Medical Specialties Commons^™

Ribosome Deficiency Induces Salmonella Filamentation Within Host Cells, Zhihui Lyu, Cierra Wilson, Kalyn Weiss, Spencer Lewis, Kurt Fredrick, William Margolin, Jiqiang Ling

Faculty, Staff and Student Publications

The ribosome is the central hub for protein synthesis and is heavily targeted by antibiotics. Ribosomal mutations, antibiotic treatment, and nutrient starvation can alter translational efficiency and lead to stressed cells. Ribosome deficiency plays a critical role in stress responses and disease progression; yet, how it affects bacteria-host interactions remains poorly understood. In this study, we show that a ribosome-deficient strain exhibits a surprising morphological change from rod shape to filamentous in Salmonella cells growing inside host macrophages. Such filamentation depends on an acidic condition within macrophages and in a defined medium mimicking macrophage conditions. Further genetic analyses revealed that …

Csf-Exosomal Mirnas And Delayed Cerebral Ischemia: Insights Into Pathophysiology But No Definitive Biomarkers, Chathathayil M Shafeeque, Devin W Mcbride, Yuanqing Yan, Hussein A Zeineddine, John P Hagen, H Alex Choi, Jude P Savarraj, Ari Dienel, Spiros L Blackburn, Peeyush Kumar Thankamani

Faculty, Staff and Student Publications

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is notoriously known for its high mortality and morbidity. Approximately one-third of the patients who survive aneurysm rupture are reported to develop delayed cerebral ischemia (DCI), which contributes to a poor clinical outcome. Currently, there are no biomarkers for identifying which aSAH patients are at risk of developing DCI. We aimed to determine the feasibility of cerebrospinal fluid (CSF) exosomal microRNAs (miRNAs) for predicting DCI post-aSAH.

Methods: aSAH patients were prospectively enrolled, and CSF samples were collected at two time points (< 24 h and 72 h post-aSAH) from individuals undergoing external ventricular drainage. Exosomal miRNAs were isolated from the CSF for analysis. In the initial group of patients (discovery cohort), an exploratory analysis was conducted using a CSF panel containing 84 miRNAs, assessed by quantitative real-time PCR (RT-qPCR). Based on this analysis, 27 miRNAs were selected for further evaluation in a second group of patients (validation cohort). Among these, 10 miRNAs had previously been reported in SAH-related CSF studies, supporting their relevance for continued investigation.

Results: In this study, RT-qPCR analysis of 84 miRNAs in CSF samples from …

Reduced Computed Tomography Scan Speed Improves Alignment Errors For Patients Undergoing Thoracic Stereotactic Body Radiation Therapy, Ramaswamy Sadagopan, Rachael M Martin-Paulpeter, Christopher R Peeler, Xiaochun Wang, Paige Nitsch, Julianne M Pollard-Larkin

Faculty, Staff and Student Publications

Objectives: We investigated the performance of a slow computed tomography (CT) protocol to reduce alignment errors arising from motion when using CT-on-rail (CTOR) for image guidance for patients receiving thoracic stereotactic body radiation therapy (SBRT).

Methods: A Quasar lung phantom with a moving tumor was programmed with three breathing rates and three motion amplitudes. MIP and average 4DCT images were used for contouring and alignment, respectively. Ten CTOR images were obtained for each of the breathing rates and amplitudes, under both CT protocols. We used in-house CAT software for image guidance, centering the tumor in the lung window …

Dalbavancin For Treatment Of Staphylococcus Aureus Bacteremia: The Dots Randomized Clinical Trial, Nicholas A Turner, Toshimitsu Hamasaki, Sarah B Doernberg, Thomas P Lodise, Heather A King, Varduhi Ghazaryan, Sara E Cosgrove, Timothy C Jenkins, Catherine Liu, Shrabani Sharma, Smitha Zaharoff, Lana Wahid, Valerie J Renard, Paul Cook, Issam Raad, Ray Hachem, Anne-Marie Chaftari, Matthew Sims, Carmen Demarco, Loren G Miller, Matthew W Mccarthy, Caryn G Morse, Chris Lucasti, Graeme N Forrest, Kartikeya Cherabuddi, Christopher Polk, Tasaduq Fazili, Mark E Rupp, George R Thompson, Kami Kim, Luke Strnad, Amanda E Schnee, James A Mckinnell, Mayur Ramesh, Fernanda P Silveira, Todd P Mccarty, Todd C Lee, Emily G Mcdonald, Kristopher Paolino, Katie Wiegand, Alison Wall, Todd Riccobene, Rinal Patel, Urania Rappo, Scott Evans, Henry F Chambers, Vance G Fowler, Thomas L Holland

Faculty, Staff and Student Publications

Importance: Dalbavancin is a long-acting intravenous lipoglycopeptide that may be effective for treatment of complicated Staphylococcus aureus bacteremia without requiring long-term intravenous access.

