Digital Commons Network^™

3’Utr Shortening Of Has2 Promotes Hyaluronan Hyper-Synthesis And Bioenergetic Dysfunction In Pulmonary Hypertension, Victor Tseng, Scott D Collum, Ayed Allawzi, Kathryn Crotty, Samantha Yeligar, Aaron Trammell, M Ryan Smith, Bum-Yong Kang, Roy L Sutliff, Jennifer L Ingram, Soma S S K Jyothula, Rajarajan A Thandavarayan, Howard J Huang, Eva S Nozik, Eric J Wagner, C Michael Hart, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

Pulmonary hypertension (PH) comprises a diverse group of disorders that share a common pathway of pulmonary vascular remodeling leading to right ventricular failure. Development of anti-remodeling strategies is an emerging frontier in PH therapeutics that requires a greater understanding of the interactions between vascular wall cells and their extracellular matrices. The ubiquitous matrix glycan, hyaluronan (HA), is markedly elevated in lungs from patients and experimental models with PH. Herein, we identified HA synthase-2 (HAS2) in the pulmonary artery smooth muscle cell (PASMC) layer as a predominant locus of HA dysregulation. HA upregulation involves depletion of NUDT21, a master regulator of …

The Effects Of Supplemental Dietary Chitosan On Broiler Performance And Myopathic Features Of White Striping, Mary F Love, Andrea Nicole Brooks, Sonya D Cox, Munachi Okpala, Gail Cooksey, Audrey Sarah Cohen, Anjail Z Sharrief

Faculty, Staff and Student Publications

Introduction

Stroke, a life-threatening stressor, often negatively impacts stroke-survivor (SS) quality of life (QoL). Annual age-adjusted incidence and death rates for stroke are significantly higher among Black Americans than among White Americans. Racism, a significant stressor, occurs at structural, cultural, and interpersonal levels and contributes to health disparities for Black SS. Resilience, a dynamic process of positive adaptation to significant stress, is impacted by factors or resources both internal and external to the individual. This study aims to examine the effects of experiences of racism and resilience on Black SS QoL during early stroke recovery. This article presents the study …

Event-Related Phase Synchronization Propagates Rapidly Across Human Ventral Visual Cortex, Oscar Woolnough, Kiefer J Forseth, Patrick S Rollo, Zachary J Roccaforte, Nitin Tandon

Faculty, Staff and Student Publications

Visual inputs to early visual cortex integrate with semantic, linguistic and memory inputs in higher visual cortex, in a manner that is rapid and accurate, and enables complex computations such as face recognition and word reading. This implies the existence of fundamental organizational principles that enable such efficiency. To elaborate on this, we performed intracranial recordings in 82 individuals while they performed tasks of varying visual and cognitive complexity. We discovered that visual inputs induce highly organized posterior-to-anterior propagating patterns of phase modulation across the ventral occipitotemporal cortex. At individual electrodes there was a stereotyped temporal pattern of phase progression …

Association Of Gangrenous, Suppurative, And Exudative Findings With Outcomes And Resource Utilization In Children With Nonperforated Appendicitis, Shannon L Cramm, Aaron M Lipskar, Dionne A Graham, Shaun M Kunisaki, Cornelia L Griggs, Myron Allukian, Robert T Russell, Nicole M Chandler, Matthew T Santore, Danielle I Aronowitz, Martin L Blakely, Brendan Campbell, Devon T Collins, Sarah J Commander, Robert A Cowles, Jennifer R Defazio, Justice C Echols, Joseph R Esparaz, Christina Feng, Richard A Guyer, David N Hanna, Katherine He, Anastasia M Kahan, Olivia A Keane, Abdulraouf Lamoshi, Carla M Lopez, Sean E Mclean, Elizabeth Pace, Maia D Regan, Stefan Scholz, Elisabeth T Tracy, Sasha A Williams, Lucy Zhang, Shawn J Rangel

Faculty, Staff and Student Publications

IMPORTANCE: The clinical significance of gangrenous, suppurative, or exudative (GSE) findings is poorly characterized in children with nonperforated appendicitis.

