Medicine and Health Sciences Commons^™

Protein Biomarkers Of Interstitial Lung Abnormalities In Relatives Of Patients With Pulmonary Fibrosis, Jonathan A Rose, Mark P Steele, Esteban J Kosak Lopez, Gisli Thor Axelsson, Andrea G Galecio Chao, Alan Waich, Katie Regan, Swati Gulati, Anthony H Maeda, Sharmin Sultana, Claire Cutting, Ann-Marcia C Tukpah, Andrew J Synn, Mary B Rice, Hilary J Goldberg, Joyce S Lee, David A Lynch, Rachel K Putman, Hiroto Hatabu, Benjamin A Raby, David A Schwartz, Ivan O Rosas, Gary M Hunninghake

Faculty, Staff and Students Publications

Rationale: First-degree relatives of patients with pulmonary fibrosis (referred to here as relatives) are at high risk for interstitial lung abnormalities (ILA), highlighting the need for biomarkers for risk prediction. We aimed to identify blood proteins associated with and predictive of ILA among relatives of patients with pulmonary fibrosis.

Methods: Relatives enrolled in two independent cohorts had protein levels measured using an aptamer-based proteomic platform. ILA were assessed with computed tomography scans as per Fleischner Society recommendations. Protein associations with ILA were assessed using regression. Significant proteins were used with clinical variables to detect ILA.

Results: Of 237 relatives from …

Cardiovascular And Renal Treatment In Heart Failure Patients With Hyperkalemia Or High Risk Of Hyperkalemia: Rationale And Design Of The Care-Hk In Hf Registry, Stephen J Greene, Michael Böhm, Biykem Bozkurt, Javed Butler, John G F Cleland, Andrew J S Coats, Nihar R Desai, Diederick E Grobbee, Ellie Kelepouris, Fausto Pinto, Giuseppe Rosano, Isabelle Morin, Peter Szecsödy, Solenn Fabien, Sandra Waechter, Maria G Crespo-Leiro, Martin Hülsmann, Tibor Kempf, Otmar Pfister, Anne-Catherine Pouleur, Andrew J Sauer, Manish Saxena, Martin Schulz, Maurizio Volterrani, Stefan D Anker, Mikhail N Kosiborod

Faculty, Staff and Students Publications

Background: Despite guideline recommendations, many patients with heart failure (HF) do not receive target dosages of renin-angiotensin-aldosterone system inhibitors (RAASis) in clinical practice due, in part, to concerns about hyperkalemia (HK).

Methods and results: This noninterventional, multinational, multicenter registry (NCT04864795; 111 sites in Europe and the USA) enrolled 2558 eligible adults with chronic HF (mostly with reduced ejection fraction [HFrEF]). Eligibility criteria included use of angiotensin-converting-enzyme inhibitor/angiotensin-II receptor blocker/angiotensin-receptor-neprilysin inhibitor, being a candidate for or treatment with a mineralocorticoid receptor antagonist, and increased risk of HK (eg, current serum potassium > 5.0 mmol/L), history of HK in the previous …

Genome-Wide Association Studies Of Down Syndrome Associated Congenital Heart Defects Suggests A Genetically Heterogeneous Risk For Chd In Ds, Elizabeth R Feldman, Yunqi Li, David J Cutler, Tracie C Rosser, Stephanie B Wechsler, Lauren Sanclemente, Angela L Rachubinski, Natalina Elliott, Paresh Vyas, Irene Roberts, Karen R Rabin, Michael Wagner, Bruce D Gelb, Joaquin M Espinosa, Philip J Lupo, Adam J De Smith, Stephanie L Sherman, Elizabeth J Leslie-Clarkson

Faculty, Staff and Students Publications

Congenital heart defects (CHDs) are the most common structural birth defect and are present in 40-50% of children born with Down syndrome (DS). To characterize the genetic architecture of DS-associated CHD, we sequenced genomes of a multiethnic group of children with DS and a CHD (n=886: atrioventricular septal defects (AVSD), n=438; atrial septal defects (ASD), n=122; ventricular septal defects (VSD), n=170; other types of CHD, n=156) and DS with a structurally normal heart (DS+NH, n=572). We performed four GWAS for common variants (MAF>0.05) comparing DS with CHD, stratified by CHD-subtype, to DS+NH controls. Although no SNP achieved genome-wide significance, …

Functional Mobility And Pain Are Improved For 6 Years After Adolescent Bariatric Surgery, Neil Thivalapill, Todd M Jenkins, Thomas H Inge, Changchun Xie, Anita P Courcoulas, Carroll M Harmon, Michael A Helmrath, Stephanie Sisley, Marc P Michalsky, Justin R Ryder, Teen‐Longitudinal Assessment Of Bariatric Surgery (Teen‐Labs) Consortium

Faculty, Staff and Students Publications

Objective: The long-term durability of improvements in functional mobility and musculoskeletal pain for adolescents after metabolic and bariatric surgery (MBS) is unknown.