Objective: To evaluate the efficacy and safety of dalbavancin vs standard therapy for completion of treatment of complicated S aureus bacteremia.

Design, setting, and participants: Open-label, assessor-masked, randomized clinical trial conducted from April 2021 to December 2023 at 23 medical centers in the US (n = 22) and Canada (n = 1). Participant follow-up lasted 70 days (180 days for participants with osteomyelitis); date of final follow-up was December 1, 2023. Hospitalized adults with complicated S aureus …

Identification Of Alkynyl Nicotinamide Hsn748 As A Ret Solvent-Front Mutant Inhibitor With Intracranial Efficacy, Ujjwol Khatri, Neetu Dayal, Kofi B Owusu, Mandeep Kaur Hunjan, Shriya Pandey, Haley Anne Harper, Carli Mcmahan, Bennett D Elzey, Tao Shen, Xueqing Hu, Kurt W Evans, Ahmed El-Sheikh, Seong Jun Jo, Frederick W Holtsberg, M Javad Aman, Funda Meric-Bernstam, Sukyung Woo, Herman O Sintim, Jie Wu

Faculty, Staff and Student Publications

RET solvent-front G810C/R/S mutations confer resistance to the currently approved RET protein tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib. Moreover, RET fusion-positive lung adenocarcinoma frequently metastasizes to the brain. To address these challenges, it is imperative to develop a RET TKI that is effective against solvent-front mutations and exhibits intracranial activity. We synthesized alkynyl nicotinamide-based RET TKIs and tested their efficacy in cell cultures in inhibiting selpercatinib/pralsetinib-resistant RET solvent-front mutants G810C/R/S found in cancer patients, and in BaF3/KIF5B-RET(G810C) cell-derived subcutaneous and intracranial tumors in vivo. We also evaluated alkynyl nicotinamide RET TKIs in KIF5B-RET-induced lung tumors in immune competent …

Defining Treatment-Resistant Bipolar Depression: Recommendations From The Isbd Task Force, Eduard Vieta, Roger S Mcintyre, Trisha Suppes, Tamsyn E Van Rheenen, Balwinder Singh, Kamilla Woznica Miskowiak, Allan H Young, Lakshmi N Yatham, Kyooseob Ha, Michael Berk, Holly A Swartz, Chantal Henry, Maja Pantovic Stefanovic, Gerard Anmella Diaz, Aysegul Ozerdem, Wiesław J Cubała, Diego Hidalgo-Mazzei, Mauricio Tohen, Isabella Pacchiarotti, Paula Villela Nunes, Carlos Lopez-Jaramillo, Ana Gonzalez-Pinto, Paolo Brambilla, Robert Post, Jair C Soares, Michael Bauer, Ana C Andreazza, Xavier Justes Fradera, Montserrat Cosials-Lopez, Giovanna Fico

Faculty, Staff and Student Publications

Objective: Despite the availability of approved treatments, a substantial proportion of patients with bipolar disorder experience treatment-resistant bipolar depression (TRBD), characterized by persistent depressive symptoms unresponsive to standard therapies. However, a universally accepted definition of TRBD is lacking. This consensus document, developed by the International Society for Bipolar Disorders (ISBD) Task Force on TRBD, aims to provide a standardized definition of TRBD to facilitate clinical trials, research, and treatment strategies.

Methods: The Task Force employed a literature review, clinical trials analysis, and expert consensus meetings to define TRBD.

Results: TRBD was defined as the failure to achieve a significant and …

Defining Treatment-Resistant Bipolar Depression: Recommendations From The Isbd Task Force, Eduard Vieta, Roger S Mcintyre, Trisha Suppes, Tamsyn E Van Rheenen, Balwinder Singh, Kamilla Woznica Miskowiak, Allan H Young, Lakshmi N Yatham, Kyooseob Ha, Michael Berk, Holly A Swartz, Chantal Henry, Maja Pantovic Stefanovic, Gerard Anmella Diaz, Aysegul Ozerdem, Wiesław J Cubała, Diego Hidalgo-Mazzei, Mauricio Tohen, Isabella Pacchiarotti, Paula Villela Nunes, Carlos Lopez-Jaramillo, Ana Gonzalez-Pinto, Paolo Brambilla, Robert Post, Jair C Soares, Michael Bauer, Ana C Andreazza, Xavier Justes Fradera, Montserrat Cosials-Lopez, Giovanna Fico

Faculty, Staff and Student Publications

Objective: Despite the availability of approved treatments, a substantial proportion of patients with bipolar disorder experience treatment-resistant bipolar depression (TRBD), characterized by persistent depressive symptoms unresponsive to standard therapies. However, a universally accepted definition of TRBD is lacking. This consensus document, developed by the International Society for Bipolar Disorders (ISBD) Task Force on TRBD, aims to provide a standardized definition of TRBD to facilitate clinical trials, research, and treatment strategies.

