Biochemistry, Biophysics, and Structural Biology Commons^™

Triglyceride-Rich Lipoproteins, Apolipoprotein C-Iii, Angiopoietin-Like Protein 3, And Cardiovascular Events In Older Adults: Atherosclerosis Risk In Communities (Aric) Study, Aliza Hussain, Caroline Sun, Elizabeth Selvin, Vijay Nambi, Josef Coresh, Xiaoming Jia, Christie M Ballantyne, Ron C Hoogeveen

Faculty, Staff and Students Publications

AIMS: Despite statin and antihypertensive therapies, older Americans have high atherosclerotic cardiovascular disease (ASCVD) risk. Novel measures of triglyceride-rich lipoproteins, low-density lipoprotein triglycerides (LDL-TG), and remnant-like particle cholesterol (RLP-C), are associated with ASCVD in middle-aged adults. Polymorphisms in genes encoding angiopoietin-related protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III), two proteins involved in triglyceride catabolism, are associated with increased risk for hypertriglyceridaemia and ASCVD and are potential therapeutic targets. We examined associations of LDL-TG, RLP-C, apoC-III, and ANGPTL3 levels with ASCVD events in older adults in the Atherosclerosis Risk in Communities (ARIC) study.

METHODS AND RESULTS: In 6359 participants (mean age …

Identification Of The Global Mir-130a Targetome Reveals A Role For Tbl1xr1 In Hematopoietic Stem Cell Self-Renewal And T(8; 21) Aml, Gabriela Krivdova, Veronique Voisin, Erwin M Schoof, Sajid A Marhon, Alex Murison, Jessica L Mcleod, Martino M Gabra, Andy G X Zeng, Stefan Aigner, Brian A Yee, Alexander A Shishkin, Eric L Van Nostrand, Karin G Hermans, Aaron C Trotman-Grant, Nathan Mbong, James A Kennedy, Olga I Gan, Elvin Wagenblast, Daniel D De Carvalho, Leonardo Salmena, Mark D Minden, Gary D Bader, Gene W Yeo, John E Dick, Eric R Lechman

Faculty, Staff and Students Publications

Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSCs) point to shared core stemness properties. However, discordance between mRNA and protein signatures highlights an important role for post-transcriptional regulation by microRNAs (miRNAs) in governing this critical nexus. Here, we identify miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impairs B lymphoid differentiation and expands long-term HSCs. Integration of protein mass spectrometry and chimeric AGO2 crosslinking and immunoprecipitation (CLIP) identifies TBL1XR1 as a primary miR-130a target, whose loss of function phenocopies miR-130a overexpression. Moreover, we report that miR-130a is highly expressed …

A Red Fluorescent Protein With Improved Monomericity Enables Ratiometric Voltage Imaging With Asap3, Benjamin B Kim, Haodi Wu, Yukun A Hao, Michael Pan, Mariya Chavarha, Yufeng Zhao, Michael Westberg, François St-Pierre, Joseph C Wu, Michael Z Lin

Faculty, Staff and Students Publications

A ratiometric genetically encoded voltage indicator (GEVI) would be desirable for tracking transmembrane voltage changes in the presence of sample motion. We performed combinatorial multi-site mutagenesis on a cyan-excitable red fluorescent protein to create the bright and monomeric mCyRFP3, which proved to be uniquely non-perturbing when fused to the GEVI ASAP3. The green/red ratio from ASAP3-mCyRFP3 (ASAP3-R3) reported voltage while correcting for motion artifacts, allowing the visualization of membrane voltage changes in contracting cardiomyocytes and throughout the cell cycle of motile cells.