Methods: We used the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study to determine the change in mobility and pain among adolescents who underwent MBS. From standardized 400-m walk tests, we analyzed walk time, heart rate (HR) parameters, and musculoskeletal pain.

Results: The mean walk time improved from 383 s (95% CI: 368-399) prior to surgery to 351 s (95% CI: 330-372) by 6 years. The mean resting HR was 90 beats per minute (bpm; 95% CI: 87-93) preoperatively …

Severe Gastrointestinal Manifestations In Childhood-Onset Lupus: A Single-Center Cohort And Review Of The Literature, James Orozco, Jessica Nguyen, Sara Mm Yasrebi, Marnie Blalock, Sara L Grisales, Craig L Jensen, Marietta M Deguzman

Faculty, Staff and Students Publications

Objective

Systemic lupus erythematosus (SLE) is a complex autoimmune condition with diverse manifestations. Childhood-onset SLE (cSLE) presents more severely than adult-onset disease with a higher incidence of severe neurologic or renal manifestations and lower estimated survival rates. There is limited literature on the range of severe gastrointestinal manifestations at presentation in cSLE, and this lack of information results in underappreciation of these potentially life-threatening complications and little guidance regarding management of these patients.

Methods

We reviewed cases of patients with cSLE and severe GI manifestations at presentation diagnosed at our institution and additionally provide a comprehensive review of existing cases …

Comparing The Performance Of 3 Sarcopenia Definitions For Predicting Adverse Events Prior To Liver Transplant, Heidi E Johnston, Hannah L Mayr, Melita Andelkovic, Tahnie G Takefala, Yanyan Chen, Aaron P Thrift, Graeme A Macdonald, Ingrid J Hickman

Faculty, Staff and Students Publications

Background: Sarcopenia is a syndrome of severe muscle wasting, associated with adverse outcomes related to liver transplantation (LT). There are several approaches used to identify sarcopenia. We aimed to investigate the prevalence of sarcopenia using 3 different criteria and determine how these performed in relation to clinical outcomes.

Methods: The cohort study included 237 adults with cirrhosis referred for LT. Sarcopenia was identified using (1) CT-defined; and the (2) original and (3) updated European Working Group on Sarcopenia in Older People criteria (EWGSOP1 and 2). Logistic regression was used to estimate OR and 95% CI for the relationships between sarcopenia …

Barriers To And Facilitators Of Sustaining A Systemic Lupus Erythematosus (Sle) Patient Decision Aid In Regular Rheumatology Outpatient Care In The Usa, Erin E Blanchard, Allyson G Hall, Ezra Gore, Parvaneh Yaghoubi Jami, Aizhan Karabukayeva, Larry R Hearld, Shelby Gontarz, Jasvinder A Singh

Faculty, Staff and Students Publications

Objective: This study investigates the barriers to and facilitators of sustaining a decision aid (DA) tool for patients with SLE in routine rheumatology outpatient care across the USA. The DA was initially developed for assisting patients with SLE in making informed medication choices by providing personalized information on their treatment process.

Methods: We conducted semi-structured interviews with clinicians, administrators, and information technology (IT) professionals from 15 geographically diverse rheumatology clinics that participated in a large-scale DA implementation trial. Interviews were transcribed and analysed using NVivo, with thematic coding to identify key factors influencing DA sustainability.

Results: The analysis identified several …

Polyclonal Plasma Cell (Polypc) Signature As A Key Indicator For Predicting The Progression Of Mgus To Multiple Myeloma, Fumou Sun, Yan Cheng, Catherine Ma, Hongwei Xu, Clyde Bailey, David Mery, Timothy Cody Ashby, Daisy Alapat, Yong Li, Ken H Young, Samer Al Hadidi, Sharmilan Thanendrarajan, Carolina Schinke, Maurizio Zangari, Frits Van Rhee, Guido Tricot, John D Shaughnessy, Fenghuang Zhan

Faculty, Staff and Students Publications

Background

Multiple myeloma (MM) is virtually always preceded by monoclonal gammopathy of undetermined significance (MGUS). Elevated serum markers are used to classify MGUS patients into clinical risk categories. Previous research has indicated that the absence of a normal plasma cell signature in MGUS is linked to early progression.