OBJECTIVE: To evaluate whether GSE findings in children with nonperforated appendicitis are associated with increased risk of surgical site infections and resource utilization.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study used data from the Appendectomy Targeted Database of the American College of Surgeons Pediatric National Surgical Quality Improvement Program, which were augmented with operative report data obtained by supplemental medical record review. Data were obtained from 15 hospitals participating in the Eastern Pediatric Surgery Network (EPSN) research consortium. The study …

Emergency Department Communication In Persons Living With Dementia And Care Partners: A Scoping Review, Christopher R Carpenter, Jesseca Leggett, Fernanda Bellolio, Marian Betz, Ryan M Carnahan, David Carr, Michelle Doering, Jennie Chin Hansen, Eric D Isaacs, Deborah Jobe, Kathleen Kelly, Nancy Morrow-Howell, Beth Prusaczyk, Bob Savage, Joe Suyama, Allan S Vann, Kristin L Rising, Ula Hwang, Manish N Shah

Faculty, Staff and Student Publications

OBJECTIVES: To synthesize published research exploring emergency department (ED) communication strategies and decision-making with persons living with dementia (PLWD) and their care partners as the basis for a multistakeholder consensus conference to prioritize future research.

DESIGN: Systematic scoping review.

SETTINGS AND PARTICIPANTS: PLWD and their care partners in the ED setting.

METHODS: Informed by 2 Patient-Intervention-Comparison-Outcome (PICO) questions, we conducted systematic electronic searches of medical research databases for relevant publications following standardized methodological guidelines. The results were presented to interdisciplinary stakeholders, including dementia researchers, clinicians, PLWD, care partners, and advocacy organizations. The PICO questions included: How does communication differ for …

Covid-19: Perceived Infection Risk And Barriers To Uptake Of Pfizer-Biontech And Moderna Vaccines Among Community Healthcare Workers, Tolulope B Famuyiro, Abayomi Ogunwale, Jude Des Bordes, Mukaila Raji

Faculty, Staff and Student Publications

Background: The health and economic ramifications of the coronavirus pandemic have prompted the need for a timely and effective vaccine development. While the rollout of the COVID-19 vaccine in record time is being hailed as a scientific feat, skepticism about the safety, side effects, and even its long-term effects remain. Acceptance of the vaccine may therefore be a challenge among healthcare workers (HCWs), whose role is considered a proxy to determining the COVID-19 vaccine uptake response by the general population.

Methods: In December 2020, prior to the arrival and receipt of the Pfizer-BioNTech and Moderna COVID-19 vaccine, we conducted a …

Expanding Acta2 Genotypes With Corresponding Phenotypes Overlapping With Smooth Muscle Dysfunction Syndrome, Anita Kaw, Kaveeta Kaw, Ellen M Hostetler, Ana Beleza-Meireles, Adam Smith-Collins, Catherine Armstrong, Ingrid Scurr, Timothy Cotts, Rajani Aatre, Michael J Bamshad, Dawn Earl, Abraham Groner, Katherine Agre, Yehuda Raveh, Callie S Kwartler, Dianna M Milewicz

Faculty, Staff and Student Publications

Pathogenic variants in ACTA2, encoding smooth muscle α-actin, predispose to thoracic aortic aneurysms and dissections. ACTA2 variants altering arginine 179 predispose to a more severe, multisystemic disease termed smooth muscle dysfunction syndrome (SMDS; OMIM 613834). Vascular complications of SMDS include patent ductus arteriosus (PDA) or aortopulmonary window, early-onset thoracic aortic disease (TAD), moyamoya-like cerebrovascular disease, and primary pulmonary hypertension. Patients also have dysfunction of other smooth muscle-dependent systems, including congenital mydriasis, hypotonic bladder, and gut hypoperistalsis. Here, we describe five patients with novel heterozygous ACTA2 missense variants, p.Arg179Gly, p.Met46Arg, p.Thr204Ile, p.Arg39Cys, and p.Ile66Asn, who have clinical complications that align or …

