Digital Commons Network^™

Detection Of Distant Relatedness In Biobanks To Identify Undiagnosed Cases Of Mendelian Disease As Applied To Long Qt Syndrome, Megan C Lancaster, Hung-Hsin Chen, M Benjamin Shoemaker, Matthew R Fleming, Teresa L Strickland, James T Baker, Grahame F Evans, Hannah G Polikowsky, David C Samuels, Chad D Huff, Dan M Roden, Jennifer E Below

Faculty, Staff and Student Publications

Rare genetic diseases are typically studied in referral populations, resulting in underdiagnosis and biased assessment of penetrance and phenotype. To address this, we develop a generalizable method of genotype inference based on distant relatedness and deploy this to identify undiagnosed Type 5 Long QT Syndrome (LQT5) rare variant carriers in a non-referral population. We identify 9 LQT5 families referred to a single specialty clinic, each carrying p.Asp76Asn, the most common LQT5 variant. We uncover recent common ancestry and a single shared haplotype among probands. Application to a non-referral population of 69,819 BioVU biobank subjects identifies 22 additional subjects sharing this …

Contrast Enhanced Ultrasound Of Liver Lesions In Patients Treated For Childhood Malignancies., Ayatullah Mostafa, Zachary Abramson, Mina Ghbrial, Som Biswas, Sherwin S. Chan, Himani Darji, Jessica Gartrell, Seth E. Karol, Yimei Li, Daniel A. Mulrooney, Tushar Patni, Tarek M. Zaghloul, M Beth Mccarville

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Patients treated for cancer have a higher incidence of focal liver lesions than the general population and there is often concern for a malignant etiology. This can result in patient, caregiver and physician anxiety and is managed by a "wait and watch" approach, or immediate additional imaging, or biopsy, depending on the degree of clinical concern. Because it is a low-cost, easily accessible, radiation and sedation free modality, we investigated the value of contrast enhanced ultrasound (CEUS) to accurately distinguish benign from malignant liver lesions in patients treated for childhood malignancies.

METHODS: We performed an IRB approved retrospective study …

Cognitive Effects Of Simulated Galactic Cosmic Radiation Are Mediated By Apoe Status, Sex, And Environment In App Knock-In Mice, Laura Wieg, Jason C Ciola, Caroline C Wasén, Fidelia Gaba, Brianna R Colletti, Maren K Schroeder, Robert G Hinshaw, Millicent N Ekwudo, David M Holtzman, Takashi Saito, Hiroki Sasaguri, Takaomi C Saido, Laura M Cox, Cynthia A Lemere

2020-Current year OA Pubs

Cosmic radiation experienced during space travel may increase the risk of cognitive impairment. While simulated galactic cosmic radiation (GCRsim) has led to memory deficits in wildtype (WT) mice, it has not been investigated whether GCRsim in combination with genetic risk factors for Alzheimer's disease (AD) worsens memory further in aging mice. Here, we investigated the central nervous system (CNS) effects of 0 Gy (sham) or 0.75 Gy five-ion GCRsim or 2 Gy gamma radiation (IRR) in 14-month-old female and male APP

Diet-Induced Obesity Induces Transcriptomic Changes In Neuroimmunometabolic-Related Genes In The Striatum And Olfactory Bulb, Rosario B Jaime-Lara, Claudia Colina-Prisco, Marcel De Jesus Vega, Sarah Williams, Ted Usdin, Bridget Matikainen-Ankney, Alayna Kinkead, Brianna Brooks, Yupeng Wang, Alexis T Franks, Alexxai Kravitz, Paule V Joseph

2020-Current year OA Pubs

The incidence of obesity has markedly increased globally over the last several decades and is believed to be associated with the easier availability of energy-dense foods, including high-fat foods. The reinforcing hedonic properties of high-fat foods, including olfactory cues, activate reward centers in the brain, motivating eating behavior. Thus, there is a growing interest in the understanding of the genetic changes that occur in the brain that are associated with obesity and eating behavior. This growing interest has paralleled advances in genomic methods that enable transcriptomic-wide analyses. Here, we examined the transcriptomic-level differences in the olfactory bulb and striatum, regions …