Depletion Of Transmembrane Mucin 4 (Muc4) Alters Intestinal Homeostasis In A Genetically Engineered Mouse Model Of Colorectal Cancer, Ramesh Pothuraju, Priya Pai, Sanjib Chaudhary, Jawed A Siddiqui, Jesse L Cox, Sukhwinder Kaur, Satyanarayana Rachagani, Hemant K Roy, Michael Bouvet, Surinder K Batra

Faculty, Staff and Students Publications

Mucins are components of the mucus layer overlying the intestinal epithelial cells, which maintains physiological homeostasis. Altered mucin expression is associated with disease progression. Expression of MUC4 decreases in colorectal cancer (CRC); however, its functional role and implications in the intestinal pathology in CRC are not studied well. Therefore, we generated a genetically engineered Muc4 knockout (Muc4-/-) CRC mouse model by crossing with Muc4-/- and Apc^flox/flox mice in the presence of colon-specific inducible Cre. We observed that deficiency of Muc4 results in an increased number of macroscopic tumors in the colon and rectal region and leads to poor survival. …

Prognostic And Predictive Biomarkers In Patients With Coronavirus Disease 2019 Treated With Tocilizumab In A Randomized Controlled Trial, Jennifer Tom, Min Bao, Larry Tsai, Aditi Qamra, David Summers, Montserrat Carrasco-Triguero, Jacqueline Mcbride, Carrie M Rosenberger, Celia J F Lin, William Stubbings, Kevin G Blyth, Jordi Carratalà, Bruno François, Thomas Benfield, Derrick Haslem, Paolo Bonfanti, Cor H Van Der Leest, Nidhi Rohatgi, Lothar Wiese, Charles Edouard Luyt, Farrah Kheradmand, Ivan O Rosas, Fang Cai

Faculty, Staff and Students Publications

OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia.

DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial.

SETTING: Hospitals in North America and Europe.

PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care.

INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo.

MEASUREMENTS AND MAIN …

Evaluation Of Factors Underlying Sex-Based Disparities In Cardiovascular Care In Adults With Self-Reported Premature Atherosclerotic Cardiovascular Disease, Vardhmaan Jain, Mahmoud Al Rifai, Rodman Turpin, Hatice Nur Eken, Ankit Agrawal, Dhruv Mahtta, Zainab Samad, Stephanie Coulter, Fatima Rodriguez, Laura A Petersen, Salim S Virani

Faculty, Staff and Students Publications

IMPORTANCE: There are limited data regarding sex-based differences in physical and mental health domains and health care access in adults with premature atherosclerotic cardiovascular disease (ASCVD).

OBJECTIVE: To study the association of sex with physical and mental health domains as well as health care access-related factors among adults with self-reported premature ASCVD.

DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort analysis of 748 090 adults aged 18 to 55 years in the Behavioral Risk Factor Surveillance System 2016 to 2019 in the US. Data were analyzed from June to July 2021.

EXPOSURES: Self-reported ASCVD, defined as having a history of coronary artery …

Syndecan-2 Regulates Pad2 To Exert Antifibrotic Effects On Ra-Ild Fibroblasts, Konstantin Tsoyi, Anthony J Esposito, Bo Sun, Ryan G Bowen, Kevin Xiong, Fernando Poli, Rafael Cardenas, Sarah G Chu, Xiaoliang Liang, Stefan W Ryter, Christine Beeton, Tracy J Doyle, Matthew J Robertson, Lindsay J Celada, Freddy Romero, Souheil Y El-Chemaly, Mark A Perrella, I-Cheng Ho, Ivan O Rosas

Faculty, Staff and Students Publications

Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression of both RA and fibrotic lung disease; however, the role of protein citrullination in RA-ILD remains unclear. Here, we demonstrate that the expression of peptidylarginine deiminase 2 (PAD2), an enzyme that catalyzes protein citrullination, is increased in lung homogenates from subjects with RA-ILD and their lung fibroblasts. Chemical inhibition or genetic knockdown of PAD2 in RA-ILD fibroblasts attenuated their activation, marked by decreased myofibroblast differentiation, gel contraction, and extracellular matrix …