Rationale And Design Of Savi-Aos: A Physiologic Study Of Patients With Symptomatic Moderate Aortic Valve Stenosis And Preserved Left Ventricular Ejection Fraction, Rob Eerdekens, Pim Tonino, Jo Zelis, Rik Adrichem, Jung-Min Ahn, Jesse Demandt, Ashkan Eftekhari, Mohamed El Farissi, Phillip Freeman, Abdul Rahman Ihdayhid, Nikolaos Kakouros, Dae-Hee Kim, Seung-Ah Lee, Nicolas M Van Mieghem, Waqas Qureshi, Nils P Johnson

Faculty, Staff and Student Publications

Background: Moderate aortic valve stenosis occurs twice as often as severe aortic stenosis (AS) and carries a similarly poor prognosis. Current European and American guidelines offer limited insight into moderate AS (MAS) patients with unexplained symptoms. Measuring valve physiology at rest while most patients experience symptoms during exertion might represent a conceptual limitation in the current grading of AS severity. The stress aortic valve index (SAVI) may delineate hemodynamically significant AS among patients with MAS.

Objectives: To investigate the diagnostic value of SAVI in symptomatic MAS patients with normal left ventricular ejection fraction (LVEF ≥ 50%): aortic valve area (AVA) …

Association Of Changes In Antithrombin Activity Over Time With Responsiveness To Enoxaparin Prophylaxis And Risk Of Trauma-Related Venous Thromboembolism, Laura E Vincent, Michael M Talanker, Dakota D Butler, Xu Zhang, Jeanette M Podbielski, Yao-Wei W Wang, Amber Chen-Goodspeed, Selina L Hernandez Gonzalez, Erin E Fox, Bryan A Cotton, Charles E Wade, Jessica C Cardenas

Faculty, Staff and Student Publications

Importance: Venous thromboembolism (VTE) affects 2% to 20% of recovering trauma patients, despite aggressive prophylaxis with enoxaparin. Antithrombin is a primary circulating anticoagulant and crucial component of enoxaparin thromboprophylaxis. Approximately 20% of trauma patients present with antithrombin deficiency (antithrombin activity < 80%).

Objective: To examine time-dependent changes in antithrombin activity, responsiveness to enoxaparin, as measured by anti-factor Xa (anti-FXa) levels, and incidence of VTE after severe trauma and to assess the association of ex vivo antithrombin supplementation with patients' sensitivity to enoxaparin prophylaxis.

Design, setting, and participants: This single-center, prospective cohort study was performed at a level 1 trauma center between January …

Predictors Of Disease Activity And Worsening In Relapsing-Remitting Multiple Sclerosis, Yinan Zhang, Stacey Cofield, Gary Cutter, Stephen Krieger, Jerry S Wolinsky, Fred Lublin

Faculty, Staff and Student Publications

Background and objectives: Disease activity in multiple sclerosis (MS) is highly variable, and there are limited prospective studies on predictors of disease outcomes. The goal of this study is to identify and assess patient characteristics in MS that predict disease activity and worsening.

Methods: The study population consisted of a prospective cohort of 1,008 participants with relapsing-remitting onset MS enrolled in the CombiRx trial. Cox regression analysis was used to determine hazard ratio (HR) associations between baseline (BL) demographics, clinical history, MRI metrics, and treatment with outcomes of time to first new disease activity over up to 7 years of …

Mechanism Of Neonatal Hypoglycemia After Late Preterm Steroids: Are Fetal Metabolic Effects Responsible?, Ashley N Battarbee, Grecio J Sandoval, Cynthia Gyamfi-Bannerman, Sean C Blackwell, Alan T N Tita, Uma M Reddy, Lucky Jain

Faculty, Staff and Student Publications

OBJECTIVE:

Betamethasone administration in the late preterm period(340/7–365/7 weeks’ gestation) not only reduces neonatal respiratory morbidity but also increases neonatal hypoglycemia through an uncertain mechanism.¹ Based on data from pregnant individuals with diabetes, excessive amounts of maternal glucose can cross the placenta and cause fetal hyperinsulinemia, which can cause neonatal hypoglycemia at birth.² Given that betamethasone can also increase maternal glucose levels,³ our objective was to explore the potential mechanisms for late preterm steroid-induced neonatal hypoglycemia by measuring the fetal metabolic effects of antenatal late preterm betamethasone and assessing the relationship of the fetal metabolic effects with …

Detecting Cognitive Impairment And Dementia In The Emergency Department: A Scoping Review, Armin Nowroozpoor, Jeff Dussetschleger, William Perry, Mary Sano, Amy Aloysi, Michael Belleville, Alexandria Brackett, Jon Mark Hirshon, William Hung, Joan Michelle Moccia, Ugochi Ohuabunwa, Manish N Shah, Ula Hwang

Faculty, Staff and Student Publications

OBJECTIVES: To identify research and practice gaps to establish future research priorities to advance the detection of cognitive impairment and dementia in the emergency department (ED).

DESIGN: Literature review and consensus-based rankings by a transdisciplinary, stakeholder task force of experts, persons living with dementia, and care partners.

SETTING AND PARTICIPANTS: Scoping reviews focused on adult ED patients.

METHODS: Two systematic scoping reviews of 7 medical research databases focusing on best tools and approaches for detecting cognitive impairment and dementia in the ED in terms of (1) most accurate and (2) most pragmatic to implement. The results were screened, reviewed, and …

Patient Preference For Virtual Versus In-Person Visits In Neuromuscular Clinical Practice, Komal Hafeez, Hani Kushlaf, Husam Al-Sultani, Anny-Claude Joseph, Zoya Zaeem, Zaeem Siddiqi, Shannon Laboy, Michael Pulley, Ali A Habib, Nathaniel M Robbins, Sean Zadeh, Muhammad Ubaid Hafeez, Yessar Hussain, Alexandria Melendez-Zaidi, Charles Kassardjian, Kristin Johnson, Holly Leonhard, Suur Biliciler, Jorge E Patino Murillas, Aziz I Shaibani

Faculty, Staff and Student Publications

INTRODUCTION/AIMS: It is unknown if patients with neuromuscular diseases prefer in-person or virtual telemedicine visits. We studied patient opinions and preference on virtual versus in-person visits, and the factors influencing such preferences.

METHODS: Telephone surveys, consisting of 11 questions, of patients from 10 neuromuscular centers were completed.

RESULTS: Five hundred and twenty surveys were completed. Twenty-six percent of respondents preferred virtual visits, while 50% preferred in-person visits. Sixty-four percent reported physical interaction as "very important." For receiving a new diagnosis, 55% preferred in-person vs 35% reporting no preference. Forty percent were concerned about a lack of physical examination vs 20% …

Supporting Self-Management For Patients With Interstitial Lung Diseases: Utility And Acceptability Of Digital Devices, Shima Aran, Orest O Kayder, Teena Chopra, Hani Abujudeh

Faculty, Staff and Student Publications

On December 2020, the US Food and Drug Administration issued the first emergency use authorization for a vaccine for the prevention of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report development of superficial thrombophlebitis in the ipsilateral breast of a 43-year-old female 7 days after receiving the first dose of the Pfizer-BioNTech COVID-19 vaccine. Given that this is the first case of superficial thrombophlebitis in the breast shortly after mRNA vaccination for COVID-19 reported to our knowledge, we suggest that this may be a rare vaccine-related event.

Sars-Cov-2 Infection: Host Response, Immunity, And Therapeutic Targets, Pooja Shivshankar, Harry Karmouty-Quintana, Tingting Mills, Marie-Francoise Doursout, Yanyu Wang, Agnieszka K Czopik, Scott E Evans, Holger K Eltzschig, Xiaoyi Yuan

Faculty, Staff and Student Publications

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in a global pandemic with severe socioeconomic effects. Immunopathogenesis of COVID-19 leads to acute respiratory distress syndrome (ARDS) and organ failure. Binding of SARS-CoV-2 spike protein to human angiotensin-converting enzyme 2 (hACE2) on bronchiolar and alveolar epithelial cells triggers host inflammatory pathways that lead to pathophysiological changes. Proinflammatory cytokines and type I interferon (IFN) signaling in alveolar epithelial cells counter barrier disruption, modulate host innate immune response to induce chemotaxis, and initiate the resolution of inflammation. Here, we discuss experimental models to study SARS-CoV-2 …