Objective

To confirm that the presence of a “polyclonal plasma cell (PolyPC) signature” serves as a robust negative predictor of MGUS progression.

Methods

374 MGUS patients were enrolled, including 334 patients with stable disease and 40 patients who progressed to MM within 10 years. An oligonucleotide microarray analysis was performed on mRNA …

Ophthalmology Examinations In Children With Skull Fractures And Underlying Focal Hemorrhage, Karli Breeden, Cindy W Christian, Joanne N Wood, Gil Binenbaum, Daniel M Lindberg, Angela Bachim, Colleen J Bressler, Lori Frasier, Terra Frazier, Nicole R Johnson, Natalie Laub, Megan M Letson, Tagrid Ruiz-Maldonado, Matthew Valente, Jenna Kiely, Jan Leonard, M Katherine Henry

Faculty, Staff and Students Publications

Objectives: To assess the frequency and yield of retinal examination in children below 2 years old undergoing abuse evaluations in the setting of skull fracture(s) and small underlying intracranial hemorrhage.

Methods: This cross-sectional study used CAPNET, a multicenter child physical abuse network, to identify children below 2 years with a skull fracture(s) and intracranial injury limited to an underlying small focal intracranial hemorrhage undergoing subspeciality child abuse evaluations. Our outcomes of interest were (1) the performance of a retinal examination, (2) the identification of retinal hemorrhages, and (3) associations of clinical factors and CAPNET site with the performance of retinal …

Linking Symptom Inventories Using Semantic Textual Similarity, Eamonn Kennedy, Shashank Vadlamani, Hannah M Lindsey, Kelly S Peterson, Kristen Dams O'Connor, Ronak Agarwal, Houshang H Amiri, Raeda K Andersen, Talin Babikian, David A Baron, Erin D Bigler, Karen Caeyenberghs, Lisa Delano-Wood, Seth G Disner, Ekaterina Dobryakova, Blessen C Eapen, Rachel M Edelstein, Carrie Esopenko, Helen M Genova, Elbert Geuze, Naomi J Goodrich-Hunsaker, Jordan Grafman, Asta K Håberg, Cooper B Hodges, Kristen R Hoskinson, Elizabeth S Hovenden, Andrei Irimia, Neda Jahanshad, Ruchira M Jha, Finian Keleher, Kimbra Kenney, Inga K Koerte, Spencer W Liebel, Abigail Livny, Marianne Løvstad, Sarah L Martindale, Jeffrey E Max, Andrew R Mayer, Timothy B Meier, Deleene S Menefee, Abdalla Z Mohamed, Stefania Mondello, Martin M Monti, Rajendra A Morey, Virginia Newcombe, Mary R Newsome, Alexander Olsen, Nicholas J Pastorek, Mary Jo Pugh, Adeel Razi, Jacob E Resch, Jared A Rowland, Kelly Russell, Nicholas P Ryan, Randall S Scheibel, Adam T Schmidt, Gershon Spitz, Jaclyn A Stephens, Assaf Tal, Leah D Talbert, Maria Carmela Tartaglia, Brian A Taylor, Sophia I Thomopoulos, Maya Troyanskaya, Eve M Valera, Harm Jan Van Der Horn, John D Van Horn, Ragini Verma, Benjamin S C Wade, Willian C Walker, Ashley L Ware, J Kent Werner, Keith Owen Yeates, Ross D Zafonte, Michael M Zeineh, Brandon Zielinski, Paul M Thompson, Frank G Hillary, David F Tate, Elisabeth A Wilde, Emily L Dennis

Faculty, Staff and Students Publications

An extensive library of symptom inventories has been developed over time to measure clinical symptoms of traumatic brain injury (TBI), but this variety has led to several long-standing issues. Most notably, results drawn from different settings and studies are not comparable. This creates a fundamental problem in TBI diagnostics and outcome prediction, namely that it is not possible to equate results drawn from distinct tools and symptom inventories. Here, we present an approach using semantic textual similarity (STS) to link symptoms and scores across previously incongruous symptom inventories by ranking item text similarities according to their conceptual likeness. We tested …