Retinal Horizontal Cells Use Different Synaptic Sites For Global Feedforward And Local Feedback Signaling, Christian Behrens, Shubhash Chandra Yadav, Maria M Korympidou, Yue Zhang, Silke Haverkamp, Stephan Irsen, Anna Schaedler, Xiaoyu Lu, Zhuohe Liu, Jan Lause, François St-Pierre, Katrin Franke, Anna Vlasits, Karin Dedek, Robert G Smith, Thomas Euler, Philipp Berens, Timm Schubert

Faculty, Staff and Students Publications

In the outer plexiform layer (OPL) of the mammalian retina, cone photoreceptors (cones) provide input to more than a dozen types of cone bipolar cells (CBCs). In the mouse, this transmission is modulated by a single horizontal cell (HC) type. HCs perform global signaling within their laterally coupled network but also provide local, cone-specific feedback. However, it is unknown how HCs provide local feedback to cones at the same time as global forward signaling to CBCs and where the underlying synapses are located. To assess how HCs simultaneously perform different modes of signaling, we reconstructed the dendritic trees of five …

Imaging-Based Screening Of Deubiquitinating Proteases Identifies Otubain-1 As A Stabilizer Of C-Myc, Shannon E Moree, Laure Maneix, Polina Iakova, Fabio Stossi, Ergun Sahin, Andre Catic

Faculty, Staff and Students Publications

The ubiquitin-proteasome pathway precisely controls the turnover of transcription factors in the nucleus, playing an important role in maintaining appropriate quantities of these regulatory proteins. The transcription factor c-MYC is essential for normal development and is a critical cancer driver. Despite being highly expressed in several tissues and malignancies, the c-MYC protein is also continuously targeted by the ubiquitin-proteasome pathway, which can either facilitate or inhibit c-MYC degradation. Deubiquitinating proteases can remove ubiquitin chains from target proteins and rescue them from proteasomal digestion. This study sought to determine novel elements of the ubiquitin-proteasome pathway that regulate c-MYC levels. We performed …

Randomized Phase Iii Bmt Ctn Trial Of Calcineurin Inhibitor-Free Chronic Graft-Versus-Host Disease Interventions In Myeloablative Hematopoietic Cell Transplantation For Hematologic Malignancies, Leo Luznik, Marcelo C Pasquini, Brent Logan, Robert J Soiffer, Juan Wu, Steven M Devine, Nancy Geller, Sergio Giralt, Helen E Heslop, Mary M Horowitz, Richard J Jones, Mark R Litzow, Adam Mendizabal, Lori Muffly, Eneida R Nemecek, Lynn O'Donnell, Richard J O'Reilly, Raquel Palencia, Johannes Schetelig, Leyla Shune, Scott R Solomon, Sumithira Vasu, Vincent T Ho, Miguel-Angel Perales

Faculty, Staff and Students Publications

PURPOSE: Calcineurin inhibitors (CNI) are standard components of graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). Prior data suggested that CNI-free approaches using donor T-cell depletion, either by ex vivo CD34 selection or in vivo post-transplant cyclophosphamide (PTCy) as a single agent, are associated with lower rates of chronic GVHD (cGVHD).

METHODS: This multicenter phase III trial randomly assigned patients with acute leukemia or myelodysplasia and an HLA-matched donor to receive CD34-selected peripheral blood stem cell, PTCy after a bone marrow (BM) graft, or tacrolimus and methotrexate after BM graft (control). The primary end point was cGVHD (moderate or …

Race/Ethnicity And Birthplace As Risk Factors For Gastric Intestinal Metaplasia In A Multiethnic United States Population, Mimi C Tan, Taher Jamali, Theresa H Nguyen, Amy Galvan, Robert J Sealock, Anam Khan, Neda Zarrin-Khameh, Ashley Holloman, Ourania Kampagianni, David Henriquez Ticas, Yan Liu, Hashem B El-Serag, Aaron P Thrift

Faculty, Staff and Students Publications

INTRODUCTION: Several US subgroups have increased risk of gastric cancer and gastric intestinal metaplasia (GIM) and may benefit from targeted screening. We evaluated demographic and clinical risk factors for GIM and examined the interaction between race/ethnicity and birthplace on GIM risk.