Donor Types And Outcomes Of Transplantation In Myelofibrosis: A Cibmtr Study, Tania Jain, Noel Estrada-Merly, M Queralt Salas, Soyoung Kim, Jakob Devos, Min Chen, Xi Fang, Rajat Kumar, Marcio Andrade-Campos, Hany Elmariah, Vaibhav Agrawal, Mahmoud Aljurf, Ulrike Bacher, Talha Badar, Sherif M Badawy, Karen Ballen, Amer Beitinjaneh, Vijaya Raj Bhatt, Christopher Bredeson, Zachariah Defilipp, Bhagirathbhai Dholaria, Nosha Farhadfar, Shatha Farhan, Arpita P Gandhi, Siddhartha Ganguly, Usama Gergis, Michael R Grunwald, Nada Hamad, Betty K Hamilton, Yoshihiro Inamoto, Madiha Iqbal, Omer Jamy, Mark Juckett, Mohamed A Kharfan-Dabaja, Maxwell M Krem, Deepesh P Lad, Jane Liesveld, Monzr M Al Malki, Adriana K Malone, Hemant S Murthy, Guillermo Ortí, Sagar S Patel, Attaphol Pawarode, Miguel-Angel Perales, Marjolein Van Der Poel, Olle Ringden, David A Rizzieri, Alicia Rovó, Bipin N Savani, Mary Lynn Savoie, Sachiko Seo, Melhem Solh, Celalettin Ustun, Leo F Verdonck, John R Wingard, Baldeep Wirk, Nelli Bejanyan, Richard J Jones, Taiga Nishihori, Betul Oran, Ryotaro Nakamura, Bart Scott, Wael Saber, Vikas Gupta

Department of Medical Oncology Faculty Papers

We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)-HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched …

Role Of Kindlin 2 In Prostate Cancer, Katarzyna Bialkowska, Lamyae El Khalki, Priyanka Rana, Wei Wang, Daniel Lindner, Yvonne Parker, Lucia Languino, Dario Altieri, Elzbieta Pluskota, Khalid Sossey-Alaoui, Edward Plow

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Kindlin-2 is a cytoskeletal adapter protein that is present in many different cell types. By virtue of its interaction with multiple binding partners, Kindlin-2 intercalates into numerous signaling pathways and cytoskeletal nodes. A specific interaction of Kindlin-2 that is of paramount importance in many cellular responses is its direct binding to the cytoplasmic tails of integrins, an interaction that controls many of the adhesive, migratory and signaling responses mediated by members of the integrin family of cell-surface heterodimers. Kindlin-2 is highly expressed in many cancers and is particularly prominent in prostate cancer cells. CRISPR/cas9 was used as a primary approach …

Evaluating The Impact Of Laboratory-Based Eligibility Criteria By Race/Ethnicity In First-Line Clinical Trials Of Dlbcl, Arushi Khurana, Raphael Mwangi, Loretta J Nastoupil, Patrick M Reagan, Umar Farooq, Jason T Romancik, Timothy J Mcdonnell, Shaun M Riska, Lzidore S Lossos, Brad S Kahl, Peter Martin, Thomas E Witzig, James R Cerhan, Christopher R Flowers, Grzegorz S Nowakowski, Matthew J Maurer

Faculty, Staff and Student Publications

Underrepresentation of racial and ethnic subgroups in cancer clinical trials remains a persistent challenge. Restrictive clinical trial eligibility criteria have been shown to exacerbate this problem. We previously identified that up to 24% of patients treated with standard immunochemotherapy would have been excluded from recent first-line trials in diffuse large B-cell lymphoma (DLBCL) based on 5 laboratory-based criteria. These ineligible patients had worse clinical outcomes and increased deaths related to lymphoma progression, suggesting the potential exclusion of patients who could have benefited most from the novel therapies being evaluated. Using data from the prospectively enrolled Lymphoma Epidemiology Outcomes cohort study, …

Single-Cell Analysis Of Chromatin And Expression Reveals Age- And Sex-Associated Alterations In The Human Heart, David F Read, Yiing Lin, Et Al.

2020-Current year OA Pubs

Sex differences and age-related changes in the human heart at the tissue, cell, and molecular level have been well-documented and many may be relevant for cardiovascular disease. However, how molecular programs within individual cell types vary across individuals by age and sex remains poorly characterized. To better understand this variation, we performed single-nucleus combinatorial indexing (sci) ATAC- and RNA-Seq in human heart samples from nine donors. We identify hundreds of differentially expressed genes by age and sex and find epigenetic signatures of variation in ATAC-Seq data in this discovery cohort. We then scale up our single-cell RNA-Seq analysis by combining …

Sexannodb, A Knowledgebase Of Sex-Specific Regulations From Multi-Omics Data Of Human Cancers, Mengyuan Yang, Yuzhou Feng, Jiajia Liu, Hong Wang, Sijia Wu, Weiling Zhao, Pora Kim, Xiaobo Zhou

Faculty, Staff and Student Publications

Background

Sexual differences across molecular levels profoundly impact cancer biology and outcomes. Patient gender significantly influences drug responses, with divergent reactions between men and women to the same drugs. Despite databases on sex differences in human tissues, understanding regulations of sex disparities in cancer is limited. These resources lack detailed mechanistic studies on sex-biased molecules.

