Medicine and Health Sciences Commons^™

Germline Hla Heterozygosity Is Associated With Decreased Lung Cancer Risk, Taotao Tan, Vikram R Shaw, Jinyoung Byun, Hyun-Sung Lee, Younghun Han, Yafang Li, Rayjean J Hung, David C Christiani, Xin-An Wang, Mattias Johansson, Xiangjun Xiao, David Zaridze, Stig Egil Bojesen, Sanjay Shete, Demetrios Albanes, Melinda C Aldrich, Adonina Tardon, Guillermo Fernandez-Tardon, Loïc Le Marchand, Gad Rennert, Heike Bickeböller, H-Erich Wichmann, Angela Risch, John K Field, Michael Davies, Penella Woll, Lambertus A Kiemeney, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Mikael Johansson, Kjell Grankvist, Matthew B Schabath, Angeline Andrew, Philip Lazarus, Susanne M Arnold, Dakai Zhu, Maria Teresa Landi, James Mckay, Christopher Amos, Chao Cheng

Faculty, Staff and Students Publications

Heterozygosity at human leukocyte antigen (HLA) loci may improve lung cancer immunosurveillance by increasing recognition of the tumor by the immune system. Previous studies utilizing data from population-level biobanks, such as the United Kingdom Biobank and FinnGen, have identified an association between germline HLA class-II heterozygosity and reduced lung cancer risk in smokers. In the present study, we evaluate the association between HLA heterozygosity and lung cancer in a large case-control study (15,302 cases; 14,580 controls) with imputed HLA allele-type information, comparing differences in HLA heterozygosity between smokers and non-smokers, amongst lung cancer subtypes, and at 2- and 4-digit HLA …

Il-18 Metabolically Reprograms Car-Expressing Natural Killer T Cells And Enhances Their Antitumor Activity, Gabriel A Barragán Bravo, David A De La Cerda, Elisa Landoni, Kshiti Dholakia, Piotr Humeniuk, Leidy D Caraballo Galva, Ying Wang, Gengwen Tian, Boning Yang, Linjie Guo, Michael S Wood, Xavier Rios, Xin Xu, Amy N Courtney, Erica J Di Pierro, Joan Jacob, Yi-Han Li, Akshaya Adaikkalavan, Norihiro Watanabe, Sufeng Mao, George Miles, Gianpietro Dotti, Leonid S Metelitsa

Faculty, Staff and Students Publications

Invariant natural killer T cells (NKTs) have intrinsic anti-tumor properties that make them promising candidates for chimeric antigen receptor (CAR) immunotherapies. Transgenic cytokine expression can enhance cellular therapy potency, and we hypothesized that co-expressing IL-18 alone or with IL-15 would boost CAR-NKT therapeutic potential. To test this, we generated retroviral constructs expressing IL-15 and/or IL-18 with an inducible caspase 9 safety switch and co-transduced them with a GD2-specific CAR into human NKTs. Co-expression of IL-18 or IL-15/IL-18 increased CAR-NKT cytotoxicity, proliferation, and cytokine secretion in vitro compared to IL-15 alone. IL-18 also enhanced GPC3.CAR and CD19.CAR NKT activity against hepatocellular …

Transcriptomic Signature-Guided Depletion Of Intermediate Alveolar Epithelial Cells Ameliorates Pulmonary Fibrosis In Mice, Fei Peng, Chun-Sun Jiang, Zhen Zheng, Shahram Aliyari, Dan Shan, Aaryan Sabharwal, Qinyan Yin, Shigeki Saito, Chao He, Ivan O Rosas, Joseph A Lasky, Victor J Thannickal, Yong Zhou

Faculty, Staff and Students Publications

Single-cell RNA sequencing (scRNA-seq) has identified intermediate epithelial states in pulmonary fibrosis, including KRT5-/KRT17+ aberrant basaloid cells in humans and Krt8+ alveolar differentiation intermediates (ADIs) in mice. Their functional contributions to fibrogenesis, however, remain unclear. Here, we introduce an RNA-sensing-dependent protein translation technology that enables selective targeting of Krt8+ ADI cells in vitro and in vivo. Transcriptomic analysis revealed Small Proline-Rich Protein 1 A (SPRR1A) mRNA as a shared marker of murine Krt8+ ADIs and human KRT5-/KRT17+ basaloid cells, distinguishing them from other lung cell populations. Using programmable RNA sensors, we demonstrated selective EGFP-labeling of Krt8+ ADI cells in vivo, …