Acylcarnitines And Genetic Variation In Fat Oxidation Genes In Hiv-Infected, Antiretroviral-Treated Children With And Without Myopathy, Brian Kirmse, Charlotte Hobbs, Lisa Aaron, Grace Montepiedra, Marshall Summar, Paige L Williams, Caitlin J Smith, Russell Van Dyke, Chunli Yu, Kelli K Ryckman, William Borkowsky

Faculty, Staff and Student Publications

BACKGROUND: Mitochondrial toxicity resulting in myopathy and lactic acidosis has been described in antiretroviral (ARV)-exposed patients. We hypothesized that myopathy in HIV-infected, ARV-treated children would be associated with metabolic (acylcarnitines) and genetic (variants in metabolic genes) markers of dysfunctional fatty acid oxidation (FAO).

METHODS: Acylcarnitine profiles (ACP) were analyzed for 74 HIV-infected children on nucleoside reverse transcriptase inhibitor (NRTI)-containing ARV. Thirty-seven participants with ≥2 creatine kinase measurements >500 IU (n = 18) or evidence of echocardiographic cardiomyopathy (n = 19) were matched with 37 participants without myopathy. Single nucleotide polymorphisms (SNPs) in FAO genes were also evaluated.

RESULTS: Abnormal ACP …

Antibody Evasion By Sars-Cov-2 Omicron Subvariants Ba2121, Ba4 And Ba5, Qian Wang, Yicheng Guo, Sho Iketani, Manoj S Nair, Zhiteng Li, Hiroshi Mohri, Maple Wang, Jian Yu, Anthony D Bowen, Jennifer Y Chang, Jayesh G Shah, Nadia Nguyen, Zhiwei Chen, Kathrine Meyers, Michael T Yin, Magdalena E Sobieszczyk, Zizhang Sheng, Yaoxing Huang, Lihong Liu, David D Ho

Faculty, Staff and Student Publications

SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 have surged notably to become dominant in the United States and South Africa, respectively1,2. These new subvariants carrying further mutations in their spike proteins raise concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. However, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike …

Hepatic Recruitment Of Eosinophils And Their Protective Function During Acute Liver Injury, Long Xu, Yang Yang, Yankai Wen, Jong-Min Jeong, Christoph Emontzpohl, Constance L Atkins, Zhaoli Sun, Kyle L Poulsen, David R Hall, J Steve Bynon, Bin Gao, William M Lee, Jody Rule, Elizabeth A Jacobsen, Hua Wang, Cynthia Ju

Faculty, Staff and Student Publications

BACKGROUND & AIMS: Beyond the classical description of eosinophil functions in parasite infections and allergic diseases, emerging evidence supports a critical role of eosinophils in resolving inflammation and promoting tissue remodeling. However, the role of eosinophils in liver injury and the underlying mechanism of their recruitment into the liver remain unclear.

METHODS: Hepatic eosinophils were detected and quantified using flow cytometry and immunohistochemical staining. Eosinophil-deficient (ΔdblGata1) mice were used to investigate the role of eosinophils in 3 models of acute liver injury. In vivo experiments using Il33

RESULTS: Hepatic accumulation of eosinophils was observed in patients with acetaminophen (APAP)-induced liver …

Generation Of A Homozygous Knock-In Human Embryonic Stem Cell Line Expressing Meos4b-Tagged Ctr1, Yi-Hung Chen, Pei-San Huang, Meng-Hsuan Wen, Manhua Pan, Dung-Fang Lee, Tai-Yen Chen

Faculty, Staff and Student Publications

Copper transporter 1 (CTR1) is the major membrane protein responsible for cellular copper (Cu) uptake and mediates cellular copper homeostasis. To elucidate CTR1's behavior using imaging approaches, we generated a homozygous knock-in human embryonic stem cell (hESC) clone expressing photoconvertible fluorescence protein mEos4b-tagged endogenous CTR1 using CRISPR-Cas9 mediated homologous recombination. The engineered cells express functional CTR1-mEos4b fusion and have normal stem cell morphology. They remain pluripotent and can be differentiated into all three germ layers in vitro. This resource allows the study of CTR1 at an endogenous level in different cellular contexts using microscopy.

