Medicine and Health Sciences Commons^™

Lung Nr3c1+ And Cxcr6high T Cells Distinguish Immunopathogenesis Of Human Emphysema, Yun Zhang, Maor Sauler, David B Corry, Scott A Ochsner, Sarah Perusich, Li-Zhen Song, Joshua Malo, Raul San Jose Estepar, Francesca Polverino, Farrah Kheradmand

Faculty, Staff and Students Publications

There is a significant knowledge gap in how T cells promote emphysema in smokers with chronic obstructive pulmonary disease (COPD). Single-cell RNA sequencing (scRNA seq) analysis of human samples and relevant clinical data can provide new mechanistic insights into disease pathogenesis. We generated a human lung scRNA seq dataset with extensive disease characteristic annotation and analyzed a second independent scRNA seq dataset to examine the pathophysiological role of T cells in emphysema. Comparisons of pulmonary immune landscapes in emphysematous (E)-COPD, non-emphysematous (NE)-COPD, and control showed positive enrichment of T cells in E-COPD. Pathway analyses identified upregulated inflammatory states in CD4 …

Biologic Management In Severe Asthma For Adults: An American College Of Chest Physicians Clinical Practice Guideline, Amber J Oberle, Farrukh Abbas, Muhammad Adrish, Ioana Agache, Megan Conroy, Angel Coz, Frederic F Little, Manoj J Mammen, Mahesh Padukudru Anand, Raju Reddy, Neha Solanki, Fernando Holguin

Faculty, Staff and Students Publications

Background: Severe asthma affects 5% to 10% of asthma patients but constitutes close to one-half of the medical costs related to asthma due to higher morbidity and health care utilization. Biologic agents have become a standard of care in those unresponsive to standard treatments yet the choice of biologic agent is complex due to the varying mechanisms of action, efficacies, and lack of head-to-head comparisons. Therefore, clinicians need further clinical guidance to optimize their use.

Study design and methods: Panelists developed key clinical questions utilizing the PICO (population, intervention, comparator, and outcome) format to address choice of a biologic agent …

Association Of Genetic Scores Related To Insulin Resistance With Neurological Outcomes In Ancestrally Diverse Cohorts From The Trans-Omics For Precision Medicine (Topmed) Program, Chloé Sarnowski, Yixin Zhang, Farah Ammous, Lincoln M P Shade, Daniel Dicorpo, Xueqiu Jian, Donna K Arnett, Thomas R Austin, Alexa Beiser, Joshua C Bis, John Blangero, Eric Boerwinkle, Jan Bressler, Joanne E Curran, Charles S Decarli, Harsha Doddapaneni, Josée Dupuis, David W Fardo, Jose C Florez, Stacey Gabriel, Richard A Gibbs, David C Glahn, Namrata Gupta, Hector M González, Kevin A González, Konstantinos Hatzikotoulas, Kathleen M Hayden, Susan R Heckbert, Bertha Hidalgo, Alicia Huerta-Chagoya, Timothy M Hughes, Sharon L R Kardia, Charles L Kooperberg, Lenore J Launer, W T Longstreth, Ravi Mandla, Rasika A Mathias, Andrew P Morris, Thomas H Mosley, Ilya M Nasrallah, Paul Nyquist, Bruce M Psaty, Qibin Qi, Laura M Raffield, Nigel W Rayner, Alexander P Reiner, Claudia L Satizabal, Elizabeth Selvin, Magdalena D R Sevilla-Gonzalez, Albert V Smith, Jennifer A Smith, Kirk Smith, Beverly M Snively, Lorraine Southam, Tamar Sofer, Ken Suzuki, Henry J Taylor, Miriam S Udler, Karine A Viaud-Martinez, Sylvia Wassertheil-Smoller, Alexis C Wood, Lisa R Yanek, Xianyong Yin, Alisa K Manning, Jerome I Rotter, Stephen S Rich, James B Meigs, Myriam Fornage, Sudha Seshadri, Alanna C Morrison, Topmed Neurocognitive Working Group, Topmed Diabetes Working Group