METHODS: We identified patients who had undergone esophagogastroduodenoscopy with gastric biopsy from 3/2006-11/2016 using the pathology database at a safety net hospital in Houston, Texas. Cases had GIM on ≥1 gastric biopsy histopathology, whereas controls lacked GIM on any biopsy. We estimated odds ratios and 95% confidence intervals (CI) for associations with GIM risk using logistic regression and developed …

Maximum Dose Food Challenges Reveal Transient Sustained Unresponsiveness In Peanut Oral Immunotherapy (Poimd Study), Carla M Davis, Aikaterini Anagnostou, Sridevi Devaraj, Daisy T Vita, Fabian Rivera, Kathleen Pitts, Melissa Hearrell, Charles Minard, Danielle Guffey, Meera Gupta, Levi Watkin, Jordan S Orange, Sara Anvari

Faculty, Staff and Students Publications

BACKGROUND: The maximum tolerated dose of peanut protein following peanut oral immunotherapy (POIT) is unknown because most research studies have not examined very high thresholds.

OBJECTIVE: To define the maximum dose tolerated by patients on POIT and severity of allergic reactions after a 1-month period of treatment discontinuation.

METHODS: In a phase 2 3-year POIT open-label study, we enrolled participants age 5 to 13 years with a 1-year build-up period followed by a 2-year daily maintenance dose of 3900 mg with assessment of the maximum tolerated dose using double-blind placebo-controlled food challenges (DBPCFCs) of 26,225 mg cumulative dose of peanut …

Detecting Anomalies In Retinal Diseases Using Generative, Discriminative, And Self-Supervised Deep Learning, Philippe Burlina, William Paul, T Y Alvin Liu, Neil M Bressler

Faculty, Staff and Students Publications

IMPORTANCE: Anomaly detectors could be pursued for retinal diagnoses based on artificial intelligence systems that may not have access to training examples for all retinal diseases in all phenotypic presentations. Possible applications could include screening of population for any retinal disease rather than a specific disease such as diabetic retinopathy, detection of novel retinal diseases or novel presentations of common retinal diseases, and detection of rare diseases with little or no data available for training.

OBJECTIVE: To study the application of anomaly detection to retinal diseases.

DESIGN, SETTING, AND PARTICIPANTS: High-resolution retinal images from the publicly available EyePACS data set …

Extensive Identification Of Genes Involved In Congenital And Structural Heart Disorders And Cardiomyopathy, Nadine Spielmann, Gregor Miller, Tudor I Oprea, Chih-Wei Hsu, Gisela Fobo, Goar Frishman, Corinna Montrone, Hamed Haseli Mashhadi, Jeremy Mason, Violeta Munoz Fuentes, Stefanie Leuchtenberger, Andreas Ruepp, Matias Wagner, Dominik S Westphal, Cordula Wolf, Agnes Görlach, Adrián Sanz-Moreno, Yi-Li Cho, Raffaele Teperino, Stefan Brandmaier, Sapna Sharma, Isabella Rikarda Galter, Manuela A Östereicher, Lilly Zapf, Philipp Mayer-Kuckuk, Jan Rozman, Lydia Teboul, Rosie K A Bunton-Stasyshyn, Heather Cater, Michelle Stewart, Skevoulla Christou, Henrik Westerberg, Amelia M Willett, Janine M Wotton, Willson B Roper, Audrey E Christiansen, Christopher S Ward, Jason D Heaney, Corey L Reynolds, Jan Prochazka, Lynette Bower, David Clary, Mohammed Selloum, Ghina Bou About, Olivia Wendling, Hugues Jacobs, Sophie Leblanc, Hamid Meziane, Tania Sorg, Enrique Audain, Arthur Gilly, Nigel W Rayner, Impc Consortium, Genomics England Research Consortium;, Marc-Phillip Hitz, Eleftheria Zeggini, Eckhard Wolf, Radislav Sedlacek, Steven A Murray, Karen L Svenson, Robert E Braun, Jaqueline K White, Lois Kelsey, Xiang Gao, Toshihiko Shiroishi, Ying Xu, Je Kyung Seong, Fabio Mammano, Glauco P Tocchini-Valentini, Arthur L Beaudet, Terrence F Meehan, Helen Parkinson, Damian Smedley, Ann-Marie Mallon, Sara E Wells, Harald Grallert, Wolfgang Wurst, Susan Marschall, Helmut Fuchs, Steve D M Brown, Ann M Flenniken, Lauryl M J Nutter, Colin Mckerlie, Yann Herault, K C Kent Lloyd, Mary E Dickinson, Valerie Gailus-Durner, Martin Hrabe De Angelis

