Diseases Commons^™

Prolylcarboxypeptidase Alleviates Hypertensive Cardiac Remodeling By Regulating Myocardial Tissue Angiotensin Ii, Binh Y Nguyen, Fangchao Zhou, Pablo Binder, Wei Liu, Susanne S Hille, Xiaojing Luo, Min Zi, Hongyuan Zhang, Antony Adamson, Fozia Z Ahmed, Sam Butterworth, Elizabeth J Cartwright, Oliver J Müller, Kaomei Guan, Elizabeth M Fitzgerald, Xin Wang

Faculty, Staff and Student Publications

Background Prolonged activation of angiotensin II is the main mediator that contributes to the development of heart diseases, so converting angiotensin II into angiotensin 1-7 has emerged as a new strategy to attenuate detrimental effects of angiotensin II. Prolylcarboxypeptidase is a lysosomal pro-X carboxypeptidase that is able to cleave angiotensin II at a preferential acidic pH optimum. However, insufficient attention has been given to the cardioprotective functions of prolylcarboxylpeptidase. Methods and Results We established a CRISPR/CRISPR-associated protein 9-mediated global prolylcarboxylpeptidase-knockout and adeno-associated virus serotype 9-mediated cardiac prolylcarboxylpeptidase overexpression mouse models, which were challenged with the angiotensin II infusion (2 mg/kg …

Pentoxifylline For Treatment Of Sepsis And Necrotising Enterocolitis In Neonates, Mohan Pammi, Khalid N Haque

Faculty, Staff and Students Publications

BACKGROUND: Mortality and morbidity due to neonatal sepsis and necrotising enterocolitis (NEC) remain high despite the use of potent antimicrobial agents. Agents that modulate inflammation may improve outcomes. Pentoxifylline (PTX), a phosphodiesterase inhibitor, is one such agent. This is an update of a review first published in 2003 and updated in 2011 and 2015.

OBJECTIVES: To assess the effectiveness and safety of intravenous PTX as an adjunct to antibiotic therapy on mortality and morbidity in neonates with suspected or confirmed sepsis and neonates with NEC.

SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and trial registries in July 2022. We …

Sox7 Deficiency Causes Ventricular Septal Defects Through Its Effects On Endocardial-To-Mesenchymal Transition And The Expression Of Wnt4 And Bmp2, Andrés Hernández-García, Katherine E Pendleton, Sangbae Kim, Yumei Li, Bum J Kim, Hitisha P Zaveri, Valerie K Jordan, Aliska M Berry, M Cecilia Ljungberg, Rui Chen, Rainer B Lanz, Daryl A Scott

Faculty, Staff and Students Publications

SOX7 is a transcription factor-encoding gene located in a region on chromosome 8p23.1 that is recurrently deleted in individuals with ventricular septal defects (VSDs). We have previously shown that Sox7-/- embryos die of heart failure around E11.5. Here, we demonstrate that these embryos have hypocellular endocardial cushions with severely reduced numbers of mesenchymal cells. Ablation of Sox7 in the endocardium also resulted in hypocellular endocardial cushions, and we observed VSDs in rare E15.5 Sox7flox/-;Tie2-Cre and Sox7flox/flox;Tie2-Cre embryos that survived to E15.5. In atrioventricular explant studies, we showed that SOX7 deficiency leads to a severe reduction in endocardial-to-mesenchymal transition (EndMT). RNA-seq …

Comparative Analyses Of The Clinicopathologic Features Of Short-Term And Long-Term Survivors Of Patients With Pancreatic Ductal Adenocarcinoma Who Received Neoadjuvant Therapy And Pancreatoduodenectomy, Tom Z Liang, Matthew H G Katz, Laura R Prakash, Deyali Chatterjee, Hua Wang, Michael Kim, Ching-Wei D Tzeng, Naruhiko Ikoma, Robert A Wolff, Dan Zhao, Eugene J Koay, Anirban Maitra, Suprateek Kundu, Huamin Wang