The Brown Foundation: Institute of Molecular Medicine

To better characterize the potential biological mechanisms underlying insulin resistance (IR) and dementia, we derive cross-population and population specific polygenic scores [PSs] for fasting insulin and IR-related partitioned PSs [pPSs]. We conduct a cross-sectional study of the associations of these genetic scores with neurological outcomes in >17k participants (36% men, mean age 55 yrs) from the Trans-Omics for Precision Medicine (TOPMed) program (50% Non-Hispanic White, 23% Black/African American, 21% Hispanic/Latino American, and 4% Asian American). We report significant negative associations (P <  0.002) of the cross-population (P = 1.3 × 10-5) and European (PEA = 3.0 × 10-8) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (BEA = -0.13, PEA = 0.0002) and lateral ventricular volume (BEA = 0.09, PEA = 0.002). We identify suggestive negative associations (P <  0.007) of metabolic syndrome and obesity pPSs with general cognitive function, and of lipodystrophy pPSs with total cranial volume. A higher genetic predisposition to IR is associated with lower brain size, and a genetic predisposition to specific IR-related type 2 diabetes subtypes, such as metabolic syndrome and mechanisms of IR mediated through obesity and lipodystrophy, is potentially involved in cognitive decline.

Occupational Health Equity: A Call To Consider Social-Structural Factors In Injury Prevention Research, Shannon Guillot-Wright, Elizabeth S Mcclure, Marizen R Ramirez, Alexis Grimes Trotter, David B Richardson

Faculty, Staff and Student Publications

Occupational health equity scholarship has been growing over the past decade, including social-structural determinants of health research that centres the voices and experiences of historically marginalised communities. In our commentary, we focus on the intersection of work-related and non-work-related factors and how they impact the health of workers, their families and their communities through community-engaged research. Case studies include the implementation of mobile clinics that are developed alongside communities, community organising to examine and reduce health disparities among racially segregated workers, the development of research instruments and measures to study racism and discrimination, and a focus on how the distribution …

Understanding Cancer Survivorship Care Needs Using Amazon Reviews: Content Analysis, Algorithm Development, And Validation Study, Liwei Wang, Qiuhao Lu, Rui Li, Taylor B. Harrison, Heling Jia, Ming Huang, Heidi Dowst, Rui Zhang, Hoda Badr, Jungwei W. Fan, Hongfang Liu

Department of Medical Oncology Faculty Papers

BACKGROUND: Complementary therapies are being increasingly used by cancer survivors. As a channel for customers to share their feelings, outcomes, and perceived knowledge about the products purchased from e-commerce platforms, Amazon consumer reviews are a valuable real-world data source for understanding cancer survivorship care needs.

OBJECTIVE: In this study, we aimed to highlight the potential of using Amazon consumer reviews as a novel source for identifying cancer survivorship care needs, particularly related to symptom self-management. Specifically, we present a publicly available, manually annotated corpus derived from Amazon reviews of health-related products and develop baseline natural language processing models using deep …

Next-Gen Tools In Cancer Neuroscience, Vera Thiel, Debpali Sur, Caroline C Picoli, Tamara Mcerlain, Katalina Couto, David J Simon, Yuan Pan, Karen Olivia Dixon, Rajan P Kulkarni, Sebastien Talbot, Alexander Birbrair

Faculty, Staff and Student Publications

The emerging field of cancer neuroscience is rapidly evolving, driven by novel technologies and tools. These include advances in single-cell and spatial transcriptomics; genetic mouse models paired with automated high-throughput; and innovative optical electrophysiological approaches, optogenetics, chemogenetics, engineered viruses, and new methods for visualizing neuronal activity. Collectively, these technologies are revolutionizing how we investigate, manipulate, and characterize distinct components that contribute to the nervous system-cancer interface. In the present review, we discuss the key technologies that are closing the gap between oncology and neuroscience, highlighting the innovations that are propelling the cancer neuroscience field forward.

