Digital Commons Network^™

B Lymphocytes Impede Tregs To Erode Islet Tolerance In Type 1 Diabetes, Christopher S Wilson, Blair T Stocks, Alexander C Falk, Daniel J Moore

Faculty, Staff and Students Publications

B lymphocytes are thought to drive β-cell destruction in type 1 diabetes (T1D) by activating anti-islet T cells. However, the observation that autoreactive T-cell activation and disease progression can occur without B cells challenges this view. Still, preclinical and clinical studies have shown that B-cell depletion alleviates β-cell destruction, suggesting a critical role for B cells in T1D. Our findings propose an alternative function for B cells, impairing regulatory T cells (Tregs) that would otherwise protect islets. In the NOD islet transplant model, we show that B-cell absence enables transplant tolerance, allowing Tregs to become responsive to immune therapy and …

The Evolution Of Public Health Statistical Modeling Approaches And How To Advance Their Incorporation Into Modern Arboviral Surveillance, Maggie Mccarter, Stella C W Self, Alex Ewing, Mufaro Kanyangarara, Sarah M Gunter, Melissa S Nolan

Faculty, Staff and Students Publications

Statistical modeling of infectious disease transmission patterns has been in existence since the mid-1700s, evolving in their utility as the scientific and technological revolutions progressed. Despite the expansion of emerging mathematical and statistical methodologies over the past 250 yr, their usage has largely remained restricted to academic settings. This forum article will discuss the evolution of disease modeling techniques, the most common types of models in use today, and recommendations on how key archetypes can be incorporated into future public health practice. With the recent global impetus to predict and forecast novel pathogens, this article raises the question: Why are …

The Use Of Artificial Intelligence In Decreasing Vaccine Skepticism And Hesitancy, Nathaniel Wolf, Nhan Nguyen, Rojelio Mejia

Faculty, Staff and Students Publications

Purpose of review: Recent advances in artificial intelligence (AI) coincide with decreases in confidence in vaccines. This review examines studies that analyze and mitigate vaccine skepticism by implementing artificial intelligence strategies in various ways.

Recent findings: Studies have explored public attitudes towards vaccines using AI to analyze language in social media postings and interactions, scrutinize AI responses to vaccine-related queries, and attempt to use AI to directly influence vaccine hesitancy. Findings show that AI can be effective in addressing vaccine hesitancy in various ways, including, but not limited to, directly interacting with vaccine-hesitant groups, identifying reasons for vaccine hesitancy, and …

Radionuclide-Stimulated Dynamic Therapy Induces Complementary Immunogenic Necroptosis And Apoptosis Cancer Cell Death Pathways, Christopher Egbulefu, Kvar Black, Xinming Su, Partha Karmakar, Lemoyne Habimana-Griffin, Gail Sudlow, Julie Prior, Ezugo Onejeme, Alex Zheleznyak, Baogang Xu, Yalin Xu, Alison Esser, Matthew Mixdorf, Evan Moss, Brad Manion, Cody Hongsermeier, Nisha Gamadia, Nicole Blasi, Luke Stallings, Chidube Alagbaoso, Nathan Reed, Matthew M Gubin, Chieh-Yu Lin, Robert Schreiber, Katherine Weilbaecher, Samuel Achilefu

Faculty, Staff and Student Publications

Radionuclide-stimulated dynamic therapy (RaST) utilizes Cerenkov-radiating radiopharmaceuticals to activate light-sensitive drugs and materials, generating reactive oxygen species (ROS) that inhibit cancer progression. However, the underlying cell death mechanisms are not fully understood. Using ROS-regenerative nanophotosensitizers coated with a tumor-targeting transferrin-titanocene complex and radiolabeled 2-fluorodeoxyglucose, we found that RaST induced apoptosis and necroptosis, characterized by the activation of RIPK-1, RIPK-3, nuclear factor kappa B, and mixed lineage kinase domain-like pseudokinase, leading to membrane permeabilization, cytokine release, and the expression of immunogenic damage-associated molecular patterns. In immune-deficient breast tumor-bearing mice with adequate stroma and growth factors, RaST did not prevent tumor growth …

Comprehensive Metabolic Profiling Across Five Lifespan Stages In Murine Hippocampus And Cortex Reveals Sex-Related Variation In Age-Related Cognitive Decline, Xi Long, Wuping Liu, Changhan Chen, Qi Guo, Yidan Wang, Fang Yu, Yujin Zhang, Rodney E Kellems, Yang Xia