Plasma Proteomics And Incident Coronary Heart Disease, Matthew P Huber, Jennifer A Brody, Colleen M Sitlani, Thomas R Austin, Usman A Tahir, Shuliang Deng, Devendra Meena, Jingsha Chen, Kunihiro Matsushita, Christie M Ballantyne, Josef Coresh, Robert E Gerszten, Russell P Tracy, Ting Ye, Bruce M Psaty, Joshua C Bis, James S Floyd

Faculty, Staff and Students Publications

Background: Systematic profiling of plasma proteins in population studies offers a complementary approach to discovery of novel risk factors and may provide new insights into the causes of coronary heart disease.

Methods: To explore relationships between the circulating proteome and coronary heart disease (CHD), we evaluated associations of 4780 plasma proteins with incident CHD in the Cardiovascular Health Study (CHS, N=2856, 575 CHD events) and replicated significant associations in the Atherosclerosis Risk in Communities Study (ARIC, N = 10456; 1375 events).

Results: We find that 11 proteins significantly associate with incident CHD after adjusting for risk factors; and eight significantly …

Maternal Immunization With Vp8* Mrna Vaccine Yields Superior Passive Transfer Of Rotavirus-Neutralizing Antibodies To Foals, Karin E R Borba, Rebecca M Legere, Nathan M Canaday, Jill W Skrobarczyk, Zachary W T Arnold, Elena Cotton-Betteridge, Cristina Poveda, Michael F Criscitiello, Angela I Bordin, Luc R Berghman, Jeroen B K Pollet, Noah D Cohen

Faculty, Staff and Students Publications

Background: Despite the availability of a killed whole-virus (KV) vaccine, diarrhea caused by equine rotavirus group A (ERVA) remains a significant health concern for foals in the United States. The vaccine is administered to pregnant mares, with foals protected by passive transfer of colostral antibodies. However, KV-induced immunity is only partially protective and maternal antibody levels in foals are often low and wane rapidly. To address these limitations, we developed a mRNA-based ERVA vaccine encoding the highly conserved VP8* protein to evaluate whether it can provide improved immune protection.

Methods: Pregnant mares (n = 12 per group) were …

Primary Cortical Neurons Precipitate And Extrude Large Mitochondria-Associated Calcium-Phosphate Sheets With A Bone-Precursor-Like Ultrastructure, Erik D Anderson, Christopher A Cronkite, Philip R Baldwin, Carlota P Abella, Joseph G Duman, Ashleigh N Simmonds, M Neal Waxham, Kimberley F Tolias, Steven J Ludtke

Faculty, Staff and Students Publications

Calcium-phosphate (CaP) is a ubiquitous inorganic compound that plays an important structural role in healthy bone and teeth formation, but its pathologic buildup can occur in dyshomeostatic calcium disorders like Alzheimer's disease and Leigh syndrome. The nexus of pathologic extracellular CaP in the nervous system is not well understood, but prior evidence suggests mitochondria could be a source. We have observed mitochondria-sized sheet-like CaP aggregates within functional wild type cortical neuron cultures at 1 and 20 days in vitro. Neurons were extracted from embryonic day 18 (E18) rat embryos following standard protocols to study neuronal structure and function. We have …

Longitudinal Observation Of Children With Achondroplasia: Findings From A Global Natural History Study (Achieve), Ciara Mcdonnell, Hanne Buciek Hove, Melita Irving, Klane K White, Cesar G Fontecha, Janet M Legare, Wolfgang Högler, Daniel G Hoernschemeyer, Dirk Schnabel, Sheila Unger, Carlos Alberto Bacino, Paul Hofman, Yongguo Yu, Huamei Ma, Chunxiu Gong, Xiaoping Luo, T Andrew Burrow, Geneviève Baujat, Stefano Mora, Melissa Fiscaletti, Carol Zhao, Michael A Makara, Aimee D Shu, Ravi Savarirayan

Faculty, Staff and Students Publications

Introduction: The ACHieve study assessed growth velocity, body proportionality, and clinical events in children with achondroplasia not receiving growth-promoting therapy.

Methods: ACHieve was a global, longitudinal, prospective, observational study. Children ≤8 years old with achondroplasia were enrolled and evaluated every 6 months for anthropometric parameters and clinical events.