Psychometric Properties Of The Spanish Yale-Brown Obsessive-Compulsive Scale - Second Edition, Eric A Storch, Jessica Sc Cheng, Miranda Higham, Josselyn S Muñoz, Vanessa Zavala Cruz, Dayan Berrones, Diana P Obando, Jacey L Anderberg, Renee M Frederick, Vissente Tapia-Cuevas, Macarena Churruca Muñoz, Constanza Uribe Villar, Pablo R Moya, Marcos E Ochoa-Panaifo, Mayra C Martinez Mallen, Andrew D Wiese, Caitlin M Pinciotti, Melisa N Sagarnaga, Joseph F Mcguire, Ogechi C Onyeka, María B Moyano, Latin American Trans-Ancestry Initiative For Ocd Genomics (Latino), Brazilian Obsessive-Compulsive Spectrum Disorder Working Group (Gttoc), Wayne K Goodman, James J Crowley

Faculty, Staff and Students Publications

The Yale-Brown Obsessive-Compulsive Scale, Second Edition (Y-BOCS-II) is an evidence-based clinician-rated measure for assessing the presence and severity of obsessive-compulsive symptoms. The Spanish version of the Y-BOCS-II has not yet been validated. The present study examines the psychometric properties of the Spanish Y-BOCS-II (Spanish-Y-BOCS-II) in adults with obsessive-compulsive disorder (OCD) who are of Hispanic/Latino ancestry. The Spanish-Y-BOCS-II was administered to 1805 adults with OCD. Participants also completed a battery of measures assessing OCD, depression, and anxiety symptoms. The internal consistency for the Symptom Checklist (Kuder-Richardson-20=0.92), Obsession Severity (α=0.87), Compulsion Severity (α=0.86), and Total Severity (α=0.92) were high. The inter-rater reliability …

Histologic- And Genomic-Directed Adjuvant Therapy For Ampullary Adenocarcinoma: A Hidden Genome-Derived Analysis, Brett L Ecker, Kenneth Seier, Ankur Choubey, Austin M Eckhoff, Gabriella N Tortorello, Vinod P Balachandran, Nicola Blackburn, Michael I D'Angelica, Ronald P Dematteo, Daniel G Blazer, Jeffrey A Drebin, William E Fisher, Anthony J Gill, Marie-Claude Gingras, T Peter Kingham, Major K Lee, Michael E Lidsky, Daniel P Nussbaum, Michael J Overman, Jaswinder S Samra, Ronglai Shen, Carlie S Sigel, Charles M Vollmer, Alice C Wei, Sabino Zani, Australian Pancreatic Genome Initiative, Robert E Roses, Mithat Gonen, William R Jarnagin

Faculty, Staff and Students Publications

Background: The benefit of adjuvant chemotherapy (AC) for ampullary adenocarcinoma is unclear. The Hidden Genome model classifies prognostic subtypes with greater accuracy than standard histologic classification (intestinal [INT] vs pancreatobiliary [PB]), but its predictive capacity to guide the use of AC remains unstudied.

Methods: We applied the Hidden Genome model to an international cohort of 183 patients with resected ampullary adenocarcinoma who underwent genomic sequencing. The model quantified the predicted cell of origin (colorectal vs pancreas/distal bile duct) in all specimens. Overall survival (OS) was compared using Kaplan-Meier estimates, stratified by AC use versus surgery alone (SA).

Results: Most patients …

Large-Scale Network Analysis Of The Cerebrospinal Fluid Proteome Identifies Molecular Signatures Of Frontotemporal Lobar Degeneration, Rowan Saloner, Nupur Ghoshal, Et Al.

2020-Current year OA Pubs

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. Here we leveraged aptamer-based proteomics (>4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN and MAPT) compared with 39 non-carrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic …

Plasma Mtbr-Tau243 Biomarker Identifies Tau Tangle Pathology In Alzheimer's Disease, Kanta Horie, Rama K Koppisetti, Nicolas R Barthélemy, Yingxin He, Chihiro Sato, Brian A Gordon, Hong Jiang, Tammie L S Benzinger, David M Holtzman, John C Morris, Suzanne E Schindler, Randall J Bateman, Et Al.