Methods: The Task Force employed a literature review, clinical trials analysis, and expert consensus meetings to define TRBD.

Results: TRBD was defined as the failure to achieve a significant and …

An Exciting Future For Microbial Molecular Biology And Physiology, Andrew A Bridges, Leah Guthrie, Mckenzie Lehman, Elizabeth H Kellogg, Samantha Wellington Miranda, Andrew Pountain, Anthony L Shiver, Andrew Varble, Molecular Biology And Physiology Community Of The Council On Microbial Sciences, Heidi B Kaplan, Elizabeth A Shank, Gisela Storz

Faculty, Staff and Student Publications

Continuous advances in technologies ranging from deep sequencing and genetic manipulation to mass spectrometry, single cell imaging, and structural biology have led to previously unimaginable advances in our understanding of microbial physiology and the molecular mechanisms underlying microbial responses in a multitude of environments. Simultaneously, these advances are revealing how much more there is to learn. At the 2024 virtual retreat of the Molecular Biology and Physiology (MBP) Community of the Council on Microbial Sciences (COMS) of the American Society for Microbiology (ASM), eight early-career investigators, along with retreat attendees, discussed some of these astounding advances, as well as the …

Macrophage Phagocytosis Of Human Norovirus-Infected Cells In An Ex Vivo Human Enteroid-Macrophage Coculture Model, Ngan Fung Li, Sue E Crawford, Sydney R Mittiga, Cristian Coarfa, Hoa Nguyen-Phuc, Budi Utama, Sarah E Blutt, Sasirekha Ramani, Mary K Estes

Faculty, Staff and Students Publications

Human norovirus (HuNoV) causes acute gastroenteritis in immunocompetent hosts and chronic infection in immunocompromised individuals. Many recent studies of replication and innate immune responses following HuNoV infection have utilized epithelium-only human intestinal enteroids (HIEs), which lack immune cells. Here, we utilized an ex vivo enteroid-macrophage coculture model consisting of HIEs and different subtypes of human peripheral blood mononuclear cell-derived macrophages to better recapitulate in vivo gut biology and explore the role of macrophages in HuNoV replication and pathogenesis. We show that HuNoV infection in HIEs polarized on Transwells leads to bilateral release of the viral genome, with predominant apical virus …

Adherence To Inhaled Corticosteroid Medications After An Asthma Exacerbation And The Risk Of Subsequent Exacerbations, Mina Khezrian, Marjan Kerkhof, Tham T Le, Tim Harrison, Tianshi David Wu, Bill Cook, Jonatan Hedberg, Kirsty Rhodes, Nicole Zubizarreta, Joshua Enxing, Trung N Tran

Faculty, Staff and Students Publications

Background: Data on the duration of improved adherence to controller medications after an exacerbation and its impact on asthma outcomes are inconsistent.

Objective: To describe levels and changes in adherence to inhaled corticosteroid (ICS)-containing medication after a severe exacerbation and the association with future exacerbation risk.

Methods: This retrospective cohort study used data from Optum's deidentified Clinformatics Data Mart Database (October 2015-December 2023). Patients with asthma, 1 or more severe exacerbations, and adherence to ICS-containing therapy (proportion of days covered [PDC]) of less than 80% in the 3 months before an exacerbation were included. Primary and secondary end points were …

Established And Emerging Asthma Biomarkers With A Focus On Biologic Trials: A Narrative Review, Philip F Lavere, Kaitlin M Phillips, Nicola A Hanania, Muhammad Adrish

Faculty, Staff and Students Publications

Chronic airway inflammation with variable airflow obstruction is clinical asthma, and it arises from distinct molecular and pathological mechanisms called endotypes. Biomarkers allow for precise endotype characterization and have been used in clinical trials to design, monitor, and evaluate outcomes for asthma biologic therapies. This review will highlight the central and evolving role of biomarkers for past, present, and future asthma, with a focus on regulatory-approved biologic therapies and emerging biomarkers. Established biomarkers, including serum immunoglobulin E (IgE), blood eosinophils, the fraction of exhaled nitric oxide (FeNO), and serum periostin, helped elucidate the complex pathophysiology of the eosinophilic type 2 …

Molecular Inflammatory Expression Profiles Associated With The Frequency Of Pain In Individuals With Sickle Cell Disease, Lana Mucalo Katunaric, Shuang Jia, Ashima Singh, Mark F. Roethle, Julie A. Panepinto, David C. Brousseau, Martin J. Hessner, Amanda M. Brandow

Department of Pediatrics Faculty Papers

Pain is the most common complication of sickle cell disease (SCD). The underlying biology of SCD pain is not well understood, which is a barrier to novel, effective analgesic and preventive therapies. A wide variability in the phenotypic expression of pain exists among individuals with SCD, despite the inheritance of a similar defective hemoglobin gene. This interindividual pain variability further complicates the ability to understand the biology and effectively treat pain. We sought to discover a biological signature comprising differentially expressed genes unique to SCD that could differentiate between individuals with varied pain frequency. We conducted plasma-induced transcription analysis from …

Assessing The Muc5b Promoter Variant In A Large Cohort Of Systemic Sclerosis-Associated Interstitial Lung Disease, Carlos Rosa-Baez, Carlos Rangel-Pelaez, Inmaculada Rodriguez-Martin, Martin Kerick, Alfredo Guillen-Del-Castillo, Carmen P Simeon-Aznar, José Luis Callejas, Alexandre E Voskuyl, Alexander Kreuter, Oliver Distler, Susanna M Proudman, Mandana Nikpour, Nicolas Hunzelmann, Jeska K De Vries-Bouwstra, Ariane L Herrick, Yannick Allanore, Lorenzo Beretta, Maureen D Mayes, Christopher P Denton, Shervin Assassi, Javier Martin, Marialbert Acosta-Herrera

Faculty, Staff and Student Publications

Objective: The common gain-of-function variant rs35705950, located in the promoter of MUC5B gene, has been strongly associated with interstitial lung diseases (ILDs) of different aetiology, such as idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated ILD (RA-ILD). In this study, we aimed to investigate the association of this variant and its nearby single nucleotide polymorphisms (SNPs) in the largest cohort of systemic sclerosis-associated ILD (SSc-ILD) to date.

Methods: Samples were collected from blood/saliva, followed by DNA extraction and genotyping using SNP arrays. Data for rs35705950 and additional 903 variants within 100 Kb were obtained using genomic imputation. Subsequently, we tested their …

Video-Based Intervention To Reduce Treatment And Outcome Disparities In Adults Living With Stroke Or Transient Ischemic Attack (Virtual): Protocol For A Randomized Controlled Trial, Munachi Okpala, Chigozirim Izeogu, Mengxi Wang, Charles Green, Gabretta Cooksey, Thuy Nguyen, Sarah Cohen, Latonya Bryant, Daphne C Hernandez, Elmer V Bernstam, Michael Gonzales, Rhonda Conyers, Olasimbo Chiadika, Kristin Varacalli, Sean I Savitz, Jose-Miguel Yamal, Anjail Z Sharrief

Faculty, Staff and Student Publications

Background: Racial and ethnic disparities in post-stroke blood pressure (BP) control persist, and effective interventions to address post-stroke care inequities are needed. We designed a randomized comparative effectiveness trial to evaluate the Video-based Intervention to Reduce Treatment and Outcome Disparities in Adults Living with Stroke or Transient Ischemic Attack (VIRTUAL) model of care for post-stroke BP reduction.

Methods: The study will enroll 534 stroke survivors in a randomized trial to receive either the VIRTUAL intervention or enhanced standard care. Individuals with ischemic stroke, hemorrhagic stroke, or transient ischemic attack (TIA) are enrolled before hospital discharge and randomized (1:1) to VIRTUAL …

Extracellular Vesicles For Clinical Diagnostics: From Bulk Measurements To Single-Vesicle Analysis, Hai Linh Tran, Wenshu Zheng, David A Issadore, Hyungsoon Im, Yoon-Kyoung Cho, Yuanqing Zhang, Dingbin Liu, Yang Liu, Bo Li, Fei Liu, David Tai Wai Wong, Jiashu Sun, Kun Qian, Mei He, Meihua Wan, Yong Zeng, Ke Cheng, Tony Jun Huang, Daniel T Chiu, Luke P Lee, Lei Zheng, Andrew K Godwin, Raghu Kalluri, Steven A Soper, Tony Y Hu

Faculty, Staff and Student Publications

Extracellular vesicles (EVs) play a crucial role in intercellular communication, signaling pathways, and disease pathogenesis by transporting biomolecules such as DNA, RNA, proteins, and lipids derived from their cells of origin, and they have demonstrated substantial potential in clinical applications. Their clinical significance underscores the need for sensitive methods to fully harness their diagnostic potential. In this comprehensive review, we explore EV heterogeneity related to biogenesis, structure, content, origin, sample type, and function roles; the use of EVs as disease biomarkers; and the evolving landscape of EV measurement for clinical diagnostics, highlighting the progression from bulk measurement to single vesicle …

Pd-1 Inhibition For Relapse After Allogeneic Transplantation In Acute Myeloid Leukemia And Myelodysplastic Syndrome, John M Magenau, David G Frame, Mary Riwes, John Maciejewski, Sarah Anand, Attaphol Pawarode, Anamarija M Perry, Marcus Geer, Thomas Braun, Monalisa Ghosh, Pavan Reddy

