pr In Runx1 Deficiency, Gauthami Jalagadugula, Guangfen Mao, Lawrence E Goldfinger, Jeremy Wurtzel, Fabiola Del Carpio-Cano, Michele P Lambert, Brian Estevez, Deborah L French, Mortimer Poncz, A Koneti Rao

Cardeza Foundation for Hematologic Research

Transcription factor RUNX1 is a master regulator of hematopoiesis and megakaryopoiesis. RUNX1 haplodeficiency (RHD) is associated with thrombocytopenia and platelet granule deficiencies and dysfunction. Platelet profiling of our study patient with RHD showed decreased expression of RAB31, a small GTPase whose cell biology in megakaryocytes (MKs)/platelets is unknown. Platelet RAB31 messenger RNA was decreased in the index patient and in 2 additional patients with RHD. Promoter-reporter studies using phorbol 12-myristate 13-acetate-treated megakaryocytic human erythroleukemia cells revealed that RUNX1 regulates RAB31 via binding to its promoter. We investigated RUNX1 and RAB31 roles in endosomal dynamics using immunofluorescence staining for markers of …

Bet Inhibition Induces Vulnerability To Mcl1 Targeting Through Upregulation Of Fatty Acid Synthesis Pathway In Breast Cancer, Gonghong Yan, Augustin Luna, Heping Wang, Behnaz Bozorgui, Xubin Li, Maga Sanchez, Zeynep Dereli, Nermin Kahraman, Goknur Kara, Xiaohua Chen, Caishang Zheng, Daniel Mcgrail, Nidhi Sahni, Yiling Lu, Ozgun Babur, Murat Cokol, Bora Lim, Bulent Ozpolat, Chris Sander, Gordon B Mills, Anil Korkut

Faculty, Staff and Student Publications

Therapeutic options for treatment of basal-like breast cancers remain limited. Here, we demonstrate that bromodomain and extra-terminal (BET) inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancer cells. Consequently, co-targeting MCL1 and BET is highly synergistic in breast cancer models. The mechanism of adaptive response to BET inhibition involves the upregulation of lipid synthesis enzymes including the rate-limiting stearoyl-coenzyme A (CoA) desaturase. Changes in lipid synthesis pathway are associated with increases in cell motility and membrane fluidity as well as re-localization and activation of HER2/EGFR. In turn, the HER2/EGFR signaling results in the accumulation …

The First Reported Case Of A Patient With Pancreatic Cancer Treated With Cone Beam Computed Tomography-Guided Stereotactic Adaptive Radiotherapy (Ct-Star), Minsol Kim, Joshua P Schiff, Alex Price, Eric Laugeman, Pamela P Samson, Hyun Kim, Shahed N Badiyan, Lauren E Henke

2020-Current year OA Pubs

BACKGROUND: Online adaptive stereotactic radiotherapy allows for improved target and organ at risk (OAR) delineation and inter-fraction motion management via daily adaptive planning. The use of adaptive SBRT for the treatment of pancreatic cancer (performed until now using only MRI or CT on rails-guided adaptive radiotherapy), has yielded promising outcomes. Herein we describe the first reported case of cone beam CT-guided stereotactic adaptive radiotherapy (CT-STAR) for the treatment of pancreatic cancer.

CASE PRESENTATION: A 61-year-old female with metastatic pancreatic cancer presented for durable palliation of a symptomatic primary pancreatic mass. She was prescribed 35 Gy/5 fractions utilizing CT-STAR. The patient …

American Society Of Hematology Living Guidelines On The Use Of Anticoagulation For Thromboprophylaxis In Patients With Covid-19: January 2022 Update On The Use Of Therapeutic-Intensity Anticoagulation In Acutely Ill Patients, Adam Cuker, Kristen M Sanfilippo, Et Al

2020-Current year OA Pubs

BACKGROUND: COVID-19-related acute illness is associated with an increased risk of venous thromboembolism (VTE).

OBJECTIVE: These evidence-based guidelines from the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation in patients with COVID-19.

METHODS: ASH formed a multidisciplinary guideline panel that included patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process and performed systematic evidence reviews (through November 2021). The panel prioritized clinical questions and outcomes according to their importance for …

American Society Of Hematology Living Guidelines On The Use Of Anticoagulation For Thromboprophylaxis For Patients With Covid-19: March 2022 Update On The Use Of Anticoagulation In Critically Ill Patients, Adam Cuker, Kristen M Sanfilippo, Et Al

2020-Current year OA Pubs

BACKGROUND: COVID-19-related critical illness is associated with an increased risk of venous thromboembolism (VTE).

OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for patients with COVID-19.