Methods

In this study, we conducted a comprehensive examination of molecular distinctions and regulatory networks across 27 cancer types, delving into sex-biased effects. Our analyses encompassed sex-biased competitive endogenous RNA networks, regulatory networks involving sex-biased RNA binding protein-exon skipping events, sex-biased transcription factor-gene regulatory networks, …

Loss Of Symmetric Cell Division Of Apical Neural Progenitors Drives Dennd5a-Related Developmental And Epileptic Encephalopathy, Emily Banks, Vincent Francis, Sheng-Jia Lin, Fares Kharfallah, Vladimir Fonov, Maxime Lévesque, Chanshuai Han, Gopinath Kulasekaran, Marius Tuznik, Armin Bayati, Reem Al-Khater, Fowzan S Alkuraya, Loukas Argyriou, Meisam Babaei, Melanie Bahlo, Behnoosh Bakhshoodeh, Eileen Barr, Lauren Bartik, Mahmoud Bassiony, Miriam Bertrand, Dominique Braun, Rebecca Buchert, Mauro Budetta, Maxime Cadieux-Dion, Daniel G Calame, Heidi Cope, Donna Cushing, Stephanie Efthymiou, Marwa Abd Elmaksoud, Huda G El Said, Tawfiq Froukh, Harinder K Gill, Joseph G Gleeson, Laura Gogoll, Elaine S-Y Goh, Vykuntaraju K Gowda, Tobias B Haack, Mais O Hashem, Stefan Hauser, Trevor L Hoffman, Jacob S Hogue, Akimoto Hosokawa, Henry Houlden, Kevin Huang, Stephanie Huynh, Ehsan G Karimiani, Silke Kaulfuß, G Christoph Korenke, Amy Kritzer, Hane Lee, James R Lupski, Elysa J Marco, Kirsty Mcwalter, Arakel Minassian, Berge A Minassian, David Murphy, Juanita Neira-Fresneda, Hope Northrup, Denis M Nyaga, Barbara Oehl-Jaschkowitz, Matthew Osmond, Richard Person, Davut Pehlivan, Cassidy Petree, Lynette G Sadleir, Carol Saunders, Ludger Schoels, Vandana Shashi, Rebecca C Spillmann, Varunvenkat M Srinivasan, Paria N Torbati, Tulay Tos, Maha S Zaki, Dihong Zhou, Christiane Zweier, Jean-François Trempe, Thomas M Durcan, Ziv Gan-Or, Massimo Avoli, Cesar Alves, Gaurav K Varshney, Reza Maroofian, David A Rudko, Peter S Mcpherson

Faculty, Staff and Student Publications

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells …

Mapping Neural Correlates Of Biological Motion Perception In Autistic Children Using High-Density Diffuse Optical Tomography, Dalin Yang, Alexandra M Svoboda, Tessa G George, Patricia K Mansfield, Muriah D Wheelock, Mariel L Schroeder, Sean M Rafferty, Arefeh Sherafati, Kalyan Tripathy, Tracy Burns-Yocum, Elizabeth Forsen, John R Pruett, Natasha M Marrus, Joseph P Culver, John N Constantino, Adam T Eggebrecht

2020-Current year OA Pubs

BACKGROUND: Autism spectrum disorder (ASD), a neurodevelopmental disorder defined by social communication deficits plus repetitive behaviors and restricted interests, currently affects 1/36 children in the general population. Recent advances in functional brain imaging show promise to provide useful biomarkers of ASD diagnostic likelihood, behavioral trait severity, and even response to therapeutic intervention. However, current gold-standard neuroimaging methods (e.g., functional magnetic resonance imaging, fMRI) are limited in naturalistic studies of brain function underlying ASD-associated behaviors due to the constrained imaging environment. Compared to fMRI, high-density diffuse optical tomography (HD-DOT), a non-invasive and minimally constraining optical neuroimaging modality, can overcome these limitations. …