Faculty, Staff and Student Publications

This study employs Barnes maze behavioral assessments, untargeted liquid chromatography-mass spectrometry metabolomics, and 13C6-glucose isotopic tracing to systematically investigate cognitive function and metabolic profiles in hippocampal and cortical tissues of male and female mice across five distinct age-ranges. Behavioral analyses reveal significant cognitive decline in both sexes by 16-months-of-age, with females exhibiting more severe impairment by 23-months, demonstrating a sex-related variation. 13C6-glucose tracing analyses reveals that glucose is rapidly and preferentially metabolized toward the Tricarboxylic acid cycle over glycolysis and the pentose phosphate pathway (PPP), with metabolism rates increasing from juvenility to meet developmental demands and maintaining homeostasis into pre-elderly. …

Successful Bacteriophage Treatment Of A Recalcitrant Intra-Abdominal Infection Caused By Multi-Drug-Resistant Pseudomonas Aeruginosa In A 2-Year-Old Child, Sanchi Malhotra, Keiko C Salazar, Neema Pithia, Ishminder Kaur, Kristina Adachi, Nanda Ramachandar, Austin L Terwilliger, Anthony Maresso, Robert S Venick, Suzanne V Mcdiarmid, John S Bradley

Faculty, Staff and Students Publications

Antimicrobial resistance is life-threatening to complex pediatric patients who receive multiple courses of broad-spectrum antibiotics. Bacteriophages offer a safe treatment alternative when our antibiotic armamentarium is no longer sufficient. We describe successful use of bacteriophage therapy on a patient with a recalcitrant Pseudomonas aeruginosa infection after receiving a multi-organ transplant.

Pesticides Associated With Incident Diabetes Among Licensed Private Pesticide Applicators In The Agricultural Health Study Cohort (1993–2021), Christine G Parks, Qian Xiao, Jesse Wilkerson, Jonathan N Hofmann, Laura E Beane Freeman, Dale P Sandler

Faculty, Staff and Student Publications

Background: Growing evidence suggests pesticides may increase risk of type 2 diabetes, but data are limited on many specific chemicals.

Methods: In 29,527 private pesticide applicators in the Agricultural Health Study cohort (enrolled 1993-1997 in Iowa and North Carolina), 3,847 incident diabetes cases were identified by self-report during follow-up surveys in 1999-2003, 2005-2010, 2013-2015, and 2019-2021. We examined 50 pesticides reported at enrollment, updated in 1999-2003 or 2005-2010, prior to diabetes diagnosis or end of follow-up, using log-binomial regression to calculate relative risks (RR) and 95% confidence intervals (CI) for ever-use and intensity-weighted lifetime days (IWLD) use (tertiles, T1-3), adjusting …

Reducing Work-Related Screen-Time In Healthcare Workers During Leisure Time (Reduce Screen) - A Randomized Controlled Trial, Karsten Bartels, Karan Shah, Emelind Sanchez Rodriguez, Julie T Hoffman, Megan L Rolfzen, Juana Mora Valdovinos, Afton L Hassett, Daniel I Sessler

Faculty, Staff and Student Publications

The ubiquitous availability of work-related applications on personal devices makes healthcare workers prone to working during leisure time. We tested the hypothesis that an intervention to reduce work-related screen time during a weekend off reduces stress in healthcare workers in a pragmatic parallel design randomized controlled trial between November 2021 and November 2023. Healthcare workers using a smartphone with a work email application were eligible. Randomization was 1:1 to no treatment or a threefold educational intervention to: 1) activate automated responses to emails received, 2) reduce screen time, and 3) uninstall work applications from personal devices. The primary outcome was …

Foxo1 Inhibition And Fadd Knockdown Have Opposing Effects On Anticancer Drug-Induced Cytotoxicity And P21 Expression In Osteosarcoma Cells, Danielle Walker, Antanay Hall, Alexis Bonwell, Nancy Gordon, Danielle Robinson, Mario G Hollomon