METHODS: ASH formed a multidisciplinary guideline panel, including 3 patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing systematic evidence reviews (up to January 2022). The panel prioritized clinical questions …

Transplant Outcomes After Cpx-351 Vs 7 + 3 In Older Adults With Newly Diagnosed High-Risk And/Or Secondary Aml, Geoffrey L Uy, Laura F Newell, Tara L Lin, Stuart L Goldberg, Matthew J Wieduwilt, Robert J Ryan, Stefan Faderl, Jeffrey E Lancet

2020-Current year OA Pubs

No abstract provided.

Serpinb3 Drives Cancer Stem Cell Survival In Glioblastoma, Adam Lauko, Josephine Volovetz, Soumya M Turaga, Defne Bayik, Daniel J Silver, Kelly Mitchell, Erin E Mulkearns-Hubert, Dionysios C Watson, Kiran Desai, Manav Midha, Jing Hao, Kathleen Mccortney, Alicia Steffens, Ulhas Naik, Manmeet S Ahluwalia, Shideng Bao, Craig Horbinski, Jennifer S Yu, Justin D Lathia

Department of Medicine Faculty Papers

Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. Knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced …

Clonal Hematopoiesis Of Indeterminate Potential, Dna Methylation, And Risk For Coronary Artery Disease, M D Mesbah Uddin, Ngoc Quynh H Nguyen, Bing Yu, Jennifer A Brody, Akhil Pampana, Tetsushi Nakao, Myriam Fornage, Jan Bressler, Nona Sotoodehnia, Joshua S Weinstock, Michael C Honigberg, Daniel Nachun, Romit Bhattacharya, Gabriel K Griffin, Varuna Chander, Richard A Gibbs, Jerome I Rotter, Chunyu Liu, Andrea A Baccarelli, Daniel I Chasman, Eric A Whitsel, Douglas P Kiel, Joanne M Murabito, Eric Boerwinkle, Benjamin L Ebert, Siddhartha Jaiswal, James S Floyd, Alexander G Bick, Christie M Ballantyne, Bruce M Psaty, Pradeep Natarajan, Karen N Conneely

Faculty, Staff and Student Publications

Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide …

Openkbp-Opt: An International And Reproducible Evaluation Of 76 Knowledge-Based Planning Pipelines, Aaron Babier, Rafid Mahmood, Binghao Zhang, Victor G L Alves, Ana Maria Barragán-Montero, Joel Beaudry, Carlos E Cardenas, Yankui Chang, Zijie Chen, Jaehee Chun, Kelly Diaz, Harold David Eraso, Erik Faustmann, Sibaji Gaj, Skylar Gay, Mary Gronberg, Bingqi Guo, Junjun He, Gerd Heilemann, Sanchit Hira, Yuliang Huang, Fuxin Ji, Dashan Jiang, Jean Carlo Jimenez Giraldo, Hoyeon Lee, Jun Lian, Shuolin Liu, Keng-Chi Liu, José Marrugo, Kentaro Miki, Kunio Nakamura, Tucker Netherton, Dan Nguyen, Hamidreza Nourzadeh, Alexander F I Osman, Zhao Peng, José Darío Quinto Muñoz, Christian Ramsl, Dong Joo Rhee, Juan David Rodriguez, Hongming Shan, Jeffrey V Siebers, Mumtaz H Soomro, Kay Sun, Andrés Usuga Hoyos, Carlos Valderrama, Rob Verbeek, Enpei Wang, Siri Willems, Qi Wu, Xuanang Xu, Sen Yang, Lulin Yuan, Simeng Zhu, Lukas Zimmermann, Kevin L Moore, Thomas G Purdie, Andrea L Mcniven, Timothy C Y Chan

Faculty, Staff and Student Publications

Objective.To establish an open framework for developing plan optimization models for knowledge-based planning (KBP).

Approach.Our framework includes radiotherapy treatment data (i.e. reference plans) for 100 patients with head-and-neck cancer who were treated with intensity-modulated radiotherapy. That data also includes high-quality dose predictions from 19 KBP models that were developed by different research groups using out-of-sample data during the OpenKBP Grand Challenge. The dose predictions were input to four fluence-based dose mimicking models to form 76 unique KBP pipelines that generated 7600 plans (76 pipelines × 100 patients). The predictions and KBP-generated plans were compared to the reference …

Implementation Of A Provider-Focused Intervention For Maximizing Human Papillomavirus (Hpv) Vaccine Uptake In Young Cancer Survivors Receiving Follow-Up Care In Pediatric Oncology Practices: Protocol For A Cluster-Randomized Trial Of The Hpv Protect Intervention, Wendy Landier, Smita Bhatia, Joshua S Richman, Paula D Campos Gonzalez, Brooke Cherven, Veronica Chollette, Jamie Aye, Sharon M Castellino, Maria M Gramatges, Susan Lindemulder, Thomas B Russell, Lucie M Turcotte, Graham A Colditz, Melissa B Gilkey, James L Klosky