Faculty, Staff and Students Publications

Relapse of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains the primary source of mortality after allogeneic hematopoietic stem cell transplantation (HCT). Targeting programmed death-1 (PD-1) for reversing T-cell exhaustion and restoring the graft-versus-leukemia (GVL) effect may have logistical advantages over donor lymphocyte infusion. In a prospective phase 1B clinical trial, pembrolizumab was administered every 3 weeks to 16 patients with AML (n = 12) and MDS (n = 4) in relapse after HCT to assess graft-versus-host disease (GVHD), clinical response, and survival. The median time to relapse after HCT was 5.5 months and the median pretreatment bone marrow …

Non-Isolated Tetralogy Of Fallot (Tof+): Exome Sequencing Efficacy And Phenotypic Expansions, Julia Volpi, Xiaonan Zhao, Nichole Owen, Tia Evans, Muriel Holder-Espinasse, Nayana Lahiri, Eleanor Sherlock, Gemma Poke, Jeroen Breckpot, Koen Devriendt, Bjorn Cools, Alfredo Brusco, Giovanni Battista Ferrero, Enrico Grosso, Pradeep Vasudevan, Sara Loddo, Antonio Novelli, Maria Cristina Digilio, Aafke Engwerda, Marrit Hitzert, Alison Male, Lucy Bownass, Ruth Newbury-Ecob, Zosia Miedzybrodzka, Ruth Armstrong, Sally Ann Lynch, Gunnar Houge, Shiyi Xiong, Seema R Lalani, Jill A Rosenfeld, Pamela N Luna, Chad A Shaw, Daryl A Scott

Faculty, Staff and Students Publications

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect (CHD). TOF may present in isolation or in conjunction with one or more non-cardiac congenital anomalies or neurodevelopmental disorders (TOF+). Uncertainty regarding the efficacy of various genetic testing strategies, and an incomplete understanding of the genetic causes of TOF+, may lead to hesitancy in recommending genetic testing, particularly, clinical exome sequencing (cES). Here, we analyzed cES data from 131 individuals with TOF+. A definitive or probable diagnosis was made for 31 individuals, yielding a diagnostic rate of 23.6% (31/131). One individual received three diagnoses. Commercially available CHD panels …

Multivalvular Native Valve E. Coli Endocarditis, Madison Baker, Jose Reyes, Natasha Singh, Samir Shah, Rohail A. Baig, Justin Nistico

Advances in Clinical Medical Research and Healthcare Delivery

E. coli is a rare cause of infective endocarditis. This report describes an 81-year-old-woman with a history of aortic stenosis and recurrent urinary tract infections who presented in sepsis secondary to E. coli urinary tract infection which was complicated by multivalvular infective endocarditis of the aortic and tricuspid native valves identified on transesophageal echocardiogram (TEE). The patient was managed medically with ceftriaxone, and resolution of both vegetations was seen on TEE without the need for cardiothoracic surgery. Literature review did not yield prior cases of multivalvular E. coli endocarditis.

Cns And Retinal Radiologic Findings Of A Young Patient With Heterozygous Prothrombin G20210a Gene Mutation, Justina Kasteri, Timothy Ehmann, Bryan Scott

Advances in Clinical Medical Research and Healthcare Delivery

Stroke is one of the leading causes of death and acquired long-term disability in the world.¹ In United States stroke is the 5^th leading cause of death with a mortality rate of 49.1 deaths per 100,000 people.² Strokes can be ischemic or hemorrhagic in origin, of which 85% are ischemic strokes. Approximately 10--15% of ischemic strokes occur in patients 18-50 years of age, and inherited thrombophilia may be a contributing factor through induction of a hypercoagulable state. Prothrombin G20210A mutation has an overall prevalence of approximately 2% of the general population, with an association between young patients …

Differential Mirna Expressions Linking Environmental Risk Factors To Triple-Negative Breast Cancer Stages At Diagnosis, Amjila Bam, Yawen Hu, Xiaocheng Wu, Meng Luo, Nubaira Rizvi, Luis Del Valle, Arnold H. Zea, Fokhrul Hossain, Denise Moore Danos, Jovanny Zabaleta, Augusto Ochoa, Lucio Miele, Edward Trapido, Qingzhao Yu

School of Public Health Faculty Publications

Background/Objectives: Triple negative breast cancer (TNBC) is an aggressive, molecularly heterogeneous subtype of breast cancer, accounting for approximately 10–15% of all cases. While reproductive and metabolic factors contribute to breast cancer development, growing concerns about environmental exposures, alongside biological and socio-cultural influences, underscore the need for targeted prevention strategies across diverse populations. Despite increasing evidence linking biological, socioeconomic, and environmental factors to TNBC outcomes, the molecular mechanisms underlying these relationships remain poorly understood. Micro-RNAs (miRNAs), which regulate gene expression and play critical roles in cancer development, have emerged as potential mediators between environmental exposures and TNBC progression. The goal of …