Mechanism Of Gabapentinoid Potentiation Of Opioid Effects On Cyclic Amp Signaling In Neuropathic Pain, Anibal Garza-Carbajal, Alexis Bavencoffe, Juan J Herrera, Kayla N Johnson, Edgar T Walters, Carmen W Dessauer

Faculty, Staff and Student Publications

Over half of spinal cord injury (SCI) patients develop opioid-resistant chronic neuropathic pain. Safer alternatives to opioids for treatment of neuropathic pain are gabapentinoids (e.g., pregabalin and gabapentin). Clinically, gabapentinoids appear to amplify opioid effects, increasing analgesia and overdose-related adverse outcomes, but in vitro proof of this amplification and its mechanism are lacking. We previously showed that after SCI, sensitivity to opioids is reduced by fourfold to sixfold in rat sensory neurons. Here, we demonstrate that after injury, gabapentinoids restore normal sensitivity of opioid inhibition of cyclic AMP (cAMP) generation, while reducing nociceptor hyperexcitability by inhibiting voltage-gated calcium channels (VGCCs). …

Clinical And Genomic-Based Decision Support System To Define The Optimal Timing Of Allogeneic Hematopoietic Stem-Cell Transplantation In Patients With Myelodysplastic Syndromes, Cristina Astrid Tentori, Caterina Gregorio, Marie Robin, Nico Gagelmann, Carmelo Gurnari, Somedeb Ball, Juan Carlos Caballero Berrocal, Luca Lanino, Saverio D'Amico, Marta Spreafico, Giulia Maggioni, Erica Travaglino, Elisabetta Sauta, Manja Meggendorfer, Lin-Pierre Zhao, Alessia Campagna, Victor Savevski, Armando Santoro, Najla Al Ali, David Sallman, Francesc Sole, Guillermo Garcia-Manero, Ulrich Germing, Nicolaus Kroger, Shahram Kordasti, Valeria Santini, Guillermo Sanz, Wolfgang Kern, Uwe Platzbecker, Maria Diez-Campelo, Jaroslaw P Maciejewski, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Amer M Zeidan, Gastone Castellani, Rami Komrokji, Francesca Ieva, Matteo Giovanni Della Porta, Genomed4all And Synthema Consortiums

Faculty, Staff and Student Publications

Purpose: Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M).

Patients and methods: We studied a retrospective population of 7,118 patients, stratified into training and validation …

Children Sustain Cooperation In A Threshold Public-Goods Game Even When Seeing Others’ Outcomes, Patricia Kanngiesser, Jahnavi Sunderarajan, Sebastian Hafenbrädl, Jan K. Woike

School of Psychology

Many societal challenges are threshold dilemmas requiring people to cooperate to reach a threshold before group benefits can be reaped. Yet receiving feedback about others’ outcomes relative to one’s own (relative feedback) can undermine cooperation by focusing group members’ attention on outperforming each other. We investigated the impact of relative feedback compared to individual feedback (only seeing one’s own outcome) on cooperation in children from Germany and India (6- to 10-year-olds, N = 240). Using a threshold public-goods game with real water as a resource, we show that, although feedback had an effect, most groups sustained cooperation at high levels …

Injectable, Reversibly Thermoresponsive Captopril-Laden Hydrogel For The Local Treatment Of Sensory Loss In Diabetic Neuropathy, Amit Chandra Das, James M Nichols, Caitlin V Crelli, Lu Liu, Riddhi Vichare, Hoang Vu Pham, Caitlyn M Gaffney, Fisher R Cherry, Peter M Grace, Andrew J Shepherd, Jelena M Janjic

Faculty, Staff and Student Publications

A major and irreversible complication of diabetes is diabetic peripheral neuropathy (DPN), which can lead to significant disability and decreased quality of life. Prior work demonstrates the peptide hormone Angiotensin II (Ang II) is released locally in neuropathy and drives inflammation and impaired endoneurial blood flow. Therefore, we proposed that by utilizing a local thermoresponsive hydrogel injection, we could deliver inhibitors of angiotensin-converting enzyme (ACE) to suppress Ang II production and reduce nerve dysfunction in DPN through local drug release. The ACE inhibitor captopril was encapsulated into a micelle, which was then embedded into a reversibly thermoresponsive pluronics-based hydrogel matrix. …