Changes Of Brain Function In Patients With Type 2 Diabetes Mellitus Measured By Different Analysis Methods: A New Coordinate-Based Meta-Analysis Of Neuroimaging, Ze-Yang Li, Teng Ma, Ying Yu, Bo Hu, Yu Han, Hao Xie, Min-Hua Ni, Zhu-Hong Chen, Yang-Ming Zhang, Yu-Xiang Huang, Wen-Hua Li, Wen Wang, Lin-Feng Yan, Guang-Bin Cui

Faculty, Staff and Student Publications

OBJECTIVE: Neuroimaging meta-analysis identified abnormal neural activity alterations in patients with type 2 diabetes mellitus (T2DM), but there was no consistency or heterogeneity analysis between different brain imaging processing strategies. The aim of this meta-analysis was to determine consistent changes of regional brain functions in T2DM

METHODS: Since the indicators obtained using varied post-processing methods reflect different neurophysiological and pathological characteristics, we further conducted a coordinate-based meta-analysis (CBMA) of the two categories of neuroimaging literature, which were grouped according to similar data processing methods: one group included regional homogeneity (ReHo), independent component analysis (ICA), and degree centrality (DC) studies, while …

Geriatric Cardiology: Coming Of Age, Parag Goyal, Min Ji Kwak, Christina Al Malouf, Manish Kumar, Namit Rohant, Abdulla A Damluji, Quin E Denfeld, Kim K Bircher, Ashok Krishnaswami, Karen P Alexander, Daniel E Forman, Michael W Rich, Nanette K Wenger, James N Kirkpatrick, Jerome L Fleg

Faculty, Staff and Student Publications

Older adults with cardiovascular disease (CVD) contend with deficits across multiple domains of health due to age-related physiological changes and the impact of CVD. Multimorbidity, polypharmacy, cognitive changes, and diminished functional capacity, along with changes in the social environment, result in complexity that makes provision of CVD care to older adults challenging. In this review, we first describe the history of geriatric cardiology, an orientation that acknowledges the unique needs of older adults with CVD. Then, we introduce 5 essential principles for meeting the needs of older adults with CVD: 1) recognize and consider the potential impact of multicomplexity; 2) …

A Case Report Of Successful Physiological Pacing In A Patient With Lamin A/C Cardiomyopathy, Nitin Chandra Mohan, Paul Foley, Badrinathan Chandrasekaran

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BACKGROUND: Lamin A/C (LMNA) mutations account for 5-8% of familial dilated cardiomyopathies, and can manifest with conduction abnormalities and ventricular arrhythmias in 78% of patients. Therefore, when suspected, it is important to implant the correct type of device.

CASE SUMMARY: A 52-year-old gentleman with a family history of cardiomyopathy, presented with asymptomatic atrial fibrillation and complete atrioventricular block associated with a narrow QRS interval. Investigations confirmed dilated and severely impaired left ventricular systolic function. He underwent successful conduction system pacing in combination with a primary prevention defibrillator. Genetic screening confirmed LMNA cardiomyopathy. During 3 years follow up, his left ventricular …

Regulation And Function Of Id2 In Plasmacytoid Dendritic Cells, Rachel L Babcock, Yifan Zhou, Bhakti Patel, Taylor T Chrisikos, Laura M Kahn, Allison M Dyevoich, Yusra B Medik, Stephanie S Watowich

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Plasmacytoid dendritic cells (pDCs) are specialized type I interferon (IFN-I) producing cells that promote anti-viral immune responses and contribute to autoimmunity. Development of pDCs requires the transcriptional regulator E2-2 and is opposed by inhibitor of DNA binding 2 (Id2). Prior work indicates Id2 is induced in pDCs upon maturation and may affect pDC IFN-I production via suppression of E2-2, suggesting an important yet uncharacterized role in this lineage. We found TLR7 agonists stimulate Id2 mRNA and protein expression in pDCs. We further show that transcriptional activation of Id2 is dependent on the E2 ubiquitin-conjugating enzyme Ubc13, but independent of IFN-I …