Faculty, Staff and Student Publications

Forkhead box class O1 (FOXO1) and fas-associated death domain (FADD) regulate cell death pathways and homeostatic processes such as cell cycle progression and apoptosis. FADD phosphorylation promotes nuclear localization of FOXO1, and FOXO1 regulates FADD expression. Therefore, it is plausible that FOXO1 and FADD have synergistic or antagonistic effects on cell cycle regulation and the response to anticancer drug treatment in cancer cells. In the present study, we report that AS1842856-mediated inhibition of FOXO1 reverses anticancer drug-induced cytotoxicity, while FADD knockdown increases anticancer drug-induced cytotoxicity in osteosarcoma (OS). Reversed anticancer drug-induced cytotoxicity was accompanied by G2/M cell cycle arrest and …

Premature Aging In Serious Mental Illness, Breno S Diniz, Gabriel R Fries, Chia-Ling Kuo, Ming Xu, Eric J Lenze

Faculty, Staff and Student Publications

Serious mental illnesses (SMIs), including major depressive disorder, bipolar disorder, and schizophrenia, have long been linked to cognitive decline, multiple chronic medical conditions, and premature mortality. These factors significantly contribute to the severe disability seen in SMIs, extending beyond the severity of psychopathology and indicating a premature aging phenotype associated with these conditions. The mechanisms that underlie the relationship between SMIs and the premature aging phenotype are not well understood, but recent evidence suggests that individuals with SMIs may exhibit accelerated biological aging. In this review, we present a comprehensive analysis of the current literature, demonstrating the potential association of …

Real-Time Hemodynamic Deterioration Following Polymorphic Ventricular Tachycardia In A Patient With Preexisting Aicd Implanted With Lvad, Dhruvil Patel, Maya Guglin, Deepa Iyer, Chonyang Albert, Jagpreet Grewal, Kenneth Dulnuan

The VAD Journal

Ventricular arrhythmias (VAs) are common in patients with a left ventricular assist device (LVAD), but the literature remains inconclusive regarding the benefits of an automatic implantable cardioverter-defibrillator (AICD) in this population, especially in those with a preexisting device before LVAD implantation. Here, we report the acute hemodynamic consequences of polymorphic ventricular tachycardia in a patient with a preexisting biventricular AICD who was implanted with an LVAD (HeartMate 3). This case underscores the importance of considering AICD placement on a case-by-case basis and highlights the need for a well-designed study to establish its benefit in this population.

A Programmable Genetic Platform For Engineering Noninvasive Biosensors, Asish N Chacko, Kaamini M Dhanabalan, Jinyang Wan, Roy Chien, Nolan T Anderson, Binzhi Xu, Katie Pham, Ritu Tiwari, Arnab Mukherjee

Faculty, Staff and Student Publications

Creating genetic sensors for noninvasive visualization of biological activities in optically opaque tissues holds immense potential for basic research and the development of genetic and cell-based therapies. Magnetic resonance imaging (MRI) stands out among deep tissue imaging methods for its ability to generate high-resolution images without ionizing radiation. However, the adoption of MRI as a mainstream biomolecular technology has been hindered by the lack of adaptable methods to link molecular events with genetically encodable contrast. Here, we introduce modular aquaporin-based protease-activatable probes for enhanced reporting (MAPPER), a platform for the systematic creation of genetic sensors for MRI. To develop MAPPER, …

Differential Blood-Brain Barrier Permeability Driven By Asymmetric Hypoperfusion In A Vascular Dementia Model, Mengjun Dai, Kuizhi Qu, Ying Jiang, Song Gao, Yan-Ning Rui, Zhen Xu

Faculty, Staff and Student Publications

Introduction: Blood-brain barrier (BBB) dysfunction has been associated with vascular dementia (VaD). However, the underlying mechanisms causing BBB dysfunction remain unclear, especially regarding cerebral hypoperfusion. This study aimed to investigate the effects of asymmetric hypoperfusion on BBB permeability using a mouse model of VaD.

Methods: Asymmetric bilateral common carotid artery stenosis (ACAS) was induced using ligature rings. BBB integrity was assessed on 3 days post-surgery using Evans blue, IgG, and albumin extravasation. A modified tissue processing protocol optimized endogenous marker detection. Regional and sex-based differences in BBB permeability were analyzed.

Results: Increased BBB permeability was observed in both corpus callosum …

Glutamatergic Projection Neurons In The Basal Forebrain Underlie Learned Olfactory Associational Valence Assignments, Pey-Shyuan Chin, Zhuokun Ding, