Medical Specialties Commons^™

Multiomic Investigations Into Lung Health And Disease, Sarah E Blutt, Cristian Coarfa, Josef Neu, Mohan Pammi

Faculty, Staff and Students Publications

Diseases of the lung account for more than 5 million deaths worldwide and are a healthcare burden. Improving clinical outcomes, including mortality and quality of life, involves a holistic understanding of the disease, which can be provided by the integration of lung multi-omics data. An enhanced understanding of comprehensive multiomic datasets provides opportunities to leverage those datasets to inform the treatment and prevention of lung diseases by classifying severity, prognostication, and discovery of biomarkers. The main objective of this review is to summarize the use of multiomics investigations in lung disease, including multiomics integration and the use of machine learning …

Systematic Design And Data-Driven Evaluation Of Social Determinants Of Health Ontology (Sdoho), Yifang Dang, Fang Li, Xinyue Hu, Vipina K Keloth, Meng Zhang, Sunyang Fu, Muhammad F Amith, J Wilfred Fan, Jingcheng Du, Evan Yu, Hongfang Liu, Xiaoqian Jiang, Hua Xu, Cui Tao

Faculty, Staff and Student Publications

Objective: Social determinants of health (SDoH) play critical roles in health outcomes and well-being. Understanding the interplay of SDoH and health outcomes is critical to reducing healthcare inequalities and transforming a "sick care" system into a "health-promoting" system. To address the SDOH terminology gap and better embed relevant elements in advanced biomedical informatics, we propose an SDoH ontology (SDoHO), which represents fundamental SDoH factors and their relationships in a standardized and measurable way.

Material and methods: Drawing on the content of existing ontologies relevant to certain aspects of SDoH, we used a top-down approach to formally model classes, relationships, and …

Early-Adulthood Spike In Protein Translation Drives Aging Via Juvenile Hormone/Germline Signaling, Harper S Kim, Danitra J Parker, Madison M Hardiman, Erin Munkácsy, Nisi Jiang, Aric N Rogers, Yidong Bai, Colin Brent, James A Mobley, Steven N Austad, Andrew M Pickering

Faculty, Staff and Student Publications

Protein translation (PT) declines with age in invertebrates, rodents, and humans. It has been assumed that elevated PT at young ages is beneficial to health and PT ends up dropping as a passive byproduct of aging. In Drosophila, we show that a transient elevation in PT during early-adulthood exerts long-lasting negative impacts on aging trajectories and proteostasis in later-life. Blocking the early-life PT elevation robustly improves life-/health-span and prevents age-related protein aggregation, whereas transiently inducing an early-life PT surge in long-lived fly strains abolishes their longevity/proteostasis benefits. The early-life PT elevation triggers proteostatic dysfunction, silences stress responses, and drives age-related …

Incidence Of Resting-State Functional Connectivity To Secondary Language Areas And Contralateral Language Areas In Patients With Brain Tumors, Angela L Young, Suprateek Kundu, Karthik K Tappa, Ping Hou, Ho-Ling Liu, Vinodh A Kumar

Faculty, Staff and Student Publications

Purpose: Secondary language areas, including the pre-supplementary motor area (pre-SMA), dorsolateral prefrontal cortex (DLPFC), and the visual word form area (VWFA) play important roles in speech, but have been under-evaluated in the realm of resting-state (rs)-fMRI. The purpose of this study is to determine the incidence that secondary language areas and contralateral language areas can be localized using seed-based correlation (SBC) rs-fMRI.

Methods: We retrospectively reviewed 40 rs-fMRIs for functional connectivity (FC) to secondary language areas in cases where FC to Broca's or Wernicke's area near tumor in the left hemisphere were successfully generated using SBC analysis. Logistical regression was …

Advances In The Radiological Evaluation Of And Theranostics For Glioblastoma, Grayson W Hooper, Shehbaz Ansari, Jason M Johnson, Daniel T Ginat

Faculty, Staff and Student Publications

Imaging is essential for evaluating patients with glioblastoma. Traditionally a multimodality undertaking, CT, including CT cerebral blood profusion, PET/CT with traditional fluorine-18 fluorodeoxyglucose (18F-FDG), and MRI have been the mainstays for diagnosis and post-therapeutic assessment. However, recent advances in these modalities, in league with the emerging fields of radiomics and theranostics, may prove helpful in improving diagnostic accuracy and treating the disease.