Hippocampal Avoidance During Prophylactic Cranial Irradiation For Patients With Small Cell Lung Cancer: Randomized Phase Ii/Iii Trial Nrg-Cc003, Vinai Gondi, Stephanie L Pugh, Minesh P Mehta, Jeffrey S Wefel, Wolfgang A Tomé, Alexander Y Sun, John Grecula, Kristin J Redmond, Shannon Fogh, Laurie Gaspar, Andre Konski, Joseph Bovi, Clifford G Robinson, Benjamin Corn, Gregory M Videtic, Benjamin H Lok, Harold A Yoon, John H Heinzerling, Albert S Denittis, Ronald C Mcgarry, Kiran Devisetty, Vijayananda Kundapur, Abraham J Wu, Edward C Mccarron, Isabelle Thibault, Edmund L Simon, Andrew M Baschnagel, Samir Narayan, Jondavid Pollock, Rebecca Paulus, Lisa A Kachnic

Faculty, Staff and Student Publications

Purpose: Hippocampal avoidance (HA) during therapeutic whole-brain radiotherapy reduces the risk of neurocognitive function (NCF) toxicity in patients with brain metastasis. This trial hypothesized that HA during prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) leads to noninferior intracranial relapse (ICR) and reduction in NCF toxicity.

Methods: This randomized phase II/III trial enrolled patients with SCLC, no brain metastases, and response to chemotherapy. The primary end points were 12-month ICR (noninferiority design, randomized phase II) and 6-month Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall (DR) failure (phase III). Secondary end points were failure in any NCF …

Keap1 And Stk11/Lkb1 Alterations Enhance Vulnerability To Atr Inhibition In Kras Mutant Non-Small Cell Lung Cancer, Ana Galan-Cobo, Natalie I Vokes, Yu Qian, David Molkentine, Kavya Ramkumar, Alvaro G Paula, Marlese Pisegna, Daniel J Mcgrail, Alissa Poteete, Sungnam Cho, Minh Truong Do, Amirali Karimi, Yifan Kong, Anisha Solanki, Ankur Karmokar, Nicolas Floc'h, Adina Hughes, Rebecca Sargeant, Lucy Young, Li Shen, Gozde Kar, Caezaan Keshvani, Claudio Arrechedera, Sharia Hernandez, Katharina Schlacher, Jing Wang, Sonia Iyer, James Conway, Mohamed Reda Keddar, Marta Milo, Ilario De Toma, Susan E Critchlow, J Carl Barrett, Jan Cosaert, Alan Lau, Viia Valge-Archer, Lauren A Byers, Simon T Barry, John V Heymach

Faculty, Staff and Student Publications

KRAS mutations frequently co-occur with alterations in STK11/LKB1 and/or KEAP1, defining an aggressive subset of lung cancers resistant to immuno- and chemotherapy. While LKB1 loss is associated with vulnerability to DNA damage response-based therapies, the impact of KEAP1 alterations remains unknown. We demonstrate that KEAP1-NRF2 pathway drives a compensatory modulation of ATR-CHK1 signaling, enhancing vulnerability to ATR inhibitors (ATRi), particularly in the setting of increased replication stress associated with LKB1 loss. ATRi shows enhanced anti-tumor activity in LKB1 and/or KEAP1-deficient non-small cell lung cancer (NSCLC) models and synergizes with gemcitabine. ATRi also enhances antitumor immunity and mitigates the immunosuppressed phenotype …

Health Outcomes Beyond Age 50 Years In Survivors Of Childhood Cancer: A Report From The Childhood Cancer Survivor Study, Rusha Bhandari, Yan Chen, Eric J Chow, Rebecca M Howell, Lisa B Kenney, Kevin R Krull, Wendy Leisenring, Paul C Nathan, Joseph P Neglia, Kirsten K Ness, Kevin C Oeffinger, Claire Snyder, Lucie M Turcotte, F Lennie Wong, Yutaka Yasui, Gregory T Armstrong, Saro H Armenian

Faculty, Staff and Student Publications

Purpose: There are limited data on the risk for mortality and health outcomes among the increasing population of older (age >50 years) survivors of childhood cancer during this later stage in life when there is an expected increase in aging-related morbidities.