Faculty, Staff and Student Publications

Neoadjuvant therapy (NAT) is increasingly used to treat patients with pancreatic ductal adenocarcinoma (PDAC). Patients with PDAC often show heterogenous responses to NAT with variable clinical outcomes, and the clinicopathologic parameters associated with these variable outcomes remain unclear. In this study, we systematically examined the clinicopathologic characteristics of 60 short-term survivors (overall survival < 15 months) and 149 long-term survivors (overall survival > 60 months) and compared them to 352 intermediate-term survivors (overall survival: 15-60 months) of PDAC who received NAT and pancreatoduodenectomy. We found that the short-term survivor group was associated with male gender (p = 0.03), tumor resectability prior to NAT (p = 0.04), poorly differentiated …

Gata6-As1 Regulates Intestinal Epithelial Mitochondrial Functions, And Its Reduced Expression Is Linked To Intestinal Inflammation And Less Favourable Disease Course In Ulcerative Colitis, Katya E Sosnovski, Tzipi Braun, Amnon Amir, Danielle Moshel, Marina Benshoshan, Kelli L Vandussen, Nina Levhar, Haya Abbas-Egbariya, Katia Beider, Rakefet Ben-Yishay, Syed Asad Ali, Sean R Moore, Subra Kugathasan, Ifat Abramovich, Efrat Glick Saar, Batya Weiss, Iris Barshack, Eyal Gottlieb, Tamar Geiger, Shomron Ben-Horin, Igor Ulitsky, Jeffrey S Hyams, Lee A Denson, Yael Haberman

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Widespread dysregulation of long non-coding RNAs [lncRNAs] including a reduction in GATA6-AS1 was noted in inflammatory bowel disease [IBD]. We previously reported a prominent inhibition of epithelial mitochondrial functions in ulcerative colitis [UC]. However, the connection between reduction of GATA6-AS1 expression and attenuated epithelial mitochondrial functions was not defined.

METHODS: Mucosal transcriptomics was used to conform GATA6-AS1 reduction in several treatment-naïve independent human cohorts [n=673]. RNA pull-down followed by mass spectrometry was used to determine the GATA6-AS1 interactome. Metabolomics and mitochondrial respiration following GATA6-AS1 silencing in Caco-2 cells were used to elaborate on GATA6-AS1 functions.

RESULTS: GATA6-AS1 …

Targeting Energy Intake And Circadian Biology To Engage Mechanisms Of Aging In Older Adults With Obesity: Calorie Restriction And Time-Restricted Eating, Satchidananda Panda, Geraldine Maier, Dennis T Villareal

Faculty, Staff and Students Publications

With the rise in obesity across age groups, it has been a hindrance to engaging in physical activity and mobility in older adults. Daily calorie restriction (CR) up to 25% has been the cornerstone of obesity management even though the safety in older adults remains incompletely understood. Although some adults can follow CR with clinically significant weight loss and improved health metrics, CR faces 2 obstacles-many fail to adopt CR and even among those who can adopt it short term, long-term compliance can be difficult. Furthermore, there is a continuing debate about the net benefits of CR-induced weight loss in …

Transmembrane Stem Factor Nanodiscs Enhanced Revascularization In A Hind Limb Ischemia Model In Diabetic, Hyperlipidemic Rabbits, Eri Takematsu, Miles Massidda, Gretchen Howe, Julia Goldman, Patricia Felli, Lei Mei, Gregory Callahan, Andrew Sligar, Richard Smalling, Aaron Baker

Faculty, Staff and Student Publications

Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. …

Tonb-Dependent Receptor Protein Displayed On Spores Of Bacillus Subtilis Stimulates Protective Immune Responses Against Acinetobacter Baumannii, Nor-Aziyah Matrahim, Kathryn Marie Jones, Brian P Keegan, Ulrich Strych, Bin Zhan, Hai-Yen Lee, Sazaly Abubakar