Biological And Procedural Predictors Of Outcome In The Stroke Preclinical Assessment Network (Span) Trial, Andreia Morais, Takahiko Imai, Xuyan Jin, Joseph J Locascio, Ligia Boisserand, Alison L Herman, Anjali Chauhan, Jessica Lamb, Karisma Nagarkatti, Marcio A Diniz, Mariia Kumskova, Nirav Dhanesha, Pradip K Kamat, Mohammad Badruzzaman Khan, Krishnan M Dhandapani, Rakesh B Patel, Brijesh Sutariya, Yanrong Shi, Klaus Van Leyen, W Taylor Kimberly, David C Hess, Jaroslaw Aronowski, Enrique C Leira, Raymond C Koehler, Anil K Chauhan, Lauren H Sansing, Patrick D Lyden, Cenk Ayata

Faculty, Staff and Student Publications

BACKGROUND: The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo.

METHODS: The study cohort included all mice enrolled and …

A Thalamic Nucleus Reuniens-Lateral Septum-Lateral Hypothalamus Circuit For Comorbid Anxiety-Like Behaviors In Chronic Itch, Su-Shan Guo, Yu Gong, Ting-Ting Zhang, Xin-Yu Su, Yan-Jiao Wu, Yi-Xiao Yan, Yue Cao, Xing-Lei Song, Jian-Cheng Xie, Dehua Wu, Qin Jiang, Ying Li, Xuan Zhao, Michael X Zhu, Tian-Le Xu, Ming-Gang Liu

Faculty, Staff and Student Publications

Chronic itch often clinically coexists with anxiety symptoms, creating a vicious cycle of itch-anxiety comorbidities that are difficult to treat. However, the neuronal circuit mechanisms underlying the comorbidity of anxiety in chronic itch remain elusive. Here, we report anxiety-like behaviors in mouse models of chronic itch and identify γ-aminobutyric acid-releasing (GABAergic) neurons in the lateral septum (LS) as the key player in chronic itch-induced anxiety. In addition, chronic itch is accompanied with enhanced activity and synaptic plasticity of excitatory projections from the thalamic nucleus reuniens (Re) onto LS GABAergic neurons. Selective chemogenetic inhibition of the Re → LS circuit notably …

Pre-Existing Immunocompromising Conditions And Outcomes Of Acute Covid-19 Patients Admitted For Pediatric Intensive Care, Courtney M Rowan, Brenna Labere, Cameron C Young, Laura D Zambrano, Margaret M Newhams, Suden Kucukak, Elizabeth R Mcnamara, Elizabeth H Mack, Julie C Fitzgerald, Katherine Irby, Aline B Maddux, Jennifer E Schuster, Michele Kong, Heda Dapul, Stephanie P Schwartz, Melania M Bembea, Laura L Loftis, Amanda R Kolmar, Christopher J Babbitt, Ryan A Nofziger, Mark W Hall, Shira J Gertz, Natalie Z Cvijanovich, Matt S Zinter, Natasha B Halasa, Tamara T Bradford, Gwenn E Mclaughlin, Aalok R Singh, Charlotte V Hobbs, Kari Wellnitz, Mary A Staat, Bria M Coates, Hillary R Crandall, Mia Maamari, Kevin M Havlin, Adam J Schwarz, Christopher L Carroll, Emily R Levy, Kristin L Moffitt, Angela P Campbell, Adrienne G Randolph, Janet Chou

Faculty, Staff and Students Publications

BACKGROUND: We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care.

METHODS: Fifty-five hospitals in 30 US states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients(PICU) or high-acuity unit for acute COVID-19 were included.

RESULTS: Of 1274 patients, 105 (8.2%) had an ICC, including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid-organ transplantation, 16 (15.2%) solid tumors, and 13 (12.4%) autoimmune disorders. Patients with ICCs were …

Hybridizing Mechanistic Modeling And Deep Learning For Personalized Survival Prediction After Immune Checkpoint Inhibitor Immunotherapy, Joseph D Butner, Prashant Dogra, Caroline Chung, Eugene J Koay, James W Welsh, David S Hong, Vittorio Cristini, Zhihui Wang

Faculty, Staff and Student Publications

We present a study where predictive mechanistic modeling is combined with deep learning methods to predict individual patient survival probabilities under immune checkpoint inhibitor (ICI) immunotherapy. This hybrid approach enables prediction based on both measures that are calculable from mechanistic models of key mechanisms underlying ICI therapy that may not be directly measurable in the clinic and easily measurable quantities or patient characteristics that are not always readily incorporated into predictive mechanistic models. A deep learning time-to-event predictive model trained on a hybrid mechanistic + clinical data set from 93 patients achieved higher per-patient predictive accuracy based on event-time concordance, …