Rna/Dna-Binding Protein Tdp43 Regulates Dna Mismatch Repair Genes With Implications For Genome Stability, Vincent E Provasek, Albino Bacolla, Suganya Rangaswamy, Manohar Kodavati, Joy Mitra, Issa O Yusuf, Vikas H Malojirao, Velmarini Vasquez, Gavin W Britz, Guo-Min Li, Zuoshang Xu, Sankar Mitra, Ralph M Garruto, John A Tainer, Muralidhar L Hegde

Faculty, Staff and Student Publications

TDP43 is an RNA/DNA-binding protein increasingly recognized for its role in neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to detrimental cytosolic aggregates and a reduction in nuclear functionality in neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expression. Here, we show that TDP43 depletion or overexpression …

Gata2 Mutation Is Associated With Immune Dysfunction And Increased Mycobacterium Haemophilum Susceptibility In Immunocompromised Individuals, Ananya Gupta, Shail B. Mehta, Abhimanyu, Bruce A. Rosa, John Martin, Mushtaq Ahmed, Shyamala Thirunavukkarasu, Farheen Fatma, Gaya K. Amarasinghe, Makedonka Mitreva, Thomas C. Bailey, David B. Clifford, Shabaana A. Khader

2020-Current year OA Pubs

Infections with nontuberculous mycobacterium (NTM) are on the rise. Here, we investigated an uncommon NTM infection, by M. haemophilum (Mh, n = 4), from a shared geographic location in the United States. All patients had underlying immunosuppressive conditions or treatments. We identified that all these individuals had a nonsynonymous mutation in GATA2 gene, which was absent in healthy controls (HCs, n = 4) from the same geographic area (Missouri, USA). Whole blood from these individuals had attenuated cytokine responses to Mh stimulation for IL-1β, IL-6, IL-8, MIP-1α and MIP-1β, but not to phytohemagglutinin (PHA) or another NTM, M. abscessus. Impaired …

Adsl Deficiency Is A Secondary Mitochondrial Disease Affecting Organelle Homeostasis And Erk2/Akt Signaling In A Linear Genotype-Phenotype Relation, Matteo Bordi, Beatrice Testa, Claudia Compagnucci, Fiorella Colasuonno, Francesca Cipressa, Elisabetta Betterini, Andrea Mancini, Claudia Carsetti, Illari Salvatori, Caterina Ferraina, Ming Yang, Rossella De Cegli, Eugenio Del Prete, Chiara Veroni, Salvatore Rizza, Sofia Mauri, Elena Ziviani, Marina Macchiaiolo, Davide Vecchio, Filippo Maria Panfili, Teresa Rizza, Gerrit Weber, Rosalba Carrozzo, Alberto Ferri, Silvia Campello, Andrea Ballabio, Christian Frezza, Gianluca Cestra, Marco Tartaglia, Andrea Bartuli, Francesco Cecconi

Duncan NRI Faculty and Staff Publications

Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues. We also identify defects in mitochondrial dynamics and transport linked to ERK2 and AKT suppression. Notably, overexpressing constitutively active ERK2 or supplementing purine intermediates partially rescues the mitochondrial phenotype. These findings suggest an alternative disease mechanism and …

Sars-Cov-2 Nsp13 Interacts With Tead To Suppress Hippo-Yap Signaling, Fansen Meng, Jong Hwan Kim, Chang-Ru Tsai, Jeffrey D Steimle, Jun Wang, Yufeng Shi, Rich G Li, Bing Xie, Vaibhav Deshmukh, Shijie Liu, Xiao Li, James F Martin

Faculty, Staff and Students Publications

The Hippo pathway controls organ development, homeostasis, and regeneration primarily by modulating YAP/TEAD-mediated gene expression. Although emerging studies report Hippo-YAP dysfunction after viral infection, it is largely unknown in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we analyzed RNA sequencing data from human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and SARS-CoV-2-infected human lung samples, and observed a decrease in YAP target gene expression. In screening SARS-CoV-2 nonstructural proteins, we found that nonstructural protein 13 (NSP13), a conserved coronavirus helicase, inhibits YAP transcriptional activity independent of the upstream Hippo kinases LATS1/2. Consistently, introducing NSP13 into mouse cardiomyocytes suppresses …