The Interplay Between H3k36 Methylation And Dna Methylation In Cancer, Jiameng Dan, Zeling Du, Jinghong Zhang, Taiping Chen

Faculty, Staff and Student Publications

No abstract provided.

Cultivated Autologous Limbal Epithelial Cell (Calec) Transplantation: Development Of Manufacturing Process And Clinical Evaluation Of Feasibility And Safety, Ula V Jurkunas, Jia Yin, Lynette K Johns, Sanming Li, Helene Negre, Kit L Shaw, Lassana Samarakoon, Allison R Ayala, Ahmad Kheirkhah, Kishore Katikireddy, Alex Gauthier, Stephan Ong Tone, Aaron R Kaufman, Stacey Ellender, Diego E Hernandez Rodriguez, Heather Daley, Reza Dana, Myriam Armant, Jerome Ritz

Faculty, Staff and Student Publications

To treat unilateral limbal stem cell (LSC) deficiency, we developed cultivated autologous limbal epithelial cells (CALEC) using an innovative xenobiotic-free, serum-free, antibiotic-free, two-step manufacturing process for LSC isolation and expansion onto human amniotic membrane with rigorous quality control in a good manufacturing practices facility. Limbal biopsies were used to generate CALEC constructs, and final grafts were evaluated by noninvasive scanning microscopy and tested for viability and sterility. Cultivated cells maintained epithelial cell phenotype with colony-forming and proliferative capacities. Analysis of LSC biomarkers showed preservation of "stemness." After preclinical development, a phase 1 clinical trial enrolled five patients with unilateral LSC …

Fetal Metabolic Adaptations To Cardiovascular Stress In Twin-Twin Transfusion Syndrome, Jacqueline G Parchem, Huihui Fan, Lovepreet K Mann, Qiuying Chen, Jong H Won, Steven S Gross, Zhongming Zhao, Heinrich Taegtmeyer, Ramesha Papanna

Faculty, Staff and Student Publications

Monochorionic-diamniotic twin pregnancies are susceptible to unique complications arising from a single placenta shared by two fetuses. Twin-twin transfusion syndrome (TTTS) is a constellation of disturbances caused by unequal blood flow within the shared placenta giving rise to a major hemodynamic imbalance between the twins. Here, we applied TTTS as a model to uncover fetal metabolic adaptations to cardiovascular stress. We compared untargeted metabolomic analyses of amniotic fluid samples from severe TTTS cases vs. singleton controls. Amniotic fluid metabolites demonstrated alterations in fatty acid, glucose, and steroid hormone metabolism in TTTS. Among TTTS cases, unsupervised principal component analysis revealed two …

Increased Sirt3 Combined With Parp Inhibition Rescues Motor Function Of Sbma Mice, David R Garcia Castro, Joseph R Mazuk, Erin M Heine, Daniel Simpson, R Seth Pinches, Caroline Lozzi, Kathryn Hoffman, Phillip Morrin, Dylan Mathis, Maria V Lebedev, Elyse Nissley, Kang Hoo Han, Tyler Farmer, Diane E Merry, Qiang Tong, Maria Pennuto, Heather L Montie

Faculty, Staff and Students Publications

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial mitochondrial and metabolic dysfunctions. SBMA is caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Activating or increasing the NAD+-dependent deacetylase, SIRT3, reduced oxidative stress and death of cells modeling SBMA. However, increasing diminished SIRT3 in AR100Q mice failed to reduce acetylation of the SIRT3 target/antioxidant, SOD2, and had no effect on increased total acetylated peptides in quadriceps. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected TCA cycle activity by decreasing acetylation of SIRT3 target proteins. We sought to boost blunted SIRT3 activity …

Developing Electronic Clinical Quality Measures To Assess The Cancer Diagnostic Process, Daniel R Murphy, Andrew J Zimolzak, Divvy K Upadhyay, Li Wei, Preeti Jolly, Alexis Offner, Dean F Sittig, Saritha Korukonda, Riyaa Murugaesh Rekha, Hardeep Singh

Faculty, Staff and Student Publications

OBJECTIVE: Measures of diagnostic performance in cancer are underdeveloped. Electronic clinical quality measures (eCQMs) to assess quality of cancer diagnosis could help quantify and improve diagnostic performance.