Faculty, Staff and Students Publications

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, …

Comparative Performance Of Risk Prediction Models For Hepatitis B-Related Hepatocellular Carcinoma In The United States, Hyun-Seok Kim, Xian Yu, Jennifer Kramer, Aaron P Thrift, Pete Richardson, Yao-Chun Hsu, Avegail Flores, Hashem B El-Serag, Fasiha Kanwal

Faculty, Staff and Students Publications

BACKGROUND & AIMS: Guidelines recommend hepatocellular carcinoma (HCC) surveillance in patients with chronic HBV infection. Several HCC risk prediction models are available to guide surveillance decisions, but their comparative performance remains unclear.

METHODS: Using a retrospective cohort of patients with HBV treated with nucleos(t)ide analogues at 130 Veterans Administration facilities between 9/1/2008 and 12/31/2018, we calculated risk scores from 10 HCC risk prediction models (REACH-B, PAGE-B, m-PAGE-B, CU-HCC, HCC-RESCUE, CAMD, APA-B, REAL-B, AASL-HCC, RWS-HCC). We estimated the models' discrimination and calibration. We calculated HCC incidence in risk categories defined by the reported cut-offs for all models.

RESULTS: Of 3,101 patients …

A Crispr Toolbox For Generating Intersectional Genetic Mouse Models For Functional, Molecular, And Anatomical Circuit Mapping, Savannah J Lusk, Andrew Mckinney, Patrick J Hunt, Paul G Fahey, Jay Patel, Andersen Chang, Jenny J Sun, Vena K Martinez, Ping Jun Zhu, Jeremy R Egbert, Genevera Allen, Xiaolong Jiang, Benjamin R Arenkiel, Andreas S Tolias, Mauro Costa-Mattioli, Russell S Ray

Faculty, Staff and Students Publications

BACKGROUND: The functional understanding of genetic interaction networks and cellular mechanisms governing health and disease requires the dissection, and multifaceted study, of discrete cell subtypes in developing and adult animal models. Recombinase-driven expression of transgenic effector alleles represents a significant and powerful approach to delineate cell populations for functional, molecular, and anatomical studies. In addition to single recombinase systems, the expression of two recombinases in distinct, but partially overlapping, populations allows for more defined target expression. Although the application of this method is becoming increasingly popular, its experimental implementation has been broadly restricted to manipulations of a limited set of …

Antibody Responses Of Healthy Adults To The P27 Peptide Of Respiratory Syncytial Virus Fusion Protein, Brittani N Blunck, Letisha Aideyan, Xunyan Ye, Vasanthi Avadhanula, Laura Ferlic-Stark, Lynn Zechiedrich, Brian E Gilbert, Pedro A Piedra

Faculty, Staff and Students Publications

The respiratory syncytial virus (RSV) fusion (F) protein undergoes two furin-cleavage events to become fusion competent, resulting in the release of a twenty-seven amino acid peptide (p27). Recent studies indicate that the p27 region of the F protein was an immunodominant antigen in young children. In this study, we evaluated the kinetics of the serum antibody response to the p27 peptide following natural RSV reinfection in adults. Nineteen healthy adults under sixty-five years of age were enrolled during the 2018-2019 RSV season in Houston, TX. Blood was collected at three study visits and RSV infection status was defined by changes …