Atrial Fibroblast-Derived Macrophage Migration Inhibitory Factor Promotes Atrial Macrophage Accumulation In Postoperative Atrial Fibrillation, Joshua A Keefe, Jose Alberto Navarro-Garcia, Shuai Zhao, Mihail G Chelu, Xander Ht Wehrens

Faculty, Staff and Students Publications

New study: Blocking MIF protein prevents irregular heartbeats after surgery by reducing harmful immune cell buildup in the atria.

Understanding Cancer Survivorship Care Needs Using Amazon Reviews: Content Analysis, Algorithm Development, And Validation Study, Liwei Wang, Qiuhao Lu, Rui Li, Taylor B Harrison, Heling Jia, Ming Huang, Heidi Dowst, Rui Zhang, Hoda Badr, Jungwei W Fan, Hongfang Liu

Faculty, Staff and Students Publications

Background: Complementary therapies are being increasingly used by cancer survivors. As a channel for customers to share their feelings, outcomes, and perceived knowledge about the products purchased from e-commerce platforms, Amazon consumer reviews are a valuable real-world data source for understanding cancer survivorship care needs.

Objective: In this study, we aimed to highlight the potential of using Amazon consumer reviews as a novel source for identifying cancer survivorship care needs, particularly related to symptom self-management. Specifically, we present a publicly available, manually annotated corpus derived from Amazon reviews of health-related products and develop baseline natural language processing models using deep …

Humanization Of Cd47 Enables Development Of Functional Human Neutrophils Via Postirradiation Remodeling Of The Bone Marrow, Esen Sefik, Liang Shan, Et Al.

2020-Current year OA Pubs

Murine and human immune systems differ significantly, particularly within the myeloid lineage. Humanized mice, generated by transplanting human hematopoietic stem, progenitor cells into genetically modified mice, are invaluable to study human immune development and function in vivo. However, a major limitation of current models is suboptimal myelopoiesis, particularly lack of functional human neutrophils, hampering the modeling of human immune responses and chronic diseases. Here, we describe a humanized mouse model, named MaGIC for genes replaced, in the

Stable Cas9 Expression Regulates Cell Growth By Facilitating Mtorc2 Activation, Le Yu, Yi Jin, Jianfeng Chen, Zhichuan Zhu, Siyuan Su, Emily M Wilkerson, Joanna Gongora, Erica W Cloer, Michael B Major, Pengda Liu

2020-Current year OA Pubs

Clustered regularly interspaced short palindromic repeats (CRISPR), widely used for gene editing, relies on bacterial endonucleases like Cas9 to study gene functions and develop therapies. However, its potential effects on mammalian cellular behavior remain unclear. Here, we systematically profiled effects of stable Cas9 expression on growth of 32 cell lines spanning 9 cancer types and non-cancerous cells, finding growth alterations in a subset. To investigate mechanisms, we established the SpCas9 interactome in DU145 and MDA-MB-231 cells, both showing Cas9-enhanced growth, and identified ribosomal proteins as the top shared interactors. RNA-seq analysis revealed that Cas9 expression in DU145 cells activated PI3K …

A Community-Engaged Approach To Enhancing Participation In Genomic Research In Rare And Understudied Cancer Populations, Saira Khan, Bailey Martin-Giacalone, Kayla Wallace, Briana Wilson, Christine Marx, Erin Linnenbringer, Jessica Mozersky, Melinda Bachini, Nancy Chollet, Dionne Stalling, Li Ding, Ryan C Fields, Graham A Colditz, Bettina F Drake

2020-Current year OA Pubs

UNLABELLED: Few studies provide insights on how to incorporate community members' perspectives of genomic research during the early phases of study development. Engaging with community members early and consistently throughout the research lifecycle could help identify and mitigate barriers to genomic research participation, particularly among groups with rare and understudied cancers.