Faculty, Staff and Students Publications

The emergence of antibiotic-resistant Acinetobacter baumannii strains with limited treatment options has become a significant global health concern. Efforts to develop vaccines against the bacteria have centred on several potential protein targets, including the TonB-dependent receptors (TBDRs). In the present study, TBDRs from A. baumannii were displayed on the surface of Bacillus subtilis spores. The immunogenicity of the recombinant spores was evaluated in orally vaccinated mice. None of the immunized mice demonstrated signs of illness and were observed to be healthy throughout the study. Sera and the intestinal secretions from the recombinant spores-treated mice demonstrated mucosal and humoral antibody responses …

Coronavirus Disease 2019 Convalescent Plasma Outpatient Therapy To Prevent Outpatient Hospitalization: A Meta-Analysis Of Individual Participant Data From 5 Randomized Trials, Adam C Levine, Yuriko Fukuta, Moises A Huaman, Jiangda Ou, Barry R Meisenberg, Bela Patel, James H Paxton, Daniel F Hanley, Bart J A Rijnders, Arvind Gharbharan, Casper Rokx, Jaap Jan Zwaginga, Andrea Alemany, Oriol Mitjà, Dan Ouchi, Pere Millat-Martinez, Valerie Durkalski-Mauldin, Frederick K Korley, Larry J Dumont, Clifton W Callaway, Romina Libster, Gonzalo Perez Marc, Diego Wappner, Ignacio Esteban, Fernando Polack, David J Sullivan

Faculty, Staff and Students Publications

BACKGROUND: Outpatient monoclonal antibodies are no longer effective and antiviral treatments for coronavirus disease 2019 (COVID-19) disease remain largely unavailable in many countries worldwide. Although treatment with COVID-19 convalescent plasma (CCP) is promising, clinical trials among outpatients have shown mixed results.

METHODS: We conducted an individual participant data meta-analysis from outpatient trials to assess the overall risk reduction for all-cause hospitalizations by day 28 in transfused participants. Relevant trials were identified by searching Medline, Embase, medRxiv, World Health Organization COVID-19 Research Database, Cochrane Library, and Web of Science from January 2020 to September 2022.

RESULTS: Five included studies from 4 …

High-Resolution Transcriptomic And Epigenetic Profiling Identifies Novel Regulators Of Copd, Uwe Schwartz, Maria Llamazares Prada, Stephanie T Pohl, Mandy Richter, Raluca Tamas, Michael Schuler, Corinna Keller, Vedrana Mijosek, Thomas Muley, Marc A Schneider, Karsten Quast, Joschka Hey, Claus P Heußel, Arne Warth, Hauke Winter, Özdemirhan Serçin, Harry Karmouty-Quintana, Soma Sk Jyothula, Manish K Patel, Felix Herth, Ina Koch, Giuseppe Petrosino, Alexandru Titimeaua, Balca R Mardin, Dieter Weichenhan, Tomasz P Jurkowski, Charles D Imbusch, Benedikt Brors, Vladimir Benes, Birgit Jung, David Wyatt, Heiko F Stahl, Christoph Plass, Renata Z Jurkowska

Faculty, Staff and Student Publications

Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. Considering its environmental cause, we hypothesized that COPD will be associated with altered epigenetic signaling in lung cells. We generated genome-wide DNA methylation maps at single CpG resolution of primary human lung fibroblasts (HLFs) across COPD stages. We show that the epigenetic landscape is changed early in COPD, with DNA methylation changes occurring predominantly in regulatory regions. RNA sequencing of matched fibroblasts demonstrated dysregulation of genes involved in proliferation, DNA repair, and extracellular matrix organization. Data integration identified 110 candidate regulators of disease phenotypes that were linked …

Contribution Of The Oral And Gastrointestinal Microbiomes To Bloodstream Infections In Leukemia Patients, Stephanie Mcmahon, Pranoti Sahasrabhojane, Jiwoong Kim, Samantha Franklin, Chia-Chi Chang, Robert R Jenq, Andrew E Hillhouse, Samuel A Shelburne, Jessica Galloway-Peña