Results: ACHieve enrolled 259 children in 15 countries, including 83 from China. Median follow-up was 21 months; median age of diagnosis was approximately 52 weeks in China and 2 weeks elsewhere. Growth parameters were similar regardless of region. Mean annualized growth velocity was 9.3 cm/year for males and 10.4 cm/year for females …

Spatially Resolved Integrative Analysis Of Transcriptomic And Metabolomic Changes In Tissue Injury Studies, Eleanor C Williams, Lovisa Franzén, Martina Olsson Lindvall, Gregory Hamm, Steven Oag, Muntasir Mamun Majumder, James Denholm, Azam Hamidinekoo, Javier Escudero Morlanes, Marco Vicari, Joakim Lundeberg, Laura Setyo, Trevor M Godfrey, Livia S Eberlin, Aleksandr Zakirov, Jorrit J Hornberg, Marianna Stamou, Patrik L Ståhl, Anna Ollerstam, Jennifer Y Tan, Irina Mohorianu

Faculty, Staff and Students Publications

Recent developments in spatially resolved -omics have enabled the joint study of gene expression, metabolite levels and tissue morphology, offering greater insights into biological pathways. Integrating these modalities from matched tissue sections to probe spatially-coordinated processes, however, remains challenging. Here we introduce MAGPIE, a framework for co-registering spatially resolved transcriptomics, metabolomics, and tissue morphology from the same or consecutive sections. We show MAGPIE's generalisability and scalability on spatial multi-omics data from multiple tissues, combining Visium with MALDI and DESI mass spectrometry imaging. MAGPIE was also applied to new multi-modal datasets generated with a specialised sampling strategy to characterise the metabolic …

Machine Learning-Based Multimodal Biomarkers Enable Accurate Diagnosis And Early Detection Of Pancreatic Ductal Adenocarcinoma, Tsung-Hung Yao, Warapen Treekitkarnmongkol, Nagireddy Putluri, Deivendran Sankaran, Tristian Nguyen, Seetharaman Balasenthil, Mark W Hurd, Meng Chen, Randall E Brand, Paul D Lampe, Abu Hena M Kamal, Vasanta Putluri, Tony Y Hu, Anirban Maitra, Eugene J Koay, Ann M Killary, Subrata Sen, Suprateek Kundu

Faculty, Staff and Students Publications

While there has been some progress on discovering clinically validated biomarkers for early detection in pancreatic ductal adenocarcinoma (PDAC), several challenges remain. Most approaches rely on single-modality biomarkers with limited sensitivity and/or specificity. Using data from a multicenter study with an age-matched cohort (n = 203 with healthy controls n = 46, pancreatitis controls n = 36, and diagnosed cases n = 121), we developed a machine learning approach integrating 2,096 microRNAs, 125 metabolites, and CA19-9. Our method performs unsupervised selection of an optimal subset of biomarkers with maximal discriminatory power for diagnosis and early detection. In training data, the …

Pathways, Outputs And Impact Of Nih-Supported Bioinformatics And Genomics Graduate Trainees In Africa, Daudi Jjingo, Andrew Walakira, Suhaila Hashim, Cisse Cheickna, Ronald Galiwango, Caleb Kibet, Florence N Kivunike, Gerald Mboowa, Fredrick Elishama Kakembo, Babajide Ayodele, Jean-Baka Domelevo Entfellner, Santie De Villiers, Karen Wambui, Segun Fatumo, Tinashe Chikowore, John Mukisa, Alfred Ssekagiri, Nicholas Bbosa, Julius Mulindwa, Samuel Kyobe, Mike Nsubuga, Grace Kebirungi, Eric Katagirya, Savannah Mwesigwa, Ibra Lujumba, Rogers Kamulegeya, Samuel Kirimunda, Stephen Kanyerezi, Shahiid Kiyaga, Ivan Sserwadda, Davis Kiberu, Bernard S Bagaya, Julius Okwir, Patricia Nabisubi, Grace Nabakooza, Mugume Twinamatsiko Atwine, Ricard Sserunjogi, Rolanda Julius, Mariam Quiñones, Meghan Mccarthy, Phillip Cruz, Karlynn Noble, Christopher J Whalen, Darrell Hurt, Maria Y Giovanni, Michael Tartakovsky, Deogratius Ssemwanga, John M Kitayimbwa, Steven J Reynolds, Christopher C Whalen, Andrew Kambugu, Neil A Hanchard, Li Jian, Peter Amoako-Yirenkyi, Graeme Mardon, I King Jordan, Samson Pandam Salifu, Mamadou Wele, Ezekiel Adebiyi, Jeffrey G Shaffer, Seydou Doumbia, David Patrick Kateete, Michelle Skelton, Nicola Mulder, Jonathan K Kayondo, Daniel Masiga, H3africa Consortium