2020-Current year OA Pubs

Insoluble tau aggregates within neurofibrillary tangles are a defining neuropathological feature of Alzheimer's disease (AD) and closely correlate with clinical symptoms. Although tau pathology can be assessed using tau positron emission tomography, a more accessible biomarker is needed for diagnosis, prognosis and tracking treatment effects. Here we present a new plasma tau species, the endogenously cleaved, microtubule-binding region containing residue 243 (eMTBR-tau243), which specifically reflects tau tangle pathology. Across the AD spectrum in three different cohorts (n = 108, 55 and 739), plasma eMTBR-tau243 levels were significantly elevated at the mild cognitive impairment stage and increased further in dementia. Plasma …

Anti-Mullerian Hormone (Amh) Protects Ovarian Follicle Loss By Downregulating Granulosa Cell Function In In Vitro And In Vivo Models, Laura Detti, Michael C Mari, Michael P Diamond, Ghassan M Saed

Faculty, Staff and Students Publications

Purpose: AMH inhibits hormone production in luteinized granulosa cells (GCs) and stalls ovarian follicle development in vitro and in vivo. We sought to confirm AMH's mechanism of action through SMAD activation and investigate AMH inhibition of follicle development and function, in vitro and in vivo.

Methods: A primary culture of GCs isolated from follicular fluid was used, and cells were treated with recombinant AMH (rAMH) or placebo for 24 h. For the mouse model, 18-weeks old C57BL female mice were either euthanized at the beginning or treated with rAMH or normal saline for 3 weeks. Primordial (PDF), primary follicle (PRF), …

Neuroanatomical Features Of Naa10 And Naa15-Related Neurodevelopmental Syndromes, Rahi Patel, Rikhil Makwana, Carolina Christ, Elaine Marchi, Christina Y Miyake, Fabricio Guimaraes Goncalves, Gholson J Lyon, Matthew T Whitehead

Faculty, Staff and Students Publications

Background: NAA10-related and NAA15-related neurodevelopmental (ND) syndromes present with intellectual disability, hypotonia, cardiac abnormalities, and delayed development. While data exists on the clinical manifestations of these conditions, there are few reports describing the neuroanatomical abnormalities present on imaging.

Objective: We aim to provide neuroimaging analyses for a subset of probands with NAA10- and NAA15-related neurodevelopmental symptoms and assess the severity and number of neuroanatomical anomalies and their associated functional impairments to better understand the pathophysiology of these disease processes.

Materials and methods: Neuroimaging studies were obtained from 26 probands (18 with pathogenic variants in NAA10, 8 with pathogenic variants in …

Plasma Microbial Cell-Free Dna Sequencing For The Detection Of Kingella Kingae Pediatric Spinal Infections, Asim A Ahmed, Sarah Y Park, Matthew J Smollin, Martin S Lindner, Adriana Sarmiento Clemente, Ana Del Valle Penella, P Marcelo Laufer, Carolina Sanchez-Vegas, Manuel R Cotilla, Marian E Melish, Connie Trieu, Nazia A Kabani, Joshua Cooper, Audrey R Lloyd, David W Kimberlin, John C Arnold, Alejandro Jordan-Villegas, Lori E Patterson, Catherine E Foster, Pablo Yagupsky

Faculty, Staff and Students Publications

Background: Diagnosis of Kingella kingae skeletal system infections is made challenging by the microbe's fastidious nature. Detection and quantification of circulating microbial cell-free DNA (mcfDNA) in plasma by the Karius Test, a commercial metagenomic sequencing test, may offer promise in diagnosing pediatric spinal infections caused by difficult-to-culture organisms such as K. kingae .

Methods: Plasma mcfDNA sequencing detections of K. kingae from April 2018 to December 2020 were reviewed to identify pediatric (age < 18 years) patients. Medical charts of those with spinal infections were reviewed, and mcfDNA sequencing diagnostic performance was compared with usual care tests (ie, cultures, polymerase chain reaction).