MATERIALS AND METHODS: We developed 2 eCQMs to assess diagnostic evaluation of red-flag clinical findings for colorectal (CRC; based on abnormal stool-based cancer screening tests or labs suggestive of iron deficiency anemia) and lung (abnormal chest imaging) cancer. The 2 eCQMs quantified rates of red-flag follow-up in CRC and lung cancer using electronic health record data repositories at 2 large healthcare systems. Each measure used clinical data to identify abnormal results, evidence of …

A Defective Mechanosensing Pathway Affects Fibroblast-To-Myofibroblast Transition In The Old Male Mouse Heart, Aude Angelini, Joann Trial, Alexander B Saltzman, Anna Malovannaya, Katarzyna A Cieslik

Faculty, Staff and Students Publications

The cardiac fibroblast interacts with an extracellular matrix (ECM), enabling myofibroblast maturation via a process called mechanosensing. Although in the aging male heart, ECM is stiffer than in the young mouse, myofibroblast development is impaired, as demonstrated in 2-D and 3-D experiments. In old male cardiac fibroblasts, we found a decrease in actin polymerization, α-smooth muscle actin (α-SMA), and Kindlin-2 expressions, the latter an effector of the mechanosensing. When Kindlin-2 levels were manipulated via siRNA interference, young fibroblasts developed an old-like fibroblast phenotype, whereas Kindlin-2 overexpression in old fibroblasts reversed the defective phenotype. Finally, inhibition of overactivated extracellular regulated kinases …

Defining The Roles Of Pyruvate Oxidation, Tca Cycle, And Mannitol Metabolism In Methicillin-Resistant Staphylococcus Aureus Catheter-Associated Urinary Tract Infection, Santosh Paudel, Sarah Guedry, Chloe L P Obernuefemann, Scott J Hultgren, Jennifer N Walker, Ritwij Kulkarni

Faculty, Staff and Student Publications

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of complicated urinary tract infection (UTI) associated with the use of indwelling urinary catheters. Previous reports have revealed host and pathogen effectors critical for MRSA uropathogenesis. Here, we sought to determine the significance of specific metabolic pathways during MRSA UTI. First, we identified four mutants from the Nebraska transposon mutant library in the MRSA JE2 background that grew normally in rich medium but displayed significantly reduced growth in pooled human urine (HU). This prompted us to transduce the uropathogenic MRSA 1369 strain with the transposon mutants in sucD and fumC (tricarboxylic acid …

Pyruvate Anaplerosis Is A Targetable Vulnerability In Persistent Leukaemic Stem Cells, Kevin M Rattigan, Zuzana Brabcova, Daniele Sarnello, Martha M Zarou, Kiron Roy, Ryan Kwan, Lucie De Beauchamp, Amy Dawson, Angela Ianniciello, Ahmed Khalaf, Eric R Kalkman, Mary T Scott, Karen Dunn, David Sumpton, Alison M Michie, Mhairi Copland, Saverio Tardito, Eyal Gottlieb, G Vignir Helgason

Faculty, Staff and Student Publications

Deregulated oxidative metabolism is a hallmark of leukaemia. While tyrosine kinase inhibitors (TKIs) such as imatinib have increased survival of chronic myeloid leukaemia (CML) patients, they fail to eradicate disease-initiating leukemic stem cells (LSCs). Whether TKI-treated CML LSCs remain metabolically deregulated is unknown. Using clinically and physiologically relevant assays, we generate multi-omics datasets that offer unique insight into metabolic adaptation and nutrient fate in patient-derived CML LSCs. We demonstrate that LSCs have increased pyruvate anaplerosis, mediated by increased mitochondrial pyruvate carrier 1/2 (MPC1/2) levels and pyruvate carboxylase (PC) activity, in comparison to normal counterparts. While imatinib reverses BCR::ABL1-mediated LSC metabolic …

The Pyrimidinosome: Orchestrating Pyrimidine Biosynthesis And Ferroptosis Defense, Boyi Gan

Faculty, Staff and Student Publications

A recent study by Yang et al.1 uncovers the pyrimidinosome, a multienzyme complex where enzymes from different subcellular compartments collaborate to enable efficient pyrimidine biosynthesis and ferroptosis defense, highlighting the remarkable adaptability of cellular metabolism and new therapeutic opportunities.