Faculty, Staff and Students Publications

Global biomedical and health research is increasingly relying on genomic and computational approaches, largely driven by the increasing volumes of nucleic acid sequencing. Concurrently, epidemiological studies and clinical records are generating enormous amounts of data amenable to disease modeling, machine learning, and artificial intelligence techniques. Bioinformatics and data science expertise is therefore essential for improved population health. Accordingly, in 2012, the US National Institutes of Health (NIH) in partnership with the Wellcome Trust, and with support from the African Society for Human Genetics, initiated the H3Africa (Human Heredity and Health in Africa) consortium. One of its key goals was to …

Erratum For Nachman Et Al., “Increased Fungal Burden In The Gastrointestinal Tract Of Brain-Dead Organ Donors”, Erika J Nachman, Colleen K Ardis, A Kyle B Ardis, Javier Nieto, Madeline M Bresson, Clare M Robertson, Maggie N Seale, Nora M Villafuerte, Zhe Lyu, Eva C Preisner, Heather A Danhof, Sara C Di Rienzi, Yolanda T Becker, Robert A Britton

Faculty, Staff and Students Publications

No abstract provided.

Predicting Sepsis In Heart Failure Patients Supported By Left Ventricular Assist Devices: The Role Of Ve-Cadherin And Adam10, Shiyi Li, Iván Murrieta-Álvarez, Ismael Garcia, Katherine V Nordick, Rishav Bhattacharya, Shreyo Ghosh, Ronald A Shaju, Adel M Hassan, Carl P Walther, Camila Hochman-Mendez, Alexis E Shafii, Kenneth K Liao, Nandan K Mondal

Faculty, Staff and Students Publications

Vascular endothelial cadherin (VE-Cadherin) is a major endothelial adhesion molecule and can be cleaved explicitly by metalloproteinase domain-containing protein 10 (ADAM10). Vascular hyperpermeability may contribute to a greater susceptibility to sepsis in left ventricular assist device (LVAD) support patients. We aim to evaluate the efficacy of VE-Cadherin and ADAM10 for predicting sepsis in LVAD patients. We prospectively recruited 50 patients with advanced heart failure receiving LVAD therapy. Baseline and weekly postoperative blood samples (weeks 1-4) were collected, and plasma VE-cadherin and ADAM10 levels were measured. Sepsis occurred in 9 of 50 patients (18.0%). Across all sampling points, plasma VE-cadherin and …

Neuronal Subtype Governs Amyloid Structure, Cellular Response, And Cognitive Outcome In Genetically Targeted App Mouse Models, Gabriella A Perez, Zoe Lai, George A Edwards Iii, Jacob M Dundee, Shannon N Leahy, Chuangye Qi, Yanyan Qi, Ye-Jin Park, Tzu-Chiao Lu, M Danish Uddin, Rong Zhao, Hui Zheng, Hongjie Li, Joanna L Jankowsky

Faculty, Staff and Students Publications

Pathological heterogeneity is increasingly appreciated in Alzheimer’s disease, yet we do not know how distinct aggregate conformations arise or influence cognitive outcomes. In an amyloid mouse model, we found that different brain regions formed structurally distinct Aβ deposits, prompting us to test whether neuronal subtypes shape aggregate conformation. To address this, we created transgenic mice expressing the same APP construct in either glutamatergic or GABAergic neurons. APP expression in GABAergic neurons resulted in diffuse plaques with high Aβ42/Aβ40 ratios and minimal gliosis, while glutamatergic expression produced neuritic plaques with activated glia. Despite similar Aβ levels, only mice with neuritic plaques …

A Systematic Literature Review Of Cvid Reveals Pervasive Detrimental Noninfectious Manifestations, G Michelle Ducasa, Rebecca A Marsh, Ali Mojebi, Hsi-En Ho, Charlotte Cunningham-Rundles, Lisa Forbes Satter, Elena W Y Hsieh, Sinisa Savic, Marta Dafne Cabañero-Navalón, Hector Balastegui-Martin, Joud Hajjar, Gulbu Uzel, Kevin S Thorneloe, Jocelyn R Farmer