Results: Ten children with K. kingae spinal infections were identified across 7 institutions. The median age was 16.5 months (range 11-23 months). All case-patients had vertebral osteomyelitis …

Protocol For A Multisite, Parallel-Group, Randomized Clinical Trial Comparing A Brief Tele-Cognitive Behavioral Therapy Intervention (Bright) With Attention Control For The Reduction Of Body Image-Related Distress Among Head And Neck Cancer Survivors, Evan M Graboyes, Jessica R Vanderlan, Patrik Pipkorn, Sidharth V Puram

2020-Current year OA Pubs

One in four head and neck cancer (HNC) survivors experience clinically significant body image distress (BID), a devastating psychosocial morbidity that adversely affects quality of life. To date, effective interventions for these patients are lacking. BRIGHT (Building a Renewed ImaGe after Head and neck cancer Treatment), a brief cognitive behavioral treatment (CBT), has shown potential efficacy as a novel treatment paradigm for HNC survivors with BID. The primary objective of this randomized clinical trial (RCT) is to test the hypothesis that BRIGHT improves BID among HNC survivors relative to an Attention Control (AC) intervention. In this multisite RCT, N = …

Burst Steroid Therapy And Quality Of Life In Patients With Acute Heart Failure: Insights From The Cortahf Trial, Matteo Pagnesi, Douglas L Mann, Et Al.

2020-Current year OA Pubs

AIMS: Patients hospitalized with acute heart failure (AHF) treated with a 7 day prednisone course in the CORTAHF pilot trial had a greater improvement in health-related quality of life (QoL) at Day 7 in both the overall population and in patients with baseline interleukin 6 > 13 pg/mL. This post-hoc analysis examines the specific QoL domains and the relationship between clinical signs of congestion and QoL.

METHODS: In the CORTAHF pilot trial, patients with AHF and high-sensitivity C-reactive protein (hsCRP) > 20 mg/L were randomized 1:1 to once-daily oral 40 mg prednisone for 7 days plus usual care or usual care alone. …

Assessment Of Frailty In Patients With Heart Failure: A New Heart Failure Frailty Score Developed By Delphi Consensus, Cristiana Vitale, Emmanuelle Berthelot, Andrew J S Coats, Hill Loreena, Nancy M Albert, Michal Tkaczyszyn, Stamatis Adamopoulos, Lisa Anderson, Markus S Anker, Stefan D Anker, Derek Bell, Tuvia Ben-Gal, Vasiliki Bistola, Biykem Bozkurt, Poppy Brooks, Miguel Camafort, Juan Jesus Carrero, Ovidiu Chioncel, Dong-Ju Choi, Wook-Jin Chung, Wolfram Doehner, Daniel Fernández-Bergés, Roberto Ferrari, Mona Fiuzat, Juan Esteban Gomez-Mesa, Finn Gustafsson, Ewa Jankowska, Seok-Min Kang, Koichiro Kinugawa, Kamlesh Khunti, F D Richard Hobbs, Christopher Lee, Yuri Lopatin, Matthew Maddocks, Giuseppe Maltese, Elena Marques-Sule, Yuya Matsue, Òscar Miró, Brenda Moura, Massimo Piepoli, Piotr Ponikowski, Giovanni Pulignano, Amina Rakisheva, Robin Ray, Angela Sciacqua, Petar Seferovic, Trinidad Sentandreu-Mañó, Shirley Sze, Alan Sinclair, Anna Strömberg, Olga Theou, Hiroyuki Tsutsui, Izabella Uchmanowicz, Maria Teresa Vidan, Maurizio Volterrani, Stephan Von Haehling, Byungsu Yoo, Jian Zhang, Yuhui Zhang, Marco Metra, Giuseppe Massimo Claudio Rosano

Faculty, Staff and Students Publications

Aims: The Heart Failure Frailty Score (HFFS) is a novel, multidimensional tool to assess frailty in patients with heart failure (HF). It has been developed to overcome limitations of existing frailty assessment tools while being practical for clinical use. The HFFS reflects the concept of frailty as a multidimensional, dynamic and potentially reversible state, which increases vulnerability to stressors and risk of poor outcomes in patients with HF.

Methods and results: The HFFS was developed through a Delphi consensus process involving 54 international experts. This approach involved iterative rounds of questionnaires and interviews, where a panel of experts provided their …

Nf2 Loss-Of-Function And Hypoxia Drive Radiation Resistance In Grade 2 Meningiomas, Bhuvic Patel, Sangami Pugazenthi, Shree S Pari, Tatenda Mahlokozera, William A Leidig, Hsiang-Chih Lu, Alicia Yang, Kaleigh Roberts, Patrick Desouza, Kyle P Mcgeehan, Diane D Mao, Namita Sinha, Joseph E Ippolito, Sonika Dahiya, Hiroko Yano, Albert H Kim, Et Al.