Preventing Cholesterol-Induced Perk (Protein Kinase Rna-Like Endoplasmic Reticulum Kinase) Signaling In Smooth Muscle Cells Blocks Atherosclerotic Plaque Formation, Abhijnan Chattopadhyay, Pujun Guan, Suravi Majumder, Kaveeta Kaw, Zhen Zhou, Chen Zhang, Siddharth K Prakash, Anita Kaw, L Maximillian Buja, Callie S Kwartler, Dianna M Milewicz

Faculty, Staff and Student Publications

BACKGROUND: Vascular smooth muscle cells (SMCs) undergo complex phenotypic modulation with atherosclerotic plaque formation in hyperlipidemic mice, which is characterized by de-differentiation and heterogeneous increases in the expression of macrophage, fibroblast, osteogenic, and stem cell markers. An increase of cellular cholesterol in SMCs triggers similar phenotypic changes in vitro with exposure to free cholesterol due to cholesterol entering the endoplasmic reticulum, triggering endoplasmic reticulum stress and activating Perk (protein kinase RNA-like endoplasmic reticulum kinase) signaling.

METHODS: We generated an SMC-specific

RESULTS: SMC-specific deletion of Perk reduces atherosclerotic plaque formation in male hyperlipidemic mice by 80%. Single-cell transcriptomic data identify 2 …

Clinical Research In Ovarian Cancer: Consensus Recommendations From The Gynecologic Cancer Intergroup, Ignace Vergote, Antonio Gonzalez-Martin, Domenica Lorusso, Charlie Gourley, Mansoor Raza Mirza, Jean-Emmanuel Kurtz, Aikou Okamoto, Kathleen Moore, Frédéric Kridelka, Iain Mcneish, Alexander Reuss, Bénédicte Votan, Andreas Du Bois, Sven Mahner, Isabelle Ray-Coquard, Elise C Kohn, Jonathan S Berek, David S P Tan, Nicoletta Colombo, Rongyu Zang, Nicole Concin, Dearbhaile O'Donnell, Alejandro Rauh-Hain, C Simon Herrington, Christian Marth, Andres Poveda, Keiichi Fujiwara, Gavin C E Stuart, Amit M Oza, Michael A Bookman, Participants Of The 6th Gynecologic Cancer Intergroup (Gcig) Ovarian Cancer Consensus Conference On Clinical Research

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The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with …

Selinexor In Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial, Mrinal M Gounder, Albiruni Abdul Razak, Neeta Somaiah, Sant Chawla, Javier Martin-Broto, Giovanni Grignani, Scott M Schuetze, Bruno Vincenzi, Andrew J Wagner, Bartosz Chmielowski, Robin L Jones, Richard F Riedel, Silvia Stacchiotti, Elizabeth T Loggers, Kristen N Ganjoo, Axel Le Cesne, Antoine Italiano, Xavier Garcia Del Muro, Melissa Burgess, Sophie Piperno-Neumann, Christopher Ryan, Mary F Mulcahy, Charles Forscher, Nicolas Penel, Scott Okuno, Anthony Elias, Lee Hartner, Tony Philip, Thierry Alcindor, Bernd Kasper, Peter Reichardt, Lore Lapeire, Jean-Yves Blay, Christine Chevreau, Claudia Maria Valverde Morales, Gary K Schwartz, James L Chen, Hari Deshpande, Elizabeth J Davis, Garth Nicholas, Stefan Gröschel, Helen Hatcher, Florence Duffaud, Antonio Casado Herráez, Roberto Diaz Beveridge, Giuseppe Badalamenti, Mikael Eriksson, Christian Meyer, Margaret Von Mehren, Brian A Van Tine, Katharina Götze, Filomena Mazzeo, Alexander Yakobson, Aviad Zick, Alexander Lee, Anna Estival Gonzalez, Andrea Napolitano, Mark A Dickson, Dayana Michel, Changting Meng, Lingling Li, Jianjun Liu, Osnat Ben-Shahar, Dane R Van Domelen, Christopher J Walker, Hua Chang, Yosef Landesman, Jatin J Shah, Sharon Shacham, Michael G Kauffman, Steven Attia

Faculty, Staff and Student Publications

Purpose: Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents.