Faculty, Staff and Students Publications

Noninfectious manifestations of common variable immunodeficiency (CVID) are not formally summarized. We performed a systematic literature review to generate a comprehensive reference for the field. Splenomegaly was the most reported manifestation across 53 publications, occurring in a median of 35.2% of patients. Frequently reported digestive system manifestations included diarrhea (median 27.8%; 21 publications), hepato(spleno)megaly (median, 21.0%; 19 publications), portal hypertension (median 21.0%; 3 publications), nodular lymphoid hyperplasia (median, 17.0%; 9 publications), and enteropathy (median, 16.0%; 34 publications). Other notable manifestations included interstitial lung disease (median, 8.7%; 32 publications) and autoimmune cytopenias (median 18.0%; 21 publications). Steroids and rituximab were the …

Neurodevelopmental Outcomes Following Hematopoietic Cell Transplantation For Patients With Severe Combined Immunodeficiency (Scid): A Pidtc Study, Virdette L Brumm, Sharon A Kidd, Brent R Logan, Farheen Chunara, Jennifer Heimall, Linda M Griffith, Donald B Kohn, Lauren Sanchez, Jeffrey J Bednarski, Caridad Martinez, Mark Vander Lugt, Neena Kapoor, Nicola Wright, Barbara Spitzer, Joseph H Oved, Sharat Chandra, Deepak Chellapandian, Christen L Ebens, Aleks Petrovic, Ahmad Rayes, Hilary L Haines, Hannah Lust, Hannah-Lise Tirado Schofield, Lauren Christopher, Lynnette L Harris, Lisa Forbes Satter, Lauri Burroughs, Christopher C Dvorak, Elie Haddad, Jennifer W Leiding, Rebecca A Marsh, Luigi D Notarangelo, Sung Yun Pai, Michael A Pulsipher, Jennifer M Puck, Morton J Cowan, Ami J Shah

Faculty, Staff and Students Publications

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for severe combined immunodeficiency (SCID). Since the initiation of newborn screening (NBS), survival rates have improved significantly, but the impact of HCT upon neurodevelopment for patients with SCID requires more investigation. We performed a cross-sectional study of subjects with SCID in North America to assess the impact of NBS, transplant conditioning regimen, and genotype on neurodevelopmental outcomes after HCT. 69 subjects with SCID from 17 PIDTC centers (excluding those with ADA deficiency), ages 6-16 years, received comprehensive standardized neurodevelopmental testing of cognitive, behavioral, and emotional function. Compared with the normative population, …

Vacmap: An Accurate Long-Read Aligner For Unraveling Complex Genomic Rearrangements, Hongyu Ding, Fritz J Sedlazeck, Christos Proukakis, Caoimhe Morley, Marco Toffoli, Anthony Hv Schapira, Zhirui Liao, Lianrong Pu, Shanfeng Zhu

Faculty, Staff and Students Publications

Sequence alignment is essential for genomic research and clinical diagnostics, yet detecting complex rearrangements such as inversions, duplications, and gene conversions remains challenging due to allele complexity and limitations of current methods. We introduce VACmap, a non-linear mapping approach to enhance the detection and representation of all genetic variations. VACmap improves duplication detection from 20% to 90% in the Challenging Medically-Relevant Genes (CMRG) benchmark and improves characterization of complex inversions in repetitive regions and gene conversion events. It improves resolving clinically significant loci, including the LPA gene (with repetitive KIV-2 units linked to coronary heart disease), GBA1 and STRC genes …

Performance Of A Rapid, Highly Multiplexed Nucleic Acid Detection Assay For Identification Of Viral And Bacterial Pathogens From Upper Respiratory Tract Specimens, Coreen L Johnson, James J Dunn

Faculty, Staff and Students Publications

Background: Accurate and timely identification of upper respiratory tract pathogens can improve patient management by decreasing unnecessary additional testing, reducing the cost of care, and informing antimicrobial stewardship. We evaluated the FDA-cleared Diasorin LIAISON PLEX® Respiratory Flex (RSP Flex), a highly multiplexed, rapid nucleic acid detection assay that can identify 14 viral and 5 bacterial respiratory pathogens.

Methods: In total, 215 residual patient upper respiratory tract specimens were tested using the RSP Flex assay and results compared to standard-of-care (SOC) molecular testing.