Effect Of P2y12 Inhibitors On Survival Free Of Organ Support Among Non-Critically Ill Hospitalized Patients With Covid-19: A Randomized Clinical Trial, Jeffrey S Berger, Lucy Z Kornblith, Michelle N Gong, Harmony R Reynolds, Mary Cushman, Yu Cheng, Bryan J Mcverry, Keri S Kim, Renato D Lopes, Bassel Atassi, Scott Berry, Grant Bochicchio, Murillo De Oliveira Antunes, Michael E Farkouh, Yonatan Greenstein, Erinn M Hade, Kristin Hudock, Robert Hyzy, Pooja Khatri, Andrei Kindzelski, Bridget-Anne Kirwan, Lisa Baumann Kreuziger, Patrick R Lawler, Eric Leifer, Jose Lopez-Sendon Moreno, Jose Lopez-Sendon, James F Luther, Lilia Nigro Maia, John Quigley, Robert Sherwin, Lana Wahid, Jennifer Wilson, Judith S Hochman, Matthew D Neal, Activ-4a Investigators

Faculty, Staff and Students Publications

IMPORTANCE: Platelets represent a potential therapeutic target for improved clinical outcomes in patients with COVID-19.

OBJECTIVE: To evaluate the benefits and risks of adding a P2Y12 inhibitor to anticoagulant therapy among non-critically ill patients hospitalized for COVID-19.

DESIGN, SETTING, AND PARTICIPANTS: An open-label, bayesian, adaptive randomized clinical trial including 562 non-critically ill patients hospitalized for COVID-19 was conducted between February 2021 and June 2021 at 60 hospitals in Brazil, Italy, Spain, and the US. The date of final 90-day follow-up was September 15, 2021.

INTERVENTIONS: Patients were randomized to a therapeutic dose of heparin plus a P2Y12 inhibitor (n = …

Mutations In Hcfc1 And Ronin Result In An Inborn Error Of Cobalamin Metabolism And Ribosomopathy, Tiffany Chern, Annita Achilleos, Xuefei Tong, Matthew C Hill, Alexander B Saltzman, Lucas C Reineke, Arindam Chaudhury, Swapan K Dasgupta, Yushi Redhead, David Watkins, Joel R Neilson, Perumal Thiagarajan, Jeremy B A Green, Anna Malovannaya, James F Martin, David S Rosenblatt, Ross A Poché

Faculty, Staff and Students Publications

Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously …

Secretogranin Iii Stringently Regulates Pathological But Not Physiological Angiogenesis In Oxygen-Induced Retinopathy, Chang Dai, Prabuddha Waduge, Liyang Ji, Chengchi Huang, Ye He, Hong Tian, Elizabeth Zuniga-Sanchez, Amit Bhatt, Iok-Hou Pang, Guanfang Su, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized …

Associations Between Resources And Practices Of Ild Centers And Outcomes In Patients With Idiopathic Pulmonary Fibrosis: Data From The Ipf-Pro Registry, Joao A De Andrade, Tejaswini Kulkarni, Megan L Neely, Anne S Hellkamp, Amy Hajari Case, Daniel A Culver, Kalpalatha Guntupalli, Shaun Bender, Craig S Conoscenti, Laurie D Snyder, Ipf-Pro Registry Investigators

Faculty, Staff and Students Publications

BACKGROUND: Performance benchmarks for the management of idiopathic pulmonary fibrosis (IPF) have not been established. We used data from the IPF-PRO Registry, an observational registry of patients with IPF managed at sites across the US, to examine associations between the characteristics of the enrolling sites and patient outcomes.