Faculty, Staff and Student Publications

Bloodstream infections (BSIs) pose a significant mortality risk for acute myeloid leukemia (AML) patients. It has been previously reported that intestinal domination (>30% relative abundance [RA] attributed to a single taxon) with the infecting taxa often precedes BSI in stem cell transplant patients. Using 16S rRNA amplicon sequencing, we analyzed oral and stool samples from 63 AML patients with BSIs to determine the correlation between the infectious agent and microbiome composition. Whole-genome sequencing and antimicrobial susceptibilities were performed on all BSI isolates. Species-level detection of the infectious agent and presence of antibiotic resistance determinants in the stool (

Hematopoietic Progenitor Kinase 1 Inhibits The Development And Progression Of Pancreatic Intraepithelial Neoplasia, Hua Wang, Rohan Moniruzzaman, Lei Li, Baoan Ji, Yi Liu, Xiangsheng Zuo, Reza Abbasgholizadeh, Jun Zhao, Guangchao Liu, Ruiqi Wang, Hongli Tang, Ryan Sun, Xiaoping Su, Tse-Hua Tan, Anirban Maitra, Huamin Wang

Faculty, Staff and Student Publications

Ras plays an essential role in the development of acinar-to-ductal metaplasia (ADM) and pancreatic ductal adenocarcinoma (PDAC). However, mutant Kras is an inefficient driver for PDAC development. The mechanisms of the switching from low Ras activity to high Ras activity that are required for development and progression of pancreatic intraepithelial neoplasias (PanINs) are unclear. In this study, we found that hematopoietic progenitor kinase 1 (HPK1) was upregulated during pancreatic injury and ADM. HPK1 interacted with the SH3 domain and phosphorylated Ras GTPase-activating protein (RasGAP) and upregulated RasGAP activity. Using transgenic mouse models of HPK1 or M46, a kinase-dead mutant of …

Microbiome Alterations Driven By Trypanosoma Cruzi Infection In Two Disjunctive Murine Models, Sergio Castañeda, Marina Muñoz, Peter J Hotez, Maria Elena Bottazzi, Alberto E Paniz-Mondolfi, Kathryn M Jones, Rojelio Mejia, Cristina Poveda, Juan David Ramírez

Faculty, Staff and Students Publications

Alterations caused by Trypanosoma cruzi in the composition of gut microbiome may play a vital role in the host-parasite interactions that shapes physiology and immune responses against infection. Thus, a better understanding of this parasite-host-microbiome interaction may yield relevant information in the comprehension of the pathophysiology of the disease and the development of new prophylactic and therapeutic alternatives. Therefore, we implemented a murine model with two mice strains (BALB/c and C57BL/6) to evaluate the impact of Trypanosoma cruzi (Tulahuen strain) infection on the gut microbiome utilizing cytokine profiling and shotgun metagenomics. Higher parasite burdens were observed in cardiac and intestinal …

Troponin In Acute Chest Pain To Risk Stratify And Guide Effective Use Of Computed Tomography Coronary Angiography (Target-Ctca): A Randomised Controlled Trial, Kuan Ken Lee, David Lowe, Rachel O'Brien, Ryan Wereski, Anda Bularga, Caelan Taggart, Matthew T H Lowry, Amy V Ferry, Michelle C Williams, Giles Roditi, John Byrne, Chris Tuck, Denise Cranley, Praveen Thokala, Steve Goodacre, Catriona Keerie, John Norrie, David E Newby, Alasdair J Gray, Nicholas L Mills

Faculty, Staff and Student Publications

BACKGROUND: The majority of patients with suspected acute coronary syndrome presenting to the emergency department will be discharged once myocardial infarction has been ruled out, although a proportion will have unrecognised coronary artery disease. In this setting, high-sensitivity cardiac troponin identifies those at increased risk of future cardiac events. In patients with intermediate cardiac troponin concentrations in whom myocardial infarction has been ruled out, this trial aims to investigate whether outpatient computed tomography coronary angiography (CTCA) reduces subsequent myocardial infarction or cardiac death.