METHODS: The Washington University Participant Engagement and Cancer Genome Sequencing (WU-PE-CGS) study formed a Participant Engagement Advisory Board (PEAB) consisting of patients, patient advocates, and patient advocacy organizations who represented the three understudied cancer populations: cholangiocarcinoma, early-onset colorectal cancer in Black Americans, and multiple myeloma in Black Americans. PEAB …

Impacts Of The Conductive Networks On Solid-State Battery Operation, Shimao Deng, Yixian Wang, Tianxiao Sun, Wenlong Li, Mingyuan Ge, Jian Wang, Peter Cloetens, Piero Pianetta, David Mitlin, Yijin Liu

Faculty, Staff and Student Publications

The micromorphology of composite cathodes is known to play a vital role in determining all‐solid‐state battery (ASSB) performance. However, much of our current understanding is derived from empirical observations, lacking a deeper mechanistic foundation. The “rocking chair” concept of battery chemistry requires maintaining charge neutrality, emphasizing the necessity of examining electrode micromorphology from the perspective of conductive networks. This study systematically investigates the microscopic electrochemical impacts of conductive network micromorphology by varying the Li+‐to‐e− channel ratio in cathodes comprising LiNbO3‐coated LiNi0.8Co0.1Mn0.1O2, Li6PS5Cl, and carbon fibers. Utilizing multiscale synchrotron‐based spectro‐microscopy, we unravel that unbalanced Li+ and e− conducting channels intensify charge …

Use Of Amplified Lewy Body Dementia Fibrils And Autoradiography To Characterize Binding Of Radioligand Tg-1-90b To Alpha-Synuclein Fibrils In Postmortem Brain Tissue, Jennifer Y O'Shea, Dhruva D Dhavale, Helen Hwang, Zachary Smith, Thomas J A Graham, Robert H Mach, Paul T Kotzbauer

2020-Current year OA Pubs

Parkinson's disease (PD) and Lewy Body Dementia (LBD) are defined by accumulation of alpha-synuclein (Asyn) fibrils within Lewy bodies (LBs) and Lewy neurites (LNs). The development of a Positron Emission Tomography (PET) tracer for quantifying Asyn fibrils would improve diagnostic accuracy and provide a biomarker for disease progression. We previously described radioligand [

Chronic Poppers Maculopathy: Case Report And Literature Comparison Of Chronic And Acute Use, Francesco Cappellani, Caterina Gagliano, Jose S. Pulido

Wills Eye Hospital Papers

RATIONALE: Alkyl nitrites ("poppers") are recreational substances known for their vasodilatory and euphoric effects. Increasing evidence links them to a vision-threatening condition termed poppers maculopathy, characterized by foveal yellow spots and outer retinal changes on optical coherence tomography. While most reports describe acute exposure, little is known about long-term consequences. This case describes one of the longest documented durations of chronic poppers use, combined with a literature review to contextualize the clinical spectrum.

PATIENT CONCERNS: A 68-year-old man with human immunodeficiency virus, type 2 diabetes, hypertension, and depression presented with progressive central vision loss in both eyes persisting for at …

Trends And Disparities In Acute Coronary Syndrome-Related Mortality In The United States: Implications For Healthcare, Muhammad Khuzzaim Khan, Ibrahim Ahmed Khan, Abdul Moiz Javed, Arslan Wazir, Hira Saleem, Muhammad Zohaib, Faisal Rasheed, Priyanka Mohan Lal, Syeda Laiba Sherazi, Amiaz Karim, Nikhil Duseja, Hussam Al Hennawi

Abington Jefferson Health Papers

Acute coronary syndrome (ACS) is a major cause of morbidity and mortality in the United States (US). However, the trends and disparities in ACS mortality are not well understood. This study aimed to analyze the ACS mortality in the US from 1999 to 2020 using the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database. The age-adjusted mortality rates (AAMR) due to ACS were calculated for each year from 1999 to 2020, stratified by sex, race, urbanization, and state. The trends and disparities in AAMR were examined using descriptive statistics and graphical methods. The AAMR due …

Human Single-Neuron Activity Is Modulated By Intracranial Theta Burst Stimulation Of The Basolateral Amygdala, Justin M Campbell, Shuo Wang, Lawrence N Eisenman, James Swift, Tao Xie, Peter Brunner, Jon Timothy Willie, Et Al.