METHODS: An online survey was used to collect information on the resources, operations, and self-assessment practices of IPF-PRO Registry sites that enrolled ≥ 10 patients. Site variability in 1-year event rates of clinically relevant outcomes, including death, death or lung transplant, and hospitalization, was assessed. Models were adjusted for differences in patient …

Aav5 Delivery Of Crispr-Cas9 Supports Effective Genome Editing In Mouse Lung Airway, Shun-Qing Liang, Christopher J Walkey, Alexa E Martinez, Qin Su, Mary E Dickinson, Dan Wang, William R Lagor, Jason D Heaney, Guangping Gao, Wen Xue

Faculty, Staff and Students Publications

Genome editing in the lung has the potential to provide long-term expression of therapeutic protein to treat lung genetic diseases. Yet efficient delivery of CRISPR to the lung remains a challenge. The NIH Somatic Cell Genome Editing (SCGE) Consortium is developing safe and effective methods for genome editing in disease tissues. Methods developed by consortium members are independently validated by the SCGE small animal testing center to establish rigor and reproducibility. We have developed and validated a dual adeno-associated virus (AAV) CRISPR platform that supports effective editing of a lox-stop-lox-Tomato reporter in mouse lung airway. After intratracheal injection of the …

Autophagosomes Fuse To Phagosomes And Facilitate The Degradation Of Apoptotic Cells In Caenorhabditis Elegans, Omar Peña-Ramos, Lucia Chiao, Xianghua Liu, Xiaomeng Yu, Tianyou Yao, Henry He, Zheng Zhou

Faculty, Staff and Students Publications

Autophagosomes are double-membrane intracellular vesicles that degrade protein aggregates, intracellular organelles, and other cellular components. During the development of the nematode Caenorhabditis elegans, many somatic and germ cells undergo apoptosis. These cells are engulfed and degraded by their neighboring cells. We discovered a novel role of autophagosomes in facilitating the degradation of apoptotic cells using a real-time imaging technique. Specifically, the double-membrane autophagosomes in engulfing cells are recruited to the surfaces of phagosomes containing apoptotic cells and subsequently fuse to phagosomes, allowing the inner vesicle to enter the phagosomal lumen. Mutants defective in the production of autophagosomes display significant …

Metastatic Insulinoma Presenting With Postprandial Hypoglycemia, Monique Debrah Maher, Dimpi Nitin Desai, Mandeep Bajaj

Faculty, Staff and Students Publications

BACKGROUND/OBJECTIVE: Patients with an insulinoma, a type of pancreatic neuroendocrine tumor, typically present with fasting hypoglycemia but can rarely present exclusively with postprandial hypoglycemia.

CASE REPORT: A 69-year-old man presented with episodes of postprandial blurry vision, sweating, and confusion for the last 2 years that were becoming more frequent over the last several weeks. Home blood glucose measurements revealed postprandial hypoglycemia (glucose level, 45-70 mg/dL), and symptoms were consistent with the Whipple triad. Continuous glucose monitoring revealed only postprandial hypoglycemia within 2 hours following meals. An outpatient fast was conducted with detectable insulin (6 μIU/mL) and C-peptide (2.0 ng/mL) levels …

Lessons Learned From An Enterprise-Wide Clinical Datathon, Andrew J Zimolzak, Jessica A Davila, Vamshi Punugoti, Ashok Balasubramanyam, Paul E Klotman, Laura A Petersen, Ryan H Rochat, Gloria Liao, Rory R Laubscher, Lee Leiber, Christopher I Amos

Faculty, Staff and Students Publications

In 2020, Baylor College of Medicine held a datathon to inform potential users of a new data warehouse, allow users to address clinical questions, identify warehouse capabilities and limitations, foster collaborations, and engage trainees. Senior faculty selected proposals based on feasibility and impact. Selectees worked with Information Technology for 2 months and presented findings. A survey of participants showed diverse levels of experience, high perceived value of the datathon, high rates of collaboration, and significant increases in knowledge. A datathon can promote familiarity with a new data warehouse, guide data warehouse improvement, and promote collaboration.

Mental Health And Access To Medical Care In Patients With Chronic Cardiovascular Conditions: An Analysis Of The Behavior Risk Factor Surveillance System, Riyad Y Kherallah, Mahmoud Al Rifai, Jing Liu, Sina Kianoush, Arunima Misra, Salim S Virani

Faculty, Staff and Students Publications

INTRODUCTION: Poor mental health is associated with worse outcomes for chronic diseases. It is unclear whether mental illness predisposes to difficulties with healthcare access.