Genetic Dissection Of Crossover Mutants Defines Discrete Intermediates In Mouse Meiosis, Tolkappiyan Premkumar, Lakshmi Paniker, Rhea Kang, Mathilde Biot, Ericka Humphrey, Honorine Destain, Isabella Ferranti, Iyinyeoluwa Okulate, Holly Nguyen, Vindhya Kilaru, Melissa Frasca, Parijat Chakraborty, Francesca Cole

Faculty, Staff and Student Publications

Crossovers (COs), the exchange of homolog arms, are required for accurate chromosome segregation during meiosis. Studies in yeast have described the single-end invasion (SEI) intermediate: a stabilized 3' end annealed with the homolog as the first detectible CO precursor. SEIs are thought to differentiate into double Holliday junctions (dHJs) that are resolved by MutLgamma (MLH1/MLH3) into COs. Currently, we lack knowledge of early steps of mammalian CO recombination or how intermediates are differentiated in any organism. Using comprehensive analysis of recombination in thirteen different genetic conditions with varying levels of compromised CO resolution, we infer CO precursors include asymmetric SEI-like …

Detection Method Has Independent Prognostic Significance In The Plco Lung Screening Trial, James P Long, Yu Shen

Faculty, Staff and Student Publications

Prognostic models in cancer use patient demographic and tumor characteristics to predict survival and dynamic disease prognosis. Past work in breast cancer has shown that cancer detection method, screen-detected or symptom-detected, has prognostic significance. We investigate this phenomenon in the lung component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial. Patients were randomized to intervention, receiving four annual chest x-rays (CXRs), or to control, receiving usual care. Patients were followed for a total of approximately 13 years. In PLCO, lung cancer detection method has independent prognostic value exceeding that of variables commonly used in lung cancer prognostic models, …

The Rise Of Degrader Drugs, Mingxing Teng, Nathanael S Gray

Faculty, Staff and Students Publications

The cancer genomics revolution has served up a plethora of promising and challenging targets for the drug discovery community. The field of targeted protein degradation (TPD) uses small molecules to reprogram the protein homeostasis system to destroy desired target proteins. In the last decade, remarkable progress has enabled the rational development of degraders for a large number of target proteins, with over 20 molecules targeting more than 12 proteins entering clinical development. While TPD has been fully credentialed by the prior development of immunomodulatory drug (IMiD) class for the treatment of multiple myeloma, the field is poised for a "Gleevec …

Computational Modeling And Minimization Of Unintended Neuronal Excitation In A Lifu Stimulation, Boqiang Fan, Wayne Goodman, Raymond Y Cho, Sameer A Sheth, Richard R Bouchard, Behnaam Aazhang

Faculty, Staff and Student Publications

The neuromodulation effect of low-intensity focused ultrasound (LIFU) is highly target-specific. Unintended off-target neuronal excitation can be elicited when the beam focusing accuracy and resolution are limited, whereas the resulted side effect has not been evaluated quantitatively. There is also a lack of methods addressing the minimization of such side effects. Therefore, this work introduces a computational model of unintended neuronal excitation during LIFU neuromodulation, which evaluates the off-target activation area (OTAA) by integrating an ultrasound field model with the neuronal spiking model. In addition, a phased array beam focusing scheme called constrained optimal resolution beamforming (CORB) is proposed to …

Enhanced Cerebroprotection Of Xenon-Loaded Liposomes In Combination With Rtpa Thrombolysis For Embolic Ischemic Stroke, Tao Peng, Keith Booher, Melanie R Moody, Xing Yin, Jaroslaw Aronowski, David D Mcpherson, Sean I Savitz, Hyunggun Kim, Shao-Ling Huang