2020-Current year OA Pubs

Direct electrical stimulation of the human brain has been used for numerous clinical and scientific applications. At present, however, little is known about how intracranial stimulation affects activity at the microscale. In this study, we recorded intracranial EEG data from a cohort of patients with medically refractory epilepsy as they completed a visual recognition memory task. During the memory task, brief trains of intracranial theta burst stimulation (TBS) were delivered to the basolateral amygdala (BLA). Using simultaneous microelectrode recordings, we isolated neurons in the hippocampus, amygdala, orbitofrontal cortex, and anterior cingulate cortex and tested whether stimulation enhanced or suppressed firing …

Rapid Mapping Of Spinal And Supraspinal Connectome Via Self-Targeting Glucose-Based Carbon Dots, Yasin B. Seven, Elif S. Seven, Emel Kirbas Cilingir, Komal Parikh, Mehmet Aydin, Edward K. Luca, Jayakrishnan Nair, Roger M. Leblanc

Department of Physical Therapy Faculty Papers

The spinal cord is a highly dynamic network, playing significant roles in the vital functions of the brain. Disorders of the spinal cord, such as spinal cord injury and amyotrophic lateral sclerosis (ALS), are associated with neurodegeneration, often resulting in morbidity and mortality. The blood-brain barrier (BBB) poses a major challenge to imaging and therapeutic agents because less than 2% of small-molecule drugs and almost no large-molecule drugs can cross the BBB. Furthermore, spatial spectroscopy studies have shown highly heterogeneous BBB crossing with significant accumulation at the unintended brain regions. Thus, targeting systems that can cross the BBB at the …

Early Blood Pressure Targets In Acute Spinal Cord Injury: A Randomized Clinical Trial, Ruba Sajdeya, N. David Yanez, Michael Kampp, Michael D. Goodman, David Zonies, Brandon Togioka, Andrew Nunn, Robert D. Winfield, Niels D. Martin, Anirudh Kohli, Toan T. Huynh, David O. Okonkwo, Roy A. Poblete, Emily J. Gilmore, Randall M. Chesnut, Aaron E. Bunnell, Tetsu Ohnuma, Mona Hashemaghaie, Miriam M. Treggiari

Department of Surgery Faculty Papers

IMPORTANCE: Early blood pressure management is central to neurologic resuscitation of spinal cord injury; however, the role of augmented blood pressure is unclear.

OBJECTIVE: To compare the efficacy and safety of augmented vs conventional blood pressure on 6-month neurologic outcomes after acute spinal cord injury.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter randomized clinical trial took place from October 3, 2017, to July 26, 2023, and assessed patients 18 years or older with spinal cord injury followed up for 6 months at 13 large US trauma centers.

INTERVENTIONS: Patients were equally randomized to augmented (>85-90 mm Hg) or conventional ( …

Connecting Innovation And Trust Through Translational Sciences – A Need For A Community Focus And Effective Education Strategiess, Filipa Godoy-Vitorino, Michelle Borrero, Josué Pérez-Santiago, Rubén García-García, Candelaria Gomez-Manzano

Faculty, Staff and Student Publications

Report of a conference held in Puerto Rico, this article highlights how interdisciplinary translational science-anchored in education, public trust, and equity-can accelerate innovation in cancer therapy while empowering underserved communities through inclusive training, collaboration, and research participation.