2020-Current year OA Pubs

BACKGROUND: World Health Organization Grade 2 meningiomas (G2Ms) often recur and resist therapies. Grade 2 meningiomas with histopathological necrosis have been associated with worse local control (LC) after radiation therapy, but the drivers and biomarkers of radiation resistance in G2Ms remain unknown.

METHODS: We performed genetic sequencing and histopathological analysis of 113 G2Ms and investigated the role of genetic and microenvironmental factors on clonogenic survival after ionizing radiation. We performed transcriptional profiling of our in vitro model and 18 human G2M tumors by bulk RNA sequencing as well as 8 G2Ms by single nuclei RNA sequencing.

RESULTS: NF2 loss-of-function (LOF) …

Phase 2 Open-Label Study Of Sacituzumab Govitecan As Second-Line Therapy In Patients With Extensive-Stage Sclc: Results From Tropics-03, Afshin Dowlati, Anne C Chiang, Andrés Cervantes, Sunil Babu, Erika Hamilton, Shu Fen Wong, Andrea Tazbirkova, Ivana Gabriela Sullivan, Cédric Van Marcke, Antoine Italiano, Jilpa Patel, Sabeen Mekan, Tia Wu, Saiama N Waqar

2020-Current year OA Pubs

INTRODUCTION: The phase 2 TROPiCS-03 study evaluated the efficacy/safety of sacituzumab govitecan (SG) as second-line treatment in patients with previously treated extensive-stage SCLC (ES-SCLC).

METHODS: TROPiCS-03 (NCT03964727) is a multicohort, open-label, phase 2 basket study of solid tumors, including ES-SCLC. Adults with ES-SCLC that progressed after one previous line of platinum-based chemotherapy and anti-programmed death-(ligand) 1 (PD-[L]1) therapy received SG 10 mg/kg on days 1 and 8 of a 21-day cycle. The primary end point was the investigator-assessed objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1. Key secondary end points included investigator-assessed duration of …

Age-Related Mesenchymal Stromal Cell Senescence Is Associated With Progression From Mgus To Multiple Myeloma, Natalya Plakhova, Sheila A Stewart, Et Al.

2020-Current year OA Pubs

The risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) increases with advancing age, suggesting that progression may be influenced by age-related changes within the bone marrow (BM) microenvironment. We hypothesise that senescent mesenchymal stromal cells (MSCs), which accumulate in the BM with age, may contribute to MGUS progression to MM. Here, we show that, like BM MSCs from aged non-cancer controls, BM MSCs from both MM and MGUS patients exhibit a senescent phenotype characterised by enlarged, flattened morphology, increased β-galactosidase activity and CDKN2A expression, and decreased proliferation rate compared with BM MSCs from healthy …

White Matter Microstructure In School-Age Children With Down Syndrome, Dea Garic, Robert C Mckinstry, Natasha Marrus, Kelly N Botteron, Et Al.

2020-Current year OA Pubs

Down syndrome (DS) is the most common genetic cause of intellectual disability, but our understanding of white matter microstructure in children with DS remains limited. Previous studies have reported reductions in white matter integrity, but nearly all studies to date have been conducted in adults or relied solely on diffusion tensor imaging (DTI), which lacks the ability to disentangle underlying properties of white matter organization. This study examined white matter microstructural differences in 7- to 12-year-old children with DS (n = 23), autism (n = 27), and typical development (n = 50) using DTI as well as High Angular Resolution …

Claustrum Volume Is Reduced In Multiple Sclerosis And Predicts Disability, Nicole Shelley, Bradley Judge, Dmitriy A Yablonskiy, Robert T Naismith, Matthew R Brier, Anne H Cross

2020-Current year OA Pubs

OBJECTIVE: The claustrum is a small, thin structure of predominantly gray matter with broad connectivity and enigmatic function. Little is known regarding the impact of claustrum pathology in multiple sclerosis (MS).

METHODS: This study assessed whether claustrum volume was reduced in MS and whether reductions were associated with specific disability domains. We compared the impact of claustrum volume reductions on neurological disability versus the well-studied thalamus. Data from the 15,793 participants in the MS PATHS study were used for primary analyses. A second cohort of 71 people with MS and healthy controls from our center was used for validation.