METHODS: TARGET-CTCA is a multicentre prospective randomised open label with blinded endpoint parallel group event driven trial. …

Antitumor Efficacy Of Dual Blockade With Encorafenib + Cetuximab In Combination With Chemotherapy In Human Brafv600e-Mutant Colorectal Cancer, Stefania Napolitano, Melanie Woods, Hey Min Lee, Vincenzo De Falco, Giulia Martini, Carminia Maria Della Corte, Erika Martinelli, Vincenzo Famiglietti, Davide Ciardiello, Amanda Anderson, Natalie Wall Fowlkes, Oscar Eduardo Villareal, Alexey Sorokin, Preeti Kanikarla, Olu Coker, Van Morris, Lucia Altucci, Josep Tabernero, Teresa Troiani, Fortunato Ciardiello, Scott Kopetz

Faculty, Staff and Student Publications

PURPOSE: Encorafenib + cetuximab (E+C) is an effective therapeutic option in chemorefractory BRAFV600E metastatic colorectal cancer (mCRC). However, there is a need to improve the efficacy of this molecular-targeted therapy and evaluate regimens suitable for untreated BRAFV600E in patients with mCRC.

EXPERIMENTAL DESIGN: We performed a series of in vivo studies using BRAFV600E mCRC tumor xenografts. Mice were randomized to receive 5-fluoruracil (5-FU), irinotecan, or oxaliplatin regimens (FOLFIRI or FOLFOX), (E+C) or the combination. Patients received long-term treatment until disease progression, with deescalation strategies used to mimic maintenance therapy. Transcriptomic changes after progression on cytotoxic chemotherapy or targeted therapy were …

Targeted Therapy With The Mutant Idh2 Inhibitor Enasidenib For High-Risk Idh2-Mutant Myelodysplastic Syndrome, Courtney D Dinardo, Sangeetha Venugopal, Curtis Lachowiez, Koichi Takahashi, Sanam Loghavi, Guillermo Montalban-Bravo, Xuemei Wang, Hetty Carraway, Mikkael Sekeres, Ameenah Sukkur, Danielle Hammond, Kelly Chien, Abhishek Maiti, Lucia Masarova, Koji Sasaki, Yesid Alvarado, Tapan Kadia, Nicholas J Short, Naval Daver, Gautam Borthakur, Farhad Ravandi, Hagop M Kantarjian, Bhumika Patel, Amy Dezern, Gail Roboz, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

The isocitrate dehydrogenase enzyme 2 (IDH2) gene is mutated in ∼5% of patients with myelodysplastic syndrome (MDS). Enasidenib is an oral, selective, mutant IDH2 inhibitor approved for IDH2-mutated (mIDH2) relapsed/refractory acute myeloid leukemia. We designed a 2-arm multicenter study to evaluate safety and efficacy of (A) the combination of enasidenib with azacitidine for newly diagnosed mIDH2 MDS, and (B) enasidenib monotherapy for mIDH2 MDS after prior hypomethylating agent (HMA) therapy. Fifty patients with mIDH2 MDS enrolled: 27 in arm A and 23 in arm B. Median age of patients was 73 years. The most common adverse events were neutropenia (40%), …

Patiromer Utility As An Adjunct Treatment In Patients Needing Urgent Hyperkalaemia Management (Platinum): Design Of A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Study, Zubaid Rafique, Jeffrey Budden, Carol Moreno Quinn, Youyou Duanmu, Basmah Safdar, Jason J Bischof, Brian E Driver, Charles A Herzog, Matthew R Weir, Adam J Singer, Stephen Boone, Karina M Soto-Ruiz, W Frank Peacock

Faculty, Staff and Students Publications

INTRODUCTION: Hyperkalaemia is common, life-threatening and often requires emergency department (ED) management; however, no standardised ED treatment protocol exists. Common treatments transiently reducing serum potassium (K