Results: Positive percentage agreement (PPA) was 100% for the following targets: adenovirus, human coronavirus, Bordetella pertussis, Bordetella parapertussis, …

Machine Learning Models Predict Long Covid Outcomes Based On Baseline Clinical And Immunologic Factors, Naresh Doni Jayavelu, Hady Samaha, Sonia Tandon Wimalasena, Annmarie Hoch, Jeremy P Gygi, Gisela Gabernet, Al Ozonoff, Shanshan Liu, Carly E Milliren, Ofer Levy, Lindsey R Baden, Esther Melamed, Lauren I R Ehrlich, Grace A Mccomsey, Rafick P Sekaly, Charles B Cairns, Elias K Haddad, Joanna Schaenman, Albert C Shaw, David A Hafler, Ruth R Montgomery, David B Corry, Farrah Kheradmand, Mark A Atkinson, Scott C Brakenridge, Nelson I Agudelo Higuit, Jordan P Metcalf, Catherine L Hough, William B Messer, Bali Pulendran, Kari C Nadeau, Mark M Davis, Linda N Gen, Ana Fernandez Sesma, Viviana Simon, Florian Krammer, Monica Kraft, Chris Bime, Carolyn S Calfee, David J Erle, Charles R Langelier, Leying Guan, Holden T Maecker, Bjoern Peters, Steven H Kleinstein, Elaine F Reed, Alison D Augustine, Joann Diray-Arce, Patrice M Becker, Nadine Rouphael, Matthew C Altman

Faculty, Staff and Students Publications

Background: The post-acute sequelae of SARS-CoV-2 (PASC), also known as long COVID, remain a significant health issue that is incompletely understood. Predicting which acutely infected individuals will develop long COVID is challenging due to the absence of established biomarkers, clear disease mechanisms, or well-defined sub-phenotypes. Machine learning (ML) models may address this gap by leveraging clinical data to enhance diagnostic precision.

Methods: Clinical data, including antibody titers and viral load measurements collected at the time of hospital admission, are used to predict the likelihood of acute COVID-19 progressing to long COVID. Machine learning models are trained and evaluated for predictive …

Anti-Csf-1r Therapy With Combined Immuno-Chemotherapy Coordinate An Adaptive Immune Response To Eliminate Macrophage Enriched Triple Negative Breast Cancers, Diego A Pedroza, Xueying Yuan, Fengshuo Liu, Hilda L Chan, Christina Zhang, William Bowie, Alex J Smith, Sebastian J Calderon, Nadia Lieu, Weiguo Wu, Paul Porter, Poonam Sarkar, Na Zhao, Constanze V Oehler, Ondrej Peller, M Waleed Gaber, Qian Zhu, Charles M Perou, Xiang H-F Zhang, Jeffrey M Rosen

Faculty, Staff and Students Publications

Women diagnosed with metastatic triple negative breast cancer (mTNBC) have limited treatment options, are more prone to develop resistance and are associated with high mortality. A cold tumor immune microenvironment (TIME) characterized by low T cells and high tumor associated macrophages (TAMs) in mTNBC is associated with the failure of standard-of-care chemotherapy and immune checkpoint blockade (ICB) treatment. We demonstrate that the combination of immunomodulatory low-dose Cyclophosphamide (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic Trp53 null TNBC transplantable syngeneic models that present with high macrophage infiltration. Mechanistically, CSF-1R inhibition along …

Findings And Recommendations From The State Of The Art (Sota) Conference On Nursing Research To Improve Veteran Outcomes, Amelia E Schlak, Sarah Krein, Laura A Petersen, David Atkins, Catherine Battaglia, Elizabeth Burkhart, Renee Colsch, Marguerite Daus, Heather Gilmartin, Nipa Kamdar, Melissa Knox, Ann Kutney-Lee, Christine M Olney, Kathryn Rugen, Tracy Weistreich, Sheila Cox Sullivan, On Behalf The Nursing Sota Planning Committee

Faculty, Staff and Students Publications

The Veterans Health Administration (VHA), the largest employer of nurses in the United States, has more than 120,000 nursing personnel providing care to over 9 million Veterans across diverse settings. Despite nursing's central role in delivering and sustaining care, research on strengthening the nursing workforce and optimizing nursing practice has remained underdeveloped in VHA. To address this gap, VHA's Office of Research and Development, in partnership with the Office of Nursing Services, convened a State of the Art (SOTA) conference in November 2023 focused on nursing. The Nursing SOTA brought together nurses, researchers, operational leaders, and other stakeholders to review …

Inducible Pou Class 2 Homeobox 3 Expression In Human Intestinal Organoids As A Model Of Human Tuft Cells, Carolyn Bomidi, Luqiong Wang, Hoa Nguyen-Phuc, Mary K Estes, Sarah E Blutt

Faculty, Staff and Students Publications

No abstract provided.