Faculty, Staff and Student Publications

Xenon (Xe) has shown great potential as a stroke treatment due to its exceptional ability to protect brain tissue without inducing side effects. We have previously developed Xe-loaded liposomes for the ultrasound-activated delivery of Xe into the cerebral region and demonstrated their therapeutic efficacy. At present, the sole FDA-approved thrombolytic agent for stroke treatment is recombinant tissue plasminogen activator (rtPA). In this study, we aimed to investigate the potential of combining Xe-liposomes with an intravenous rtPA treatment in a clinically relevant embolic rat stroke model. We evaluated the combinational effect using an in vitro clot lysis model and an in …

Platelet-Derived Exerkine Cxcl4/Platelet Factor 4 Rejuvenates Hippocampal Neurogenesis And Restores Cognitive Function In Aged Mice, Odette Leiter, David Brici, Stephen J Fletcher, Xuan Ling Hilary Yong, Jocelyn Widagdo, Nicholas Matigian, Adam B Schroer, Gregor Bieri, Daniel G Blackmore, Perry F Bartlett, Victor Anggono, Saul A Villeda, Tara L Walker

Faculty, Staff and Student Publications

The beneficial effects of physical activity on brain ageing are well recognised, with exerkines, factors that are secreted into the circulation in response to exercise, emerging as likely mediators of this response. However, the source and identity of these exerkines remain unclear. Here we provide evidence that an anti-geronic exerkine is secreted by platelets. We show that platelets are activated by exercise and are required for the exercise-induced increase in hippocampal precursor cell proliferation in aged mice. We also demonstrate that increasing the systemic levels of the platelet-derived exerkine CXCL4/platelet factor 4 (PF4) ameliorates age-related regenerative and cognitive impairments in …

Dynamics Of Anti-Influenza Mucosal Iga Over A Season In A Cohort Of Individuals Living Or Working In A Long-Term Care Facility, Matt D T Hitchings, Brooke A Borgert, Adam Shir, Bingyi Yang, Kyra H Grantz, Jacob Ball, Carlos A Moreno, Kenneth Rand, Parker A Small, Keith R Fowke, Derek A T Cummings

Faculty, Staff and Student Publications

BACKGROUND: Serological surveys are used to ascertain influenza infection and immunity, but evidence for the utility of mucosal immunoglobulin A (IgA) as a correlate of infection or protection is limited.

METHODS: We performed influenza-like illness (ILI) surveillance on 220 individuals living or working in a retirement community in Gainesville, Florida from January to May 2018, and took pre- and postseason nasal samples of 11 individuals with polymerase chain reaction (PCR)-confirmed influenza infection and 60 randomly selected controls. Mucosal IgA against 10 strains of influenza was measured from nasal samples.

RESULTS: Overall, 28.2% and 11.3% of individuals experienced a 2-fold and …

Liposome-Based Carriers For Crispr Genome Editing, Xing Yin, Romain Harmancey, David D Mcpherson, Hyunggun Kim, Shao-Ling Huang

Faculty, Staff and Student Publications

The CRISPR-based genome editing technology, known as clustered regularly interspaced short palindromic repeats (CRISPR), has sparked renewed interest in gene therapy. This interest is accompanied by the development of single-guide RNAs (sgRNAs), which enable the introduction of desired genetic modifications at the targeted site when used alongside the CRISPR components. However, the efficient delivery of CRISPR/Cas remains a challenge. Successful gene editing relies on the development of a delivery strategy that can effectively deliver the CRISPR cargo to the target site. To overcome this obstacle, researchers have extensively explored non-viral, viral, and physical methods for targeted delivery of CRISPR/Cas9 and …

Automated Lung Ultrasound Pulmonary Disease Quantification Using An Unsupervised Machine Learning Technique For Covid-19, Hersh Sagreiya, Michael A Jacobs, Alireza Akhbardeh

Faculty, Staff and Student Publications

COVID-19 is an ongoing global health pandemic. Although COVID-19 can be diagnosed with various tests such as PCR, these tests do not establish pulmonary disease burden. Whereas point-of-care lung ultrasound (POCUS) can directly assess the severity of characteristic pulmonary findings of COVID-19, the advantage of using US is that it is inexpensive, portable, and widely available for use in many clinical settings. For automated assessment of pulmonary findings, we have developed an unsupervised learning technique termed the calculated lung ultrasound (CLU) index. The CLU can quantify various types of lung findings, such as A or B lines, consolidations, and pleural …