METHODS AND ANALYSIS: PLATINUM is a Phase 4, multicentre, randomised, double-blind, placebo-controlled study in participants who present to the ED at approximately 30 US sites. Approximately 300 adult participants with hyperkalaemia (K

ETHICS AND DISSEMINATION: A central Institutional Review Board (IRB) and Ethics Committee provided protocol approval (#20201569), with subsequent approval by local IRBs at each site, and participants will provide written consent. Primary results will be published in peer-reviewed manuscripts promptly following study …

Whole Genome Analysis For 163 Grnas In Cas9-Edited Mice Reveals Minimal Off-Target Activity, Kevin A Peterson, Sam Khalouei, Nour Hanafi, Joshua A Wood, Denise G Lanza, Lauri G Lintott, Brandon J Willis, John R Seavitt, Robert E Braun, Mary E Dickinson, Jacqueline K White, K C Kent Lloyd, Jason D Heaney, Stephen A Murray, Arun Ramani, Lauryl M J Nutter

Faculty, Staff and Students Publications

Genome editing with CRISPR-associated (Cas) proteins holds exceptional promise for "correcting" variants causing genetic disease. To realize this promise, off-target genomic changes cannot occur during the editing process. Here, we use whole genome sequencing to compare the genomes of 50 Cas9-edited founder mice to 28 untreated control mice to assess the occurrence of S. pyogenes Cas9-induced off-target mutagenesis. Computational analysis of whole-genome sequencing data detects 26 unique sequence variants at 23 predicted off-target sites for 18/163 guides used. While computationally detected variants are identified in 30% (15/50) of Cas9 gene-edited founder animals, only 38% (10/26) of the variants in 8/15 …

Preparation And Immunofluorescence Staining Of Bundles And Single Fiber Cells From The Cortex And Nucleus Of The Eye Lens, Michael P Vu, Catherine Cheng

Faculty, Staff and Student Publications

The lens is a transparent and ellipsoid organ in the anterior chamber of the eye that changes shape to finely focus light onto the retina to form a clear image. The bulk of this tissue comprises specialized, differentiated fiber cells that have a hexagonal cross section and extend from the anterior to the posterior poles of the lens. These long and skinny cells are tightly opposed to neighboring cells and have complex interdigitations along the length of the cell. The specialized interlocking structures are required for normal biomechanical properties of the lens and have been extensively described using electron microscopy …

Early Postpartum Hba1c After Hyperglycemia First Detected In Pregnancy-Imperfect But Not Without Value, Ankia Coetzee, David R Hall, Mari Van De Vyver, Magda Conradie

Faculty, Staff and Student Publications

BACKGROUND: South African women of childbearing age are disproportionally affected by obesity and at significant risk of Type 2 Diabetes Mellitus (T2DM). Unless pregnant, they do not readily undergo screening for T2DM. With a local focus on improved antenatal care, hyperglycemia is often first detected in pregnancy (HFDP). This may erroneously be attributed to Gestational Diabetes Mellitus (GDM) in all without considering T2DM. Glucose evaluation following pregnancy is essential for early detection and management of women with T2DM in whom persistent hyperglycemia is to be expected. Conventional testing with an oral glucose tolerance test (OGTT) is cumbersome, prompting investigation for …

Targeting Neddylation And Sumoylation In Chemoresistant Triple Negative Breast Cancer, Wei Ruan, Jiwen Li, Seungwon Choi, Xinxin Ma, Yafen Liang, Ragini Nair, Xiaoyi Yuan, Tingting W Mills, Holger K Eltzschig

Faculty, Staff and Student Publications

Previous studies implicate extracellular adenosine signaling in attenuating myocardial ischemia and reperfusion injury (IRI). This extracellular adenosine signaling is terminated by its uptake into cells by equilibrative nucleoside transporters (ENTs). Thus, we hypothesized that targeting ENTs would function to increase cardiac adenosine signaling and concomitant cardioprotection against IRI. Mice were exposed to myocardial ischemia and reperfusion injury. Myocardial injury was attenuated in mice treated with the nonspecific ENT inhibitor dipyridamole. A comparison of mice with global Ent1 or Ent2 deletion showed cardioprotection only in Ent1-/- mice. Moreover, studies with tissue-specific Ent deletion revealed that mice with myocyte-specific Ent1 deletion (Ent1loxP/loxP …