Methods: SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of …

Impact Of Somatic Mutations On Survival Outcomes In Patients With Anaplastic Thyroid Carcinoma, Jennifer Rui Wang, Matthew Montierth, Li Xu, Maitrayee Goswami, Xiao Zhao, Gilbert Cote, Wenyi Wang, Priyanka Iyer, Ramona Dadu, Naifa L Busaidy, Stephen Y Lai, Neil D Gross, Renata Ferrarotto, Charles Lu, Gary Brandon Gunn, Michelle D Williams, Mark Routbort, Mark E Zafereo, Maria E Cabanillas

Faculty, Staff and Student Publications

PURPOSE: Anaplastic thyroid carcinoma (ATC) uniformly present with aggressive disease, but the mutational landscape of tumors varies. We aimed to determine whether tumor mutations affect survival outcomes in ATC.

MATERIALS AND METHODS: Patients who underwent mutation sequencing using targeted gene panels between 2005 and 2019 at a tertiary referral center were included. Associations between mutation status and survival outcomes were assessed using Cox proportional hazards models.

RESULTS: A total of 202 patients were included, where 122 died of ATC (60%). The median follow-up was 31 months (interquartile range, 18-45 months). The most common mutations were in

CONCLUSION: Mutation analysis provides …

Probing The Structure And Function Of Polymerase Θ Helicase-Like Domain, Scott Vanson, Yuzhen Li, Richard D Wood, Sylvie Doublié

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DNA Polymerase θ is the key actuator of the recently identified double-strand break repair pathway, theta-mediated end joining (TMEJ). It is the only known polymerase to have a 3-domain architecture containing an independently functional family A DNA polymerase tethered by a long central region to an N-terminal helicase-like domain (HLD). Full-length polymerase θ and the isolated HLD hydrolyze ATP in the presence of DNA, but no processive DNA duplex unwinding has been observed. Based on sequence and structure conservation, the HLD is classified as a member of helicase superfamily II and, more specifically, the Ski2-like family. The specific subdomain composition …

Phase Ii Study Of Durvalumab (Anti-Pd-L1) And Trametinib (Meki) In Microsatellite Stable (Mss) Metastatic Colorectal Cancer (Mcrc), Benny Johnson, Cara L Haymaker, Edwin R Parra, Luisa Maren Solis Soto, Xuemei Wang, Jane V Thomas, Arvind Dasari, Van K Morris, Kanwal Raghav, Eduardo Vilar, Bryan K Kee, Cathy Eng, Christine M Parseghian, Robert A Wolff, Younghee Lee, Daniele Lorenzini, Caddie Laberiano-Fernandez, Anuj Verma, Wenhua Lang, Ignacio I Wistuba, Andrew Futreal, Scott Kopetz, Michael J Overman

Faculty, Staff and Student Publications

Background: Monotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by successfully priming and activating T-cells.

Methods: Open-label, single-center, phase II trial with primary endpoint of immune-related response rate for combination of T+D in refractory MSS mCRC pts (NCT03428126). T is 2 mg/day orally starting 1 week prior to D, which is given 1500 mg intravenously every 4 weeks. Simon 2-stage design used to enroll 29 pts into first stage, …

Novel Mitochondria-Targeting Compounds Selectively Kill Human Leukemia Cells, Svetlana B Panina, Jingqi Pei, Natalia Baran, Elissa Tjahjono, Shraddha Patel, Gheath Alatrash, Sergej Konoplev, Leonid A Stolbov, Vladimir V Poroikov, Marina Konopleva, Natalia V Kirienko

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is a heterogeneous group of aggressive hematological malignancies commonly associated with treatment resistance, high risk of relapse, and mitochondrial dysregulation. We identified six mitochondria-affecting compounds (PS compounds) that exhibit selective cytotoxicity against AML cells in vitro. Structure-activity relationship studies identified six analogs from two original scaffolds that had over an order of magnitude difference between LD50 in AML and healthy peripheral blood mononuclear cells. Mechanistically, all hit compounds reduced ATP and selectively impaired both basal and ATP-linked oxygen consumption in leukemic cells. Compounds derived from PS127 significantly upregulated production of reactive oxygen species (ROS) in AML …