2020-Current year OA Pubs

BACKGROUND: Childhood cancer survivors are at high risk for developing new cancers (such as cervical and anal cancer) caused by persistent infection with the human papillomavirus (HPV). HPV vaccination is effective in preventing the infections that lead to these cancers, but HPV vaccine uptake is low among young cancer survivors. Lack of a healthcare provider recommendation is the most common reason that cancer survivors fail to initiate the HPV vaccine. Strategies that are most successful in increasing HPV vaccine uptake in the general population focus on enhancing healthcare provider skills to effectively recommend the vaccine, and reducing barriers faced by …

Septic Cardiomyopathy: From Pathophysiology To The Clinical Setting, Federico Carbone, Luca Liberale, Alberto Preda, Thomas Hellmut Schindler, Fabrizio Montecucco

2020-Current year OA Pubs

The onset of cardiomyopathy is a common feature in sepsis, with relevant effects on its pathophysiology and clinical care. Septic cardiomyopathy is characterized by reduced left ventricular (LV) contractility eventually associated with LV dilatation with or without right ventricle failure. Unfortunately, such a wide range of ultrasonographic findings does not reflect a deep comprehension of sepsis-induced cardiomyopathy, but rather a lack of consensus about its definition. Several echocardiographic parameters intrinsically depend on loading conditions (both preload and afterload) so that it may be challenging to discriminate which is primitive and which is induced by hemodynamic perturbances. Here, we explore the …

Whole-Exome Sequencing Of 14 389 Individuals From The Esp And Charge Consortia Identifies Novel Rare Variation Associated With Hemostatic Factors, Nathan Pankratz, Peng Wei, Jennifer A Brody, Ming-Huei Chen, Paul S De Vries, Jennifer E Huffman, Mary Rachel Stimson, Paul L Auer, Eric Boerwinkle, Mary Cushman, Moniek P M De Maat, Aaron R Folsom, Oscar H Franco, Richard A Gibbs, Kelly K Haagenson, Albert Hofman, Jill M Johnsen, Christie L Kovar, Robert Kraaij, Barbara Mcknight, Ginger A Metcalf, Donna Muzny, Bruce M Psaty, Weihong Tang, André G Uitterlinden, Jeroen G J Van Rooij, Abbas Dehghan, Christopher J O'Donnell, Alex P Reiner, Alanna C Morrison, Nicholas L Smith

Faculty, Staff and Student Publications

Plasma levels of fibrinogen, coagulation factors VII and VIII and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole-exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and the National Heart, Lung and Blood Institute's Exome Sequencing Project. Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in fibrinogen gamma chain (FGG) (with fibrinogen, P = 9.1 × 10-13), coagulation factor VII (F7) (with factor VII, P = 1.3 × 10-72; seven novel variants) and VWF (with factor VIII and vWF; P = 3.2 × 10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; P = 4.2 × 10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to AAs (rs3211938) in CD36 molecule (CD36). This variant has previously been linked to dyslipidemia but not with the levels of a hemostatic factor. These efforts represent the largest integration of whole-exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.

A Case Study Of Adapting A Health Insurance Decision Intervention From Trial Into Routine Cancer Care, Miles E Charles, Lindsay M Kuroki, Ana A Baumann, Rachel G Tabak, Aimee James, Krista Cooksey, Mary C Politi

2020-Current year OA Pubs

OBJECTIVE: This study adapted Improving Cancer Patients' Insurance Choices (I Can PIC), an intervention to help cancer patients navigate health insurance decisions and care costs. The original intervention improved knowledge and confidence making insurance decisions, however, users felt limited by choices provided in insurance markets. Using decision trees and frameworks to guide adaptations, we modified I Can PIC to focus on using rather than choosing health insurance. The COVID-19 pandemic introduced unforeseen obstacles, prompting changes to study protocols. As a result, we allowed users outside of the study to use I Can PIC (> 1050 guest users) to optimize public …

Measure Dx: Implementing Pathways To Discover And Learn From Diagnostic Errors, Andrea Bradford, Marjorie Shofer, Hardeep Singh

Faculty, Staff and Students Publications

Despite the high frequency of diagnostic errors, multiple barriers, including measurement, make it difficult learn from these events. This article discusses Measure Dx, a new resource from the Agency for Healthcare Research and Quality that translates knowledge from diagnostic safety measurement research into actionable recommendations. Measure Dx guides healthcare organizations to detect, analyze, and learn from diagnostic safety events as part of a continuous learning and feedback cycle. Wider adoption of Measure Dx, along with the implementation of solutions that result, can advance new frontiers in reducing preventable diagnostic harm to patients.