Methods: We assessed cause-specific mortality, incident new cancers, chronic health conditions (CHCs), frailty, and health status among survivors from the Childhood Cancer Survivor Study, conditional on surviving to 50 years. We calculated conditional survival rates, standardized mortality ratios (SMRs), and, for incident new cancers, cumulative burden, standardized incidence ratios (SIRs), and relative rates (RRs), compared with the general US …

Botulinum Toxin For The Treatment Of Tremors, Steven Bellows, Joseph Jankovic

Faculty, Staff and Students Publications

Tremor, an oscillatory movement disorder, is commonly encountered in clinical practice in the setting of a variety of etiologies, such as essential tremor and Parkinson's disease. Despite its high prevalence, treatment options are somewhat limited. Oral medications are often ineffective or limited by side effects, and other treatments, such as deep brain stimulation, are more invasive and costly. Botulinum toxin (BoNT) injections are a well-established therapy in the treatment of dystonia, but its use in the treatment of tremors has not been fully explored. In this review, we discuss the available randomized controlled trials and open-label evidence for the use …

Polo-Like Kinase 1 Inactivation Enhances Pi3k Inhibition-Mediated Apoptosis Of Notch1-Mutant Head And Neck Squamous Cell Carcinoma, Pooja A Shah, Tuhina Mazumdar, Soma Ghosh, Lacin Yapindi, Reid T Powell, Yong S Park, Li Shen, Anne M Fernandez, Clifford C Stephan, Jing Wang, Andrew G Sikora, Jawad Kazi, Mitchell J Frederick, Faye M Johnson

Children’s Nutrition Research Center Staff Publications

PI3K inhibition causes apoptosis selectively in NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC), but modest single-agent responses and acquired resistance (AR) limit the clinical efficacy of targeted agents. To address these limitations, we investigated novel combination therapies. We tested the efficacy of 5768 compounds as single agents and 139 in combination with PI3K inhibitors in sensitive and AR NOTCH1-mutant HNSCC cell lines. We generated synergy/efficacy classifications for the combinations using multiple metrics of statistical drug synergy and growth rate indices. The PLK1/PI3K combination's efficacy was validated using orthogonal in vitro methods and in two HNSCC xenograft models. Compound efficacy …

Mutant P53 Confers Chemoresistance By Activating Kmt5b-Mediated Dna Repair Pathway In Nasopharyngeal Carcinoma, Haidan Luo, Mo-Fan Huang, An Xu, Donghui Wang, Julian A Gingold, Jian Tu, Ruoyu Wang, Zijun Huo, Yen-Ting Chiang, Kuang-Lei Tsai, Jie Su, Danielle A Bazer, Mien-Chie Hung, Canmao Xie, Yubiao Guo, Dung-Fang Lee, Huiling Yang, Ruiying Zhao

Faculty, Staff and Student Publications

Nasopharyngeal carcinoma (NPC), a malignancy arising from the nasopharyngeal epithelium, is common in the east and southeast area of Asia. Treatments for locally advanced and recurrent NPC include chemotherapy (usually combined with 5-Fluorouracil, 5-FU) and radiotherapy, but response is limited due to chemo-resistance. p53 mutation is a critical factor for 5-FU resistance in some cancers, but its role in NPC chemo-resistance remains unclear. Here, we demonstrate that p53(R280T), a common p53 somatic mutation found in multiple NPC tumor samples, induces gain-of-function upregulation of DNA repair genes which leads to 5-FU resistance in NPC. p53(R280T) specifically upregulates the expression of DNA …

Correction: Development And Extensive Sequencing Of A Broadly-Consented Genome In A Bottle Matched Tumor-Normal Pair, Jennifer H Mcdaniel, Vaidehi Patel, Nathan D Olson, Hua-Jun He, Zhiyong He, Kenneth D Cole, Alexander A Gooden, Anthony Schmitt, Kristin Sikkink, Fritz J Sedlazeck, Harsha Doddapaneni, Shalini N Jhangiani, Donna M Muzny, Marie-Claude Gingras, Heer Mehta, Sairam Behera, Luis F Paulin, Alex R Hastie, Hung-Chun Yu, Victor Weigman, Alison Rojas, Katie Kennedy, Jamie Remington, Isai Salas-González, Mitch Sudkamp, Kelly Wiseman, Bryan R Lajoie, Shawn Levy, Miten Jain, Stuart Akeson, Giuseppe Narzisi, Zoe Steinsnyder, Catherine Reeves, Jennifer Shelton, Sarah B Kingan, Christine Lambert, Primo Baybayan, Aaron M Wenger, Ian J Mclaughlin, Aaron Adamson, Christopher Kingsley, Melanie Wescott, Young Kim, Benedict Paten, Jimin Park, Ivo Violich, Karen H Miga, Joshua Gardner, Brandy Mcnulty, Gail L Rosen, Rajiv Mccoy, Francesco Brundu, Erfan Sayyari, Konrad Scheffler, Sean Truong, Severine Catreux, Lesley Chapman Hannah, Doron Lipson, Hila Benjamin, Nika Iremadze, Ilya Soifer, Gat Krieger, Stephen Eacker, Mary Wood, Erin Cross, Greg Husar, Stephen Gross, Michael Vernich, Mikhail Kolmogorov, Tanveer Ahmad, Ayse G Keskus, Asher Bryant, Francoise Thibaud-Nissen, Jonathan Trow, Jacqueline Proszynski, Jeremy Wain Hirschberg, Krista Ryon, Christopher E Mason, Mital S Bhakta, J Zachary Sanborn, Elizabeth M Munding, Justin Wagner, Chunlin Xiao, Andrew S Liss, Justin M Zook

Faculty, Staff and Students Publications

No abstract provided.