Efficacy And Safety Of Rigosertib In Patients With Recessive Dystrophic Epidermolysis Bullosa-Associated Advanced/Metastatic Cutaneous Squamous Cell Carcinoma, Martin Laimer, Andrew P. South, Elisabeth Mayr, Sophie Kitzmueller, Lauren Banner, Michael Alexander, Linda Hosler, Henry Yang, Matthew Parris, Meena Arora, Georg Zimmermann, Gregor Schweighofer-Zwink, Johann Bauer, Neda Nikbakht

Department of Dermatology and Cutaneous Biology Faculty Papers

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is an epithelial fragility disease primarily affecting the skin and is caused by variants in the COL7A1 gene. Individuals with RDEB are predisposed to develop highly aggressive cutaneous squamous cell carcinomas (SCCs) which are the most common cause of premature death. There is a lack of effective prevention or treatment options for patients with RDEB-SCC.

OBJECTIVES: To evaluate the antitumour activity and safety of the polo-like kinase-1 (PLK1) inhibitor, rigosertib, two investigator-initiated open-label, single-arm phase II studies were opened in Europe and the USA and enrolled five patients with RDEB diagnosed with locally advanced …

Salvage Therapies For First Relapse Of Shh Medulloblastoma In Early Childhood., Craig Erker, Martin Mynarek, Marie Simbozel, Brandon T. Craig, Virginia L. Harrod, Andrea M. Cappellano, Kenneth J. Cohen, Vicente Santa-Maria Lopez, Andres Morales La Madrid, Chantel Cacciotti, Lorena Baroni, Ralph Salloum, Ashley S. Margol, George Michaiel, Dolly Aguilera, Claire M. Mazewski, Cassie N. Kline, Jonathan L. Finlay, Mohamed S. Abdelbaki, Jeffrey C. Murray, Kathleen Dorris, Bruce Crooks, Kevin Ginn, Nisreen Amayiri, Stephan Tippelt, Gudrun Fleischhack, Svenja Tonn, Nicolas U. Gerber, Alvaro Lassaletta, Jordan R. Hansford, Sara Khan, Stephen W. Gilheeney, Lindsey M. Hoffman, Michal Zapotocky, Valérie Larouche, Shafqat Shah, Vijay Ramaswamy, Amar Gajjar, Sébastien Perreault, Sabine Mueller, Juliette Hukin, Sylvia Cheng, Zhihong J. Wang, Kara Matheson, Simon Bailey, Eric Bouffet, Steven C. Clifford, Giles Robinson, Christelle Dufour, Stefan Rutkowski, Lucie Lafay-Cousin

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Sonic hedgehog (SHH) medulloblastoma is the most common molecular group of infant and early childhood medulloblastoma (iMB) and has no standard of care at relapse. This work aimed to evaluate the post-relapse survival (PRS) and explore prognostic factors of patients with nodular desmoplastic (ND) and/or SHH iMB.

METHODS: This international retrospective study included 147 subjects diagnosed with relapsed ND/SHH iMB between 1995 and 2017, < 6 years old at original diagnosis, and treated without initial craniospinal irradiation (CSI). Univariable and multivariable Cox models with propensity score analyses were used to assess PRS for those in the curative intent cohort.

RESULTS: The 3-year PRS was 61.6% (95% confidence interval [CI], 52.2-69.6). The median age at relapse was 3.4 years (interquartile range [IQR], 2.6-4.1). Those with local relapse (40.8%) more often received salvage treatment with surgery …

Genome-Wide Association Study Meta-Analysis Uncovers Novel Genetic Variants Associated With Olfactory Dysfunction, Mohammed Aslam Imtiaz, Konstantinos Melas, Adrienne Tin, Valentina Talevi, Honglei Chen, Myriam Fornage, Srishti Shrestha, Martin Gögele, David Emmert, Cristian Pattaro, Peter Pramstaller, Franz Förster, Katrin Horn, Thomas H Mosley, Christian Fuchsberger, Markus Scholz, Monique M B Breteler, N Ahmad Aziz

Faculty, Staff and Student Publications

Background: Olfactory dysfunction is among the earliest signs of many age-related neurodegenerative diseases and has been associated with increased mortality in older adults; however, its genetic basis remains largely unknown. Therefore, here we aimed to elucidate its genetic architecture through a genome-wide association study meta-analysis (GWMA).