RESULTS: …

Clinical Trial Readiness In Limb Girdle Muscular Dystrophy R1 (Lgmdr1): A Grasp Consortium Study, Stephanie M Hunn, Amanda Clause, Conrad C Weihl, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Identifying functional measures that are both valid and reliable in the limb girdle muscular dystrophy (LGMD) population is critical for quantifying the level of functional impairment related to disease progression in order to establish clinical trial readiness in the context of anticipated therapeutic trials.

METHODS: Through the Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) Consortium, 42 subjects with LGMDR1 were enrolled in a 12-month natural history study across 11 international sites. Each subject completed a battery of clinical outcome assessments (COA), including the North Star Assessment for Limb Girdle-Type Dystrophies (NSAD), 10-m walk/run, and Performance of the …

Anti-Viral Cd8 Central Memory Veto Cells As A New Platform For Car T Cell Therapy, Wei-Hsin Liu, Anat Globerson Levin, Assaf Lask, Galit Horn, Tova Waks, Bar Nathansohn Levi, Irit Milman Krentsis, Einav Shoshan, Xiaohua Su, Maksim Mamonkin, Richard E Champlin, Yair Reisner, Esther Bachar Lustig

Faculty, Staff and Student Publications

Central memory CD8 T cells exhibit marked veto activity enhancing engraftment in several mouse models of T cell-depleted bone marrow (TDBM) allografting. Graft-versus-host disease (GVHD) can be prevented by stimulation of mouse or human memory CD8 T cells against their cognate antigens under cytokine deprivation, in the early phase of culture followed by further expansion with IL21, IL15, and IL7. Thus, human anti-viral CD8 central memory veto T cells generated from CMV and EBV-positive donors are currently evaluated in a clinical trial at MD Anderson Cancer Centre (MDACC). Results in 15 patients indicate a low risk of GVHD. Considering that …

Colorectal Cancer And The Risk Of Mortality Among Individuals With Suicidal Ideation, Srikanta Banerjee, Jagdish Khubchandani, Stanley Nkemjika

Department of Psychiatry and Human Behavior Faculty Papers

Suicide is a major public health problem that has grown at alarming rates in the last two decades. Colorectal cancer (CRC) is one of the most common causes of cancer deaths in the United States in both males and females. However, the influence of suicidal ideation (SI) on the association between CRC and risk of mortality has not been well examined.

METHODS: For this study, the 2005-2018 National Health and Nutrition Examination Survey (NHANES), a nationally representative survey of United States adults aged 20 years or older, was utilized. CRC survivorship was determined from self-reported data on CRC, and mortality …

Development And Validation Of The Immune Profile Score (Ips), A Novel Multiomic Algorithmic Assay For Stratifying Outcomes In A Real-World Cohort Of Patients With Advanced Solid Cancer Treated With Immune Checkpoint Inhibitors, Alia D Zander, Douglas Adkins, Et Al.

2020-Current year OA Pubs

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed the oncology treatment landscape. Despite substantial improvements for some patients, the majority do not benefit from ICIs, indicating a need for predictive biomarkers to better inform treatment decisions.

METHODS: A de-identified pan-cancer cohort from the Tempus multimodal real-world database was used for the development and validation of the Immune Profile Score (IPS) algorithm leveraging Tempus xT (648 gene DNA panel) and xR (RNA sequencing) (N=1,707 development cohort; N=1,600 validation cohort). The cohort consisted of patients with advanced stage cancer with solid tumor carcinomas across 16 cancer types treated with any ICI-containing regimen as …

Neovascular Pruning By Ido1 Inhibitors Can Potentiate Immunogenic Cytotoxicity Of Ischemia-Targeted Agents To Synergistically Enhance Anti-Pd-1 Responsiveness, Shih-Chun Shen, Souvik Dey, James B. Duhadaway, Erika Sutanto-Ward, Maurice T. Hampton, Serguei V. Kozlov, George C. Prendergast, Alexander J. Muller

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Strategies for deploying indoleamine 2,3-dioxygenase 1 (IDO1)-targeted therapies for use against cancer have focused on IDO1's role in promoting peripheral immune tolerance that shields tumors from effector T cells. However, preclinical investigation of both primary and metastatic tumor development in the lungs has uncovered a previously unappreciated role for IDO1 in directing a counterregulatory response to interferon (IFN)-γ that realigns the local inflammatory environment to promote tumor neovascularization. Understanding how to therapeutically leverage the ability of IDO1 inhibitors to subvert inflammatory neovascularization within the tumor microenvironment has potential ramifications for future clinical development of these compounds.

METHODS: Pulmonary metastases …