Infant And Adult Human Intestinal Enteroids Are Morphologically And Functionally Distinct, Grace O Adeniyi-Ipadeola, Julia D Hankins, Amal Kambal, Xi-Lei Zeng, Ketki Patil, Victoria Poplaski, Carolyn Bomidi, Hoa Nguyen-Phuc, Sandra L Grimm, Cristian Coarfa, Fabio Stossi, Sue E Crawford, Sarah E Blutt, Allison L Speer, Mary K Estes, Sasirekha Ramani

Faculty, Staff and Students Publications

UNLABELLED: Human intestinal enteroids (HIEs) are gaining recognition as physiologically relevant models of the intestinal epithelium. While HIEs from adults are used extensively in biomedical research, few studies have used HIEs from infants. Considering the dramatic developmental changes that occur during infancy, it is important to establish models that represent infant intestinal characteristics and physiological responses. We established jejunal HIEs from infant surgical samples and performed comparisons to jejunal HIEs from adults using RNA sequencing (RNA-Seq) and morphologic analyses. We then validated differences in key pathways through functional studies and determined whether these cultures recapitulate known features of the infant …

Prostate Cancer-Induced Endothelial-Cell-To-Osteoblast Transition Drives Immunosuppression In The Bone-Tumor Microenvironment Through Wnt Pathway-Induced M2 Macrophage Polarization, Guoyu Yu, Paul G Corn, Celia Sze Ling Mak, Xin Liang, Miao Zhang, Patricia Troncoso, Jian H Song, Song-Chang Lin, Xingzhi Song, Jingjing Liu, Jianhua Zhang, Christopher J Logothetis, Marites P Melancon, Theocharis Panaretakis, Guocan Wang, Sue-Hwa Lin

Faculty, Staff and Student Publications

Immune checkpoint therapy has limited efficacy for patients with bone-metastatic castration-resistant prostate cancer (bmCRPC). To improve immunotherapy for bmCRPC, we aimed to identify the mechanism of bmCRPC-induced changes in the immune microenvironment. Among bmCRPC patients, higher levels of a 32-gene M2-like macrophage signature in bone metastasis samples correlated with shorter overall survival. Immunohistochemistry showed that CD206-positive (CD206+) macrophages were enriched in bmCRPC bone biopsy specimens compared with primary tumors or lymph node metastases. In preclinical osteogenic prostate cancer (Pca) xenograft models, CD206+ macrophages were recruited to areas with tumor-induced bone. RNA sequencing (RNAseq) analysis showed higher expression of an M2-like …

Vigorous Exercise In Patients With Congenital Long Qt Syndrome: Results Of The Prospective, Observational, Multinational Live-Lqts Study, Rachel Lampert, Sharlene Day, Barbara Ainsworth, Matthew Burg, Bradley S Marino, Lisa Salberg, Maria Teresa Tome Esteban, Dominic J Abrams, Peter F Aziz, Cheryl Barth, Elijah R Behr, Cheyanne Bell, Charles I Berul, Johan M Bos, David Bradley, David S Cannom, Bryan C Cannon, Maryann Anandi Concannon, Marina Cerrone, Richard J Czosek, Anne M Dubin, James Dziura, Christopher C Erickson, N A Mark Estes, Susan P Etheridge, Ilan Goldenberg, Belinda Gray, Carla Haglund-Turnquist, Kimberly Harmon, Cynthia A James, Christopher Johnsrude, Prince Kannankeril, Alice Lara, Ian H Law, Fangyong Li, Mark S Link, Silvana M Molossi, Brian Olshansky, Peter A Noseworthy, Elizabeth V Saarel, Shubhayan Sanatani, Maully Shah, Laura Simone, Jonathan Skinner, Gordon F Tomaselli, James Simon Ware, Gregory Webster, Wojciech Zareba, Douglas P Zipes, Michael J Ackerman

Faculty, Staff and Students Publications

Background: Whether vigorous exercise increases risk of ventricular arrhythmias for individuals diagnosed and treated for congenital long QT syndrome (LQTS) remains unknown.