Class-Driven Synergy And Antagonism Between A Pseudomonas Phage And Antibiotics, Paul Nicholls, Justin R Clark, Carmen Gu Liu, Austen Terwilliger, Anthony W Maresso

Faculty, Staff and Students Publications

The ubiquitous bacterial pathogen Pseudomonas aeruginosa is responsible for severe infections in patients with burns, cystic fibrosis, and neutropenia. Biofilm formation gives physical refuge and a protected microenvironment for sessile cells, rendering cure by antibiotics a challenge. Bacteriophages have evolved to prey on these biofilms over millions of years, using hydrolases and depolymerases to penetrate biofilms and reach cellular targets. Here, we assessed how a newly discovered KMV-like phage (ΦJB10) interacts with antibiotics to treat P. aeruginosa more effectively in both planktonic and biofilm forms. By testing representatives of four classes of antibiotics (cephalosporins, aminoglycosides, fluoroquinolones, and carbapenems), we demonstrated …

Labeling Piezo2 Activity In The Peripheral Nervous System, Nicholas W Villarino, Yasmeen M F Hamed, Britya Ghosh, Adrienne E Dubin, Amanda H Lewis, Max A Odem, Meaghan C Loud, Yu Wang, M Rocio Servin-Vences, Ardem Patapoutian, Kara L Marshall

Duncan NRI Faculty and Staff Publications

Sensory neurons detect mechanical forces from both the environment and internal organs to regulate physiology. PIEZO2 is a mechanosensory ion channel critical for touch, proprioception, and bladder stretch sensation, yet its broad expression in sensory neurons suggests it has undiscovered physiological roles. To fully understand mechanosensory physiology, we must know where and when PIEZO2-expressing neurons detect force. The fluorescent styryl dye FM 1-43 was previously shown to label sensory neurons. Surprisingly, we find that the vast majority of FM 1-43 somatosensory neuron labeling in mice in vivo is dependent on PIEZO2 activity within the peripheral nerve endings. We illustrate the …

Combining Native Mass Spectrometry And Lipidomics To Uncover Specific Membrane Protein-Lipid Interactions From Natural Lipid Sources, Yun Zhu, Melanie T Odenkirk, Pei Qiao, Tianqi Zhang, Samantha Schrecke, Ming Zhou, Michael T Marty, Erin S Baker, Arthur Laganowsky

Faculty, Staff and Students Publications

While it is known that lipids play an essential role in regulating membrane protein structure and function, it remains challenging to identify specific protein-lipid interactions. Here, we present an innovative approach that combines native mass spectrometry (MS) and lipidomics to identify lipids retained by membrane proteins from natural lipid extracts. Our results reveal that the bacterial ammonia channel (AmtB) enriches specific cardiolipin (CDL) and phosphatidylethanolamine (PE) from natural headgroup extracts. When the two extracts are mixed, AmtB retains more species, wherein selectivity is tuned to bias headgroup selection. Using a series of natural headgroup extracts, we show TRAAK, a two-pore …

Genome-Wide Association Studies And Fine-Mapping Identify Genomic Loci For N-3 And N-6 Polyunsaturated Fatty Acids In Hispanic American And African American Cohorts, Chaojie Yang, Jenna Veenstra, Traci M Bartz, Matthew C Pahl, Brian Hallmark, Yii-Der Ida Chen, Jason Westra, Lyn M Steffen, Christopher D Brown, David Siscovick, Michael Y Tsai, Alexis C Wood, Stephen S Rich, Caren E Smith, Timothy D O'Connor, Dariush Mozaffarian, Struan F A Grant, Floyd H Chilton, Nathan L Tintle, Rozenn N Lemaitre, Ani Manichaikul

Faculty, Staff and Students Publications

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the FADS locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of P < 5 × 10

Targeting Bcl2 Overcomes Resistance And Augments Response To Aurora Kinase B Inhibition By Azd2811 In Small Cell Lung Cancer, Kavya Ramkumar, Azusa Tanimoto, Carminia M Della Corte, C Allison Stewart, Qi Wang, Li Shen, Robert J Cardnell, Jing Wang, Urszula M Polanska, Courtney Andersen, Jamal Saeh, J Elizabeth Pease, Jon Travers, Giulia Fabbri, Carl M Gay, Jelena Urosevic, Lauren A Byers

Faculty, Staff and Student Publications

PURPOSE: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy.