Sewers To Solutions: A Guide To Wastewater Pathogen Monitoring, Justin R Clark, Anthony W Maresso

Faculty, Staff and Students Publications

Wastewater-based epidemiology (WBE) is the analysis of wastewater to detect pathogen levels or activity for public health awareness or action. Pioneered in the 1940s, WBE underwent a resurgence during the COVID-19 pandemic, providing important information about number of cases, outbreaks, and seasonal impact. With advancements in detection technologies and growing interest in environmental surveillance, WBE is poised to become a standard practice in public health monitoring. Here, we provide an overview of the current state of the art of pathogen WBE, including methods of molecular detection, analysis of wastewater data, real-world applications and programs, public health interventions, and benefits and …

Editorial: Advances In Phage Applications: Deciphering Phage Biological And Ecological Mechanisms Through Metagenomics, Tasha M Santiago-Rodriguez, Gary A Toranzos

Faculty, Staff and Students Publications

No abstract provided.

Identification Of Cand1 As A Dna-Dependent Protein Kinase-Regulated Coactivator Of Androgen Receptor And The Arv7 Splice Variant, Ross A Hamilton, Basil Paul, Ping Yi, Kimal Rajapakshe, Anil K Panigrahi, Sandra L Grimm, Cristian Coarfa, Anna Malovannaya, Nancy L Weigel, David M Lonard, Charles E Foulds

Faculty, Staff and Students Publications

ARv7, the most prevalent androgen receptor (AR) variant in castration-resistant prostate cancer, lacks the ligand binding domain (LBD), rendering it resistant to LBD-targeted therapies. Identifying new therapeutic targets requires defining the coregulators and associated regulatory enzymes that govern AR and ARv7 transcriptional activity. Here, we have developed a cell-free DNA pulldown assay employing androgen response elements (AREs) to isolate and characterize the AR- and ARv7-associated coregulator complexes formed on DNA. Mass spectrometry analyses of ARE DNA pulldowns revealed previously unrecognized AR and ARv7 associating coregulators, such as cullin-associated NEDD8-dissociated protein 1 (CAND1), in addition to previously known coregulators. ARv7 showed …

Helicobacter Pylori And Cancer: What's The Link?, Elettra Merola, Giovanni Mario Pes, David Yates Graham, Maria Pina Dore

Faculty, Staff and Students Publications

Helicobacter pylori (H. pylori) is a human bacterial pathogen that causes one of the most common chronic bacterial infections worldwide. The microorganism has been classified by the International Agency for Research on Cancer as a Group I carcinogen. While the etiological link to gastric cancer is well established, the precise molecular and cellular mechanisms driving this transformation are highly complex and incompletely understood. Fundamentally, the infection results from the chronic presence of acute on chronic gastric mucosal inflammation. H. pylori pathogenicity is increased by bacterial virulence factors including the cytotoxin-associated gene A (CagA) and Vacuolating cytotoxin A (VacA) …

Autologous Multiantigen-Targeted T Cell Therapy For Pancreatic Cancer: A Phase 1/2 Trial, Benjamin L Musher, Spyridoula Vasileiou, Brandon G Smaglo, Catherine S Robertson, Mengfen Wu, Tao Wang, Ayumi Watanabe, Manik Kuvalekar, Yovana Velazquez, Shamika Ketkar, Tamadar Al Doheyan, Penelope G Papayanni, Aakash Shah, Natalia Lapteva, Bambi J Grilley, George Van Buren, Premal D Lulla, Helen E Heslop, Cliona M Rooney, Malcolm K Brenner, Ann M Leen