Methods: The National Institutes of Health-funded LIVE-LQTS study (Lifestyle and Exercise in the Long QT Syndrome) prospectively enrolled individuals 8 to 60 years of age with phenotypic and/or genotypic LQTS from 37 sites in 5 countries from May 2015 to February 2019. Participants (or parents) answered physical activity and clinical events surveys every 6 months for 3 years with follow-up completed in February 2022. Vigorous exercise was defined as ≥6 metabolic equivalents for >60 hours per year. A …

Pediatric Glioma Immune Profiling Identifies Tim3 As A Therapeutic Target In Braf Fusion Pilocytic Astrocytoma, Shashwat Tripathi, Hinda Najem, Corey Dussold, Sebastian Pacheco, Ruochen Du, Moloud Sooreshjani, Lisa Hurley, James P Chandler, Roger Stupp, Adam M Sonabend, Craig M Horbinski, Rimas V Lukas, Joanne Xiu, Giselle Lopez, Theodore P Nicolaides, Valerie Brown, Nitin R Wadhwani, Sandi K Lam, Charles David James, Ganesh Rao, Maria G Castro, Amy B Heimberger, Michael Decuypere

Faculty, Staff and Students Publications

Despite being the leading cause of cancer-related childhood mortality, pediatric gliomas have been relatively understudied, and the repurposing of immunotherapies has not been successful. Whole-transcriptome sequencing, single-cell sequencing, and sequential multiplex immunofluorescence were used to identify an immunotherapeutic strategy that could be applied to multiple preclinical glioma models. MAPK-driven pediatric gliomas have a higher IFN signature relative to other molecular subgroups. Single-cell sequencing identified an activated and cytotoxic microglia (MG) population designated MG-Act in BRAF-fused, MAPK-activated pilocytic astrocytoma (PA), but not in high-grade gliomas or normal brain. T cell immunoglobulin and mucin domain 3 (TIM3) was expressed on MG-Act and …

Pediatric Glioma Immune Profiling Identifies Tim3 As A Therapeutic Target In Braf Fusion Pilocytic Astrocytoma, Shashwat Tripathi, Hinda Najem, Corey Dussold, Sebastian Pacheco, Ruochen Du, Moloud Sooreshjani, Lisa Hurley, James P Chandler, Roger Stupp, Adam M Sonabend, Craig M Horbinski, Rimas V Lukas, Joanne Xiu, Giselle Lopez, Theodore P Nicolaides, Valerie Brown, Nitin R Wadhwani, Sandi K Lam, Charles David James, Ganesh Rao, Maria G Castro, Amy B Heimberger, Michael Decuypere

Faculty, Staff and Students Publications

Despite being the leading cause of cancer-related childhood mortality, pediatric gliomas have been relatively understudied, and the repurposing of immunotherapies has not been successful. Whole-transcriptome sequencing, single-cell sequencing, and sequential multiplex immunofluorescence were used to identify an immunotherapeutic strategy that could be applied to multiple preclinical glioma models. MAPK-driven pediatric gliomas have a higher IFN signature relative to other molecular subgroups. Single-cell sequencing identified an activated and cytotoxic microglia (MG) population designated MG-Act in BRAF-fused, MAPK-activated pilocytic astrocytoma (PA), but not in high-grade gliomas or normal brain. T cell immunoglobulin and mucin domain 3 (TIM3) was expressed on MG-Act and …

Personalized Neoantigen Vaccines As Early Intervention In Untreated Patients With Lymphoplasmacytic Lymphoma: A Non-Randomized Phase 1 Trial, Szymon J Szymura, Lin Wang, Tiantian Zhang, Soung-Chul Cha, Joo Song, Zhenyuan Dong, Aaron Anderson, Elizabeth Oh, Vincent Lee, Zhe Wang, Sapna Parshottam, Sheetal Rao, Jasper B Olsem, Brandon N Crumpton, Hans C Lee, Elisabet E Manasanch, Sattva Neelapu, Larry W Kwak, Sheeba K Thomas

Faculty, Staff and Student Publications

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. …

Phase I Trial Of Gd2cart Cells Augmented With Constitutive Interleukin-7 Receptor For Treatment Of High-Grade Pediatric Cns Tumors, Frank Y Lin, Austin Stuckert, Candise Tat, Mark White, Lucia Ruggieri, Huimin Zhang, Birju Mehta, Natalia Lapteva, Zhuyong Mei, Angela Major, Sachin Thakkar, Thomas Shum, Kathan Parikh, Meng-Fen Wu, Holly B Lindsay, Lauren Scherer, Meghan Shekar, Patricia Baxter, Tao Wang, Bambi Grilley, Karen Moeller, John Hicks, Angshumoy Roy, Jamie Anastas, Fatema Malbari, Guillermo Aldave, Murali Chintagumpala, Susan Blaney, D Williams Parsons, Malcolm K Brenner, Helen E Heslop, Cliona M Rooney, Bilal Omer

Center for Medical Ethics and Health Policy Staff Publications

Purpose: T cells modified with chimeric antigen receptors (CARTs) have demonstrated efficacy for hematologic malignancies; however, benefit for patients with CNS tumors has been limited. To enhance T cell activity against GD2+ CNS malignancies, we modified GD2-directed CART cells (GD2.CARTs) with a constitutively active interleukin (IL)-7 receptor (C7R-GD2.CARTs).