EXPERIMENTAL DESIGN: Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. …

Enigma Chek2gether Project: A Comprehensive Study Identifies Functionally Impaired Chek2 Germline Missense Variants Associated With Increased Breast Cancer Risk, Lenka Stolarova, Petra Kleiblova, Petra Zemankova, Barbora Stastna, Marketa Janatova, Jana Soukupova, Maria Isabel Achatz, Christine Ambrosone, Paraskevi Apostolou, Banu K Arun, Paul Auer, Mollie Barnard, Birgitte Bertelsen, Biobank Japan, Marinus J Blok, Nicholas Boddicker, Joan Brunet, Elizabeth S Burnside, Mariarosaria Calvello, Ian Campbell, Sock Hoai Chan, Fei Chen, Jian Bang Chiang, Anna Coppa, Laura Cortesi, Ana Crujeiras-González, Consortium Czecanca, Kim De Leeneer, Robin De Putter, Allison Depersia, Lisa Devereux, Susan Domchek, Anna Efremidis, Christoph Engel, Corinna Ernst, D Gareth R Evans, Lidia Feliubadaló, Florentia Fostira, Olivia Fuentes-Ríos, Encarna B Gómez-García, Sara González, Christopher Haiman, Thomas Van Overeem Hansen, Jan Hauke, James Hodge, Chunling Hu, Hongyan Huang, Nur Diana Binte Ishak, Yusuke Iwasaki, Irene Konstantopoulou, Peter Kraft, James Lacey, Conxi Lázaro, Na Li, Weng Khong Lim, Sara Lindstrom, Adriana Lori, Elana Martinez, Alexandra Martins, Koichi Matsuda, Giuseppe Matullo, Simone Mcinerny, Kyriaki Michailidou, Marco Montagna, Alvaro N A Monteiro, Luigi Mori, Katherine Nathanson, Susan L Neuhausen, Heli Nevanlinna, Janet E Olson, Julie Palmer, Barbara Pasini, Alpa Patel, Maria Piane, Bruce Poppe, Paolo Radice, Alessandra Renieri, Nicoletta Resta, Marcy E Richardson, Toon Rosseel, Kathryn J Ruddy, Marta Santamariña, Elizabeth Santana Dos Santos, Lauren Teras, Amanda E Toland, Amy Trentham-Dietz, Celine M Vachon, Alexander E Volk, Nana Weber-Lassalle, Jeffrey N Weitzel, Lisa Wiesmuller, Stacey Winham, Siddhartha Yadav, Drakoulis Yannoukakos, Song Yao, Valentina Zampiga, Magnus Zethoven, Ze Wen Zhang, Tomas Zima, Amanda B Spurdle, Ana Vega, Maria Rossing, Jesús Del Valle, Arcangela De Nicolo, Eric Hahnen, Kathleen B M Claes, Joanne Ngeow, Yukihide Momozawa, Paul A James, Fergus J Couch, Libor Macurek, Zdenek Kleibl

Faculty, Staff and Student Publications

PURPOSE: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT).

EXPERIMENTAL DESIGN: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case-control datasets, including …

Estrogen-Related Receptor Gamma Gene Therapy Promotes Therapeutic Angiogenesis And Muscle Recovery In Preclinical Model Of Pad, Danesh H Sopariwala, Andrea S Rios, Addison Saley, Ashok Kumar, Vihang A Narkar

Faculty, Staff and Student Publications

Background Peripheral arterial disease and critical limb ischemia are cardiovascular complications associated with vascular insufficiency, oxidative metabolic dysfunction, and myopathy in the limbs. Estrogen-related receptor gamma (ERRγ) has emerged as a dual regulator of paracrine angiogenesis and oxidative metabolism through transgenic mouse studies. Here our objective was to investigate whether postischemic intramuscular targeting of ERRγ via gene therapy promotes ischemic recovery in a preclinical model of peripheral arterial disease/critical limb ischemia. Methods and Results Adeno-associated virus 9 (AAV9)