METHODS: Using a combined dataset of the 2016-2019 Behavioral Risk Factor Surveillance System, this study focused on individuals who reported a chronic cardiovascular condition. Weighted multivariable logistic regression analyses were used to explore the association between domains of mental health and measures of healthcare access including delaying medical care, more than one year since last routine checkup, lack of a primary care physician, and cost-related medication nonadherence.

RESULTS: Among 1,747,397 participants, 27% had a chronic cardiovascular …

Endpoints In Heart Failure Drug Development, Aliza Hussain, Arunima Misra, Biykem Bozkurt

Faculty, Staff and Students Publications

Heart failure (HF) is a major health problem worldwide. The development of effective drug and/or device therapy is crucial to mitigate the significant morbidity, mortality and healthcare costs associated with HF. The choice of endpoint in clinical trials has important practical and clinical implications. Outcomes of interest including mortality and HF hospitalisations provide robust evidence for regulatory approval granted there is sufficiency of safety data. At the same time, it is important to recognise that HF patients experience significant impairments in functional capacity and quality of life, underscoring the need to incorporate parameters of symptoms and patient-reported outcomes in clinical …

“I Have Nothing More To Give”: Disparities In Burnout And The Protective Role Of Immigrant Status During The Covid-19 Pandemic, Gene Chibuchim Otuonye, Nancy Shenoi, Tianshi David Wu, Kalpalatha Guntupalli, Nidal Moukaddam

Faculty, Staff and Students Publications

Burnout is an epidemic, with deleterious effects on individuals, patient care, and healthcare systems. The Coronavirus Disease 2019 (COVID-19) pandemic may be exacerbating this problem. We aimed to explore socio-cultural and gender norms that modulate burnout development in physicians during the pandemic and analyze any disparities associated with gender, marital and immigration status and work-life balance. We conducted an online cross-sectional survey of physicians (August-November, 2021): The Maslach Burnout Inventory-Human Services Survey (MBI-HSS) was used to measure burnout, combined with a validated survey assessing work-life balance. Demographic data was obtained for each participant. MBI-HSS subscales were measured, along with work …

Meta-Analysis Comparing Outcomes Of High-Power Short-Duration And Low-Power Long-Duration Radiofrequency Ablation For Atrial Fibrillation, Dibbendhu Khanra, Abdul Hamid, Saurabh Deshpande, Anindya Mukherjee, Sanjiv Petkar, Mohammad Saeed, Indranill Basu-Ray

Faculty, Staff and Students Publications

OBJECTIVE: High power short duration (HPSD) ablation strategy is proposed to be more effective than low power long duration (LPLD) for radiofrequency ablation of atrial fibrillation. Although small trials abound, data from a large cohort are lacking. This meta-analysis compares all the existing studies comparing these two approaches to evaluate perceived advantages of one over the other.

METHODS: A systematic search of PubMed, EMBASE, and Cochrane databases identified studies comparing HPSD to LPLD ablation. All the analyses used the random-effects model.

RESULTS: Ablation settings varied widely across 20 studies comprising 2,136 patients who underwent HPSD and 1,753 patients who underwent …

Targeting Type I Interferons In Systemic Lupus Erythematous, Sebastian Bruera, Thandiwe Chavula, Riya Madan, Sandeep K Agarwal

Faculty, Staff and Students Publications

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with systemic clinical manifestations including, but not limited to, rash, inflammatory arthritis, serositis, glomerulonephritis, and cerebritis. Treatment options for SLE are expanding and the increase in our understanding of the immune pathogenesis is leading to the development of new therapeutics. Autoantibody formation and immune complex formation are important mediators in lupus pathogenesis, but an important role of the type I interferon (IFN) pathway has been identified in SLE patients and mouse models of lupus. These studies have led to the development of therapeutics targeting type I IFN and related pathways for …