Methods: Patients age 1-21 years with H3K27-altered diffuse midline glioma (DMG) or other recurrent GD2-expressing CNS tumors were eligible for this phase I trial (ClinicalTrials.gov identifier: NCT04099797). All subjects received standard-of-care adjuvant radiation therapy or chemotherapy before study enrollment. The first treatment cohort received GD2.CARTs alone (1 × 107 cells/m2), and …

Dual Inhibition Of The Trka And Jak2 Pathways Using Entrectinib And Pacritinib Suppresses The Growth And Metastasis Of Her2-Positive And Triple-Negative Breast Cancers, Angelina T Regua, Shivani Bindal, Mariana K Najjar, Chuling Zhuang, Munazza Khan, Austin B J Arrigo, Anneliese O Gonzalez, Xinhai R Zhang, Jay-Jiguang Zhu, Kounosuke Watabe, Hui-Wen Lo

Faculty, Staff and Student Publications

HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness …

Absence Of Motor Impairments Or Pathological Changes In Tmem230 Knockout Rats, Wenjuan Zhang, Hao Peng, Daihe Yang, Guohua Song, Juan He, Yun Zhou, Cao Huang, Bo Huang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Parkinson's disease (PD), which is the second most common neurodegenerative disorder, is characterized by progressive movement impairment and loss of midbrain dopaminergic neurons in the substantia nigra. Although mutations in TMEM230 are linked to familial PD, the pathogenic mechanism underlying TMEM230-associated PD remains to be elucidated. To explore the effect of TMEM230 depletion in vivo, we created TMEM230 knockout rats using CRISPR-Cas9 technology. TMEM230 knockout rats did not exhibit any core features of PD, including impaired motor function, loss of dopaminergic neurons in the substantia nigra, or altered expression of proteins related to autophagy, the Rab family, or vesicular trafficking. …

Proximity Analysis Of Native Proteomes Reveals Phenotypic Modifiers In A Mouse Model Of Autism And Related Neurodevelopmental Conditions, Yudong Gao, Daichi Shonai, Matthew Trn, Jieqing Zhao, Erik J Soderblom, S Alexandra Garcia-Moreno, Charles A Gersbach, William C Wetsel, Geraldine Dawson, Dmitry Velmeshev, Yong-Hui Jiang, Laura G Sloofman, Joseph D Buxbaum, Scott H Soderling

Faculty, Staff and Students Publications

One of the main drivers of autism spectrum disorder is risk alleles within hundreds of genes, which may interact within shared but unknown protein complexes. Here we develop a scalable genome-editing-mediated approach to target 14 high-confidence autism risk genes within the mouse brain for proximity-based endogenous proteomics, achieving the identification of high-specificity spatial proteomes. The resulting native proximity proteomes are enriched for human genes dysregulated in the brain of autistic individuals, and reveal proximity interactions between proteins from high-confidence risk genes with those of lower-confidence that may provide new avenues to prioritize genetic risk. Importantly, the datasets are enriched for …

Loss Of Transient Receptor Potential Channel 5 Causes Obesity And Postpartum Depression, Yongxiang Li, Tessa M Cacciottolo, Na Yin, Yang He, Hesong Liu, Hailan Liu, Yuxue Yang, Elana Henning, Julia M Keogh, Katherine Lawler, Edson Mendes De Oliveira, Eugene J Gardner, Katherine A Kentistou, Panayiotis Laouris, Rebecca Bounds, Ken K Ong, John R B Perry, Inês Barroso, Longlong Tu, Jonathan C Bean, Meng Yu, Kristine M Conde, Mengjie Wang, Olivia Ginnard, Xing Fang, Lydia Tong, Junying Han, Tia Darwich, Kevin W Williams, Yongjie Yang, Chunmei Wang, Shelagh Joss, Helen V Firth, Yong Xu, I Sadaf Farooqi

Duncan NRI Faculty and Staff Publications

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of …