Micbg406a Polymorphism Reduces Risk Of Mechanical Ventilation And Death During Viral Acute Lung Injury, Harry Pickering, Narges Alipanah-Lechner, Ernie Chen, Dylan Duchen, Holden T Maecker, Seunghee Kim-Schulze, Ruth R Montgomery, Chris Cotsapas, Hanno Steen, Florian Krammer, Charles R Langelier, Ofer Levy, Lindsey R Baden, Esther Melamed, Lauren Ir Ehrlich, Grace A Mccomsey, Rafick P Sekaly, Charles B Cairns, Elias K Haddad, Albert C Shaw, David A Hafler, David B Corry, Farrah Kheradmand, Mark A Atkinson, Scott C Brakenridge, Nelson I Agudelo Higuita, Jordan P Metcalf, Catherine L Hough, William B Messer, Bali Pulendran, Kari C Nadeau, Mark M Davis, Ana Fernandez Sesma, Viviana Simon, Monica Kraft, Chris Bime, David J Erle, Joanna Schaenmann, Al Ozonoff, Bjoern Peters, Steven H Kleinstein, Alison D Augustine, Joann Diray-Arce, Patrice M Becker, Nadine Rouphael, Matthew C Altman, Steve Bosinger, Walter Eckalbar, Carolyn S Calfee, Oscar A Aguilar, Elaine F Reed, John R Greenland, Daniel R Calabrese

Faculty, Staff and Students Publications

MHC class I polypeptide-related sequence B (MICB) is a ligand for NKG2D. We have shown NK cells are central to lung transplant acute lung injury (ALI) via NKG2D activation, and increased MICB in bronchoalveolar lavage predicts ALI severity. Separately, we found a MICB polymorphism (MICBG406A) is associated with decreased ALI risk. We hypothesized this polymorphism would protect against severe SARS-CoV-2 respiratory disease. We analyzed 1,036 patients hospitalized with SARS-CoV-2 infection from IMPACC. Associations between MICBG406A and outcomes were determined by linear regression or Cox proportional hazards models. We also measured immune profiles of peripheral blood and the upper and lower …

Dual-Function Polyester Nanoparticles For Amplified Anti-Inflammatory Effects, Ingrid M Heyns, Abiodun T Wahab, Raghu Ganugula, David Sheikh-Hamad, M N V Ravi Kumar, Meenakshi Arora

Faculty, Staff and Students Publications

This study investigates a dual-acting drug delivery system using naringenin (NAR) as a folate receptor ligand to enhance intestinal uptake and encapsulated NAR for combating inflammation. The dual-acting systems were tested in vitro on cisplatin-induced human kidney-2 cells and in vivo in a mouse model of cisplatin-induced acute kidney injury (AKI). NAR-loaded passive nanoparticles [P2Ns(NAR)] and dual-acting systems [P2Ns-NAR(NAR)] showed notable advantages over unformulated NAR, reducing the required dose by up to 57 and 79%, respectively. These nanoparticles modulated immune responses, restored T cell function, and shifted macrophage polarization from proinflammatory M1 to tissue-repairing M2. In addition, P2Ns-NAR(NAR) alleviated AKI …

Frontline Acalabrutinib, Lenalidomide And Rituximab For Advanced Stage Follicular Lymphoma With High Tumor Burden: Phase Ii Trial, Paolo Strati, Lei Feng, Jason R Westin, Ranjit Nair, Luis E Fayad, Maria A Rodriguez, Dai Chihara, Luis Malpica, Jared Henderson, Mariana Gallardo, Marissa Rivera, Iris Wang, Anastasiia Bolshakova, Anastasia Radko, David Kurtz, Stefan K Alig, Christopher R Flowers, Ash A Alizadeh, Sattva S Neelapu

Faculty, Staff and Student Publications

This phase II trial aims to determine the efficacy and safety of frontline acalabrutinib, lenalidomide and rituximab for patients with advanced stage follicular lymphoma (FL) and high tumor burden. The primary endpoint was best complete response (CR) rate; the secondary endpoints were overall response rate (ORR), duration of response measured as CR at 30 months (CR30), progression of disease at 24 months (POD24) rate, progression-free survival (PFS), overall survival and safety. Twenty-four patients with previously untreated FL were included in this phase 2 single arm study (NCT04404088). The most common grade 3-4 adverse events were neutropenia (58%) and …