Non-Melanoma Skin Cancer Detection In The Age Of Advanced Technology: A Review, Haleigh Stafford, Jane Buell, Elizabeth Chiang, Uma Ramesh, Michael Migden, Priyadharsini Nagarajan, Moran Amit, Dan Yaniv

Faculty, Staff and Student Publications

Skin cancer is the most common cancer diagnosis in the United States, with approximately one in five Americans expected to be diagnosed within their lifetime. Non-melanoma skin cancer is the most prevalent type of skin cancer, and as cases rise globally, physicians need reliable tools for early detection. Artificial intelligence has gained substantial interest as a decision support tool in medicine, particularly in image analysis, where deep learning has proven to be an effective tool. Because specialties such as dermatology rely primarily on visual diagnoses, deep learning could have many diagnostic applications, including the diagnosis of skin cancer. Furthermore, with …

Esophageal Lesion Reveals An Aortic Pseudoaneurysm In The Setting Of Actinomyces Odontolyticus Bacteremia, Anneliese Grewing, Harsha Jujjavarapu, Cameron Price, Lindsay F Eilers, Sloane Zimmerman, Nahid Hiermandi, Athar M Qureshi, Richard Kellermayer, Jolie J Britt

Faculty, Staff and Students Publications

A toddler presented with hematemesis a few weeks after ingesting a penny. Workup revealed an esophageal lesion communicating with an aortic pseudoaneurysm in the setting of Actinomyces odontolyticus bacteremia. A. odontolytica is an oropharyngeal bacteria known to cause fistulas when introduced into tissue planes. (Level of Difficulty: Intermediate.)

A Nurse-Led Telehealth Program For Diabetes Foot Care: Feasibility And Usability Study, Hsiao-Hui Ju, Rashmi Momin, Stanley Cron, Jed Jularbal, Jeffery Alford, Constance Johnson

Faculty, Staff and Student Publications

BACKGROUND: Diabetes mellitus can lead to severe and debilitating foot complications, such as infections, ulcerations, and amputations. Despite substantial progress in diabetes care, foot disease remains a major challenge in managing this chronic condition that causes serious health complications worldwide.

OBJECTIVE: The primary aim of this study was to examine the feasibility and usability of a telehealth program focused on preventive diabetes foot care. A secondary aim was to descriptively measure self-reported changes in diabetes knowledge, self-care, and foot care behaviors before and after participating in the program.

METHODS: The study used a single-arm, pre-post design in 2 large family …

Achondroplasia Natural History Study (Clarity): 60-Year Experience In Orthopedic Surgery From Four Skeletal Dysplasia Centers, Nickolas J Nahm, W G Stuart Mackenzie, William G Mackenzie, Ethan Gough, S Shahrukh Hashmi, Jacqueline T Hecht, Janet M Legare, Mary Ellen Little, Peggy Modaff, Richard M Pauli, David F Rodriguez-Buritica, Maria Elena Serna, Cory J Smid, Julie Hoover-Fong, Michael B Bober

Faculty, Staff and Student Publications

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database.

RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. …

Achondroplasia Natural History Study (Clarity): 60-Year Experience In Orthopedic Surgery From Four Skeletal Dysplasia Centers, Nickolas J Nahm, W G Stuart Mackenzie, William G Mackenzie, Ethan Gough, S Shahrukh Hashmi, Jacqueline T Hecht, Janet M Legare, Mary Ellen Little, Peggy Modaff, Richard M Pauli, David F Rodriguez-Buritica, Maria Elena Serna, Cory J Smid, Julie Hoover-Fong, Michael B Bober

Faculty, Staff and Student Publications

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database.

RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. …

Mapping Human Norovirus Antigens During Infection Reveals The Breadth Of The Humoral Immune Response, Lynn Su, Wanzhi Huang, Frederick H Neill, Mary K Estes, Robert L Atmar, Timothy Palzkill

Faculty, Staff and Students Publications

Human noroviruses (HuNoV) are the leading cause of acute gastroenteritis worldwide. The humoral immune response plays an important role in clearing HuNoV infections and elucidating the antigenic landscape of HuNoV during an infection can shed light on antibody targets to inform vaccine design. Here, we utilized Jun-Fos-assisted phage display of a HuNoV genogroup GI.1 genomic library and deep sequencing to simultaneously map the epitopes of serum antibodies of six individuals infected with GI.1 HuNoV. We found both unique and common epitopes that were widely distributed among both nonstructural proteins and the major capsid protein. Recurring epitope profiles suggest immunodominant antibody …

Achondroplasia Natural History Study (Clarity): 60-Year Experience In Orthopedic Surgery From Four Skeletal Dysplasia Centers, Nickolas J Nahm, W G Stuart Mackenzie, William G Mackenzie, Ethan Gough, S Shahrukh Hashmi, Jacqueline T Hecht, Janet M Legare, Mary Ellen Little, Peggy Modaff, Richard M Pauli, David F Rodriguez-Buritica, Maria Elena Serna, Cory J Smid, Julie Hoover-Fong, Michael B Bober

Faculty, Staff and Student Publications

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database.

RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. …

17Β-Estradiol Promotes Extracellular Vesicle Release And Selective Mirna Loading In Erα-Positive Breast Cancer, Rares Drula, Barbara Pardini, Xiao Fu, Mireia Cruz De Los Santos, Ancuta Jurj, Lan Pang, Sherien M El-Daly, Linda Fabris, Erik Knutsen, Mihnea P Dragomir, Recep Bayraktar, Yongfeng Li, Meng Chen, Filippo Del Vecchio, Léa Berland, Jessica Dae, Daniel Fan, Masayoshi Shimizu, Anh M Tran, Mercedes Barzi, Carlotta Pioppini, Angelica M Gutierrez, Cristina Ivan, Salyna Meas, Carolyn S Hall, Suresh K Alahari, Ioana Berindan-Neagoe, Muller Fabbri, Anthony Lucci, Banu Arun, Simone Anfossi, George A Calin

Faculty, Staff and Student Publications

The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor-positive (ER+) BC, we hypothesized that 17β-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17β-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7's miRNAs into EVs. In multiple patient cohorts, …

Chromatin Alternates Between A And B Compartments At Kilobase Scale For Subgenic Organization, Hannah L Harris, Huiya Gu, Moshe Olshansky, Ailun Wang, Irene Farabella, Yossi Eliaz, Achyuth Kalluchi, Akshay Krishna, Mozes Jacobs, Gesine Cauer, Melanie Pham, Suhas S P Rao, Olga Dudchenko, Arina Omer, Kiana Mohajeri, Sungjae Kim, Michael H Nichols, Eric S Davis, Dimos Gkountaroulis, Devika Udupa, Aviva Presser Aiden, Victor G Corces, Douglas H Phanstiel, William Stafford Noble, Guy Nir, Michele Di Pierro, Jeong-Sun Seo, Michael E Talkowski, Erez Lieberman Aiden, M Jordan Rowley

Faculty, Staff and Students Publications

Nuclear compartments are prominent features of 3D chromatin organization, but sequencing depth limitations have impeded investigation at ultra fine-scale. CTCF loops are generally studied at a finer scale, but the impact of looping on proximal interactions remains enigmatic. Here, we critically examine nuclear compartments and CTCF loop-proximal interactions using a combination of in situ Hi-C at unparalleled depth, algorithm development, and biophysical modeling. Producing a large Hi-C map with 33 billion contacts in conjunction with an algorithm for performing principal component analysis on sparse, super massive matrices (POSSUMM), we resolve compartments to 500 bp. Our results demonstrate that essentially all …