Methods: This GWMA included the participants of European ancestry (N = 22,730) enrolled in four different large population-based studies followed by a multi-ancestry GWMA including participants of African ancestry (N = 1,030). Olfactory dysfunction was assessed using a 12-item smell identification test.

Results: GWMA revealed a novel genome-wide significant locus (tagged by single nucleotide …

Bard1: A Friend Or Foe In Pancreatic Ductal Adenocarcinoma?, Lily Zekavat, Aditi Jain

Department of Surgery Faculty Papers

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid malignancy with poor overall prognosis and limited response to standard treatments. Growing interest in the modulation of DNA repair mechanisms, including the homologous recombination (HR) repair pathway, has opened new avenues for therapeutic development. BARD1 (BRCA1-Associated RING Domain 1) plays a complex role in tumor biology, functioning either as a tumor suppressor or as an oncogenic driver, depending on isoform expression, cellular context, and regulatory environment. In this review, we examine the dual roles of BARD1, focusing on its regulation and paradoxical activities in PDAC. We summarize evidence that BARD1 and BARD1 …

Evaluating And Optimizing Just-In-Time Adaptive Interventions In A Digital Mental Health Intervention (Wysa For Chronic Pain) For Middle-Aged And Older Adults With Chronic Pain: Protocol For A Series Of Randomized Trials, Abby L Cheng, Joanna Abraham, Sarah M Hartz, Eric B Laber, J Philip Miller

2020-Current year OA Pubs

BACKGROUND: On a population level, digital mental health interventions effectively reduce depression and anxiety symptoms. However, middle-aged and older adults with chronic pain and coexisting depression or anxiety have not been adequately represented in digital mental health studies.

OBJECTIVE: The goal of this study is to refine an existing mobile, digital mental health intervention (Wysa for Chronic Pain) that addresses symptoms of depression, anxiety, and coexisting chronic pain for the unique challenges and technology use patterns of middle-aged and older adults.

METHODS: Using a mixed methods, human-centered design approach and a series of randomized trials, we will test and iteratively …

Salvage Therapies For First Relapse Of Shh Medulloblastoma In Early Childhood, Craig Erker, Mohamed S Abdelbaki, Et Al.

2020-Current year OA Pubs

BACKGROUND: Sonic hedgehog (SHH) medulloblastoma is the most common molecular group of infant and early childhood medulloblastoma (iMB) and has no standard of care at relapse. This work aimed to evaluate the post-relapse survival (PRS) and explore prognostic factors of patients with nodular desmoplastic (ND) and/or SHH iMB.

METHODS: This international retrospective study included 147 subjects diagnosed with relapsed ND/SHH iMB between 1995 and 2017, < 6 years old at original diagnosis, and treated without initial craniospinal irradiation (CSI). Univariable and multivariable Cox models with propensity score analyses were used to assess PRS for those in the curative intent cohort.

RESULTS: The 3-year PRS was 61.6% (95% confidence interval [CI], 52.2-69.6). The median age at relapse was 3.4 years (interquartile range [IQR], 2.6-4.1). Those with local relapse (40.8%) more often received salvage treatment with surgery …

Galntl5 Binds Galnac And Is Required For Migration Through The Uterotubal Junction And Sperm-Zona Pellucida Binding, Taichi Noda, Reika Uriu, Daisuke Mashiko, Hina Shinohara, Yongcun Qu, Ayumu Taira, Ryan M Matzuk, Duri Tahala, Motochika Nakano, Kimi Araki, Zhifeng Yu, Ying Zhang, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Objective: To review the global impact of the COVID-19 pandemic on stroke care-metrics and report data from a health system in Houston.

Methods: We performed a meta-analysis of the published literature reporting stroke admissions, intracerebral hemorrhage (ICH) cases, number of thrombolysis (tPA) and thrombectomy (MT) cases, and time metrics (door to needle, DTN; and door to groin time, DTG) during the pandemic compared to prepandemic period. Within our hospital system, between January-June 2019 and January-June 2020, we compared the proportion of stroke admissions and door to tPA and MT times.

Results: A total of 32,640 stroke admissions from 29 studies …