Faculty, Staff and Students Publications

T cell therapy has proven challenging for pancreatic ductal adenocarcinoma (PDAC), partly due to heterogeneous expression of tumor-associated antigens (TAAs). To address tumor heterogeneity and mitigate immune evasion, an ex vivo expanded, polyclonal, T helper 1 cell-polarized T cell product targeting five TAAs—PRAME, SSX2, MAGEA4, Survivin and NY-ESO-1—was developed. These antigens were chosen based on their tumor specificity, oncogenicity, immunogenicity and level of expression. In a phase 1/2 trial, this autologous nonengineered T cell product was administered (1 × 107 cells m−2 per infusion) monthly to patients with advanced PDAC responding (arm A, n = 13) or refractory (arm B, …

Discovery Of Genetic Susceptibility Variants In Pediatric And Adult Ependymoma, Joshua D Strauss, Priya B Shetty, Spiridon Tsavachidis, Jinyoung Byun, Stephen C Mack, Xiao Xiangjun, Terri S Armstrong, Mark R Gilbert, (On Behalf Of Nci-Connect);, Lisa Mirabello, Smita Bhatia, Wendy M Leisenring, Lindsay M Morton, Gregory T Armstrong, Jon Foss-Skiftesvik, Christian Munch Hagen, Jonas Bybjerg-Grauholm, (On Behalf Of Gicc), Manel Ghozal, Audrey Bonaventure, Jacqueline Clavel, Melissa L Bondy, Christopher I Amos, Thanh T Hoang, Michael E Scheurer

Faculty, Staff and Students Publications

Background: Ependymoma is a malignancy of the neuroepithelium-derived ependyma that lines the spinal cord and ventricles of the brain, occurring most frequently in young children and older adults. Genetic susceptibility to ependymoma has proven difficult to assess due to disease rarity.

Methods: We performed genome-wide association studies (GWAS) of 478 ependymoma patients and 4,841 disease-free controls of European ancestry. Ependymoma patients consisted of 117 children (< 18 years old) with whole-genome sequencing (WGS), 142 children with genotyping, and 219 adults (≥18 years old) with genotyping. Genotyped samples were imputed using the 1,000 Genomes Project as the reference panel and underwent quality control filtering. The GWAS was performed separately by age group and technology (genotyped or WGS). GWAS variants were considered significant at P < 5 × 10-8.

Results: Among pediatric subjects with WGS data, we identified a significant intronic variant in EDIL3 (rs149378, P = 1.9 × 10-8) and a nearly significant intronic variant in LHX4 (rs79008224, P = 7.2 …

From Local Burden To Global Threat: Neglected Tropical Diseases In An Era Of Climate Change And Human Mobility, Francisco Javier Membrillo, Juan-Carlos Navarro, Diana Marcela Pava-Garzón, Jill Weatherhead, José A Suárez, Alfonso J Rodriguez-Morales

Faculty, Staff and Students Publications

No abstract provided.

Δnp63 Defines An Exocrine-Committed Subset Of Murine Pancreatic Progenitor Cells, Katarina Coolens, Melissa Van Der Vliet, Jente Van Campenhout, Natalia Del Pozo, Alejo Torres-Cano, Catharina Olsen, Jianming Xu, Rose-Anne Romano, Heiko Lickert, Meritxell Rovira, Isabelle Houbracken, Jonathan Baldan, Francisco X Real, Francesca M Spagnoli, Ilse Rooman

Faculty, Staff and Students Publications

No abstract provided.

Once-Weekly Navepegritide In Children With Achondroplasia: The Approach Randomized Clinical Trial, Ravi Savarirayan, Ciara Mcdonnell, Carlos A Bacino, Daniel G Hoernschemeyer, Janet M Legare, M Jennifer Abuzzahab, Paul L Hofman, Philippe M Campeau, Josep Maria De Bergua Domingo, Leanne M Ward, Kevin Smit, Alden Smith, Meng Mao, Michael S Ominsky, Lærke C Freiberg, Aimee D Shu, Hanne B Hove

Faculty, Staff and Students Publications

Importance: Historically considered a skeletal dysplasia characterized by disproportionate short stature, achondroplasia is a condition with multisystemic effects due to the widespread expression of the fibroblast growth factor receptor 3 variant throughout the body, impacting muscle, neurological function, cardiorespiratory health, and health-related quality of life.

Objective: To evaluate the efficacy, safety, and tolerability of once-weekly navepegritide, an investigational prodrug of C-type natriuretic peptide, while assessing benefits beyond growth that may have important implications for complications and health-related quality of life in children with achondroplasia.

Design, setting, and participants: Enrollment for this pivotal phase 2b, randomized, double-blind, placebo-controlled trial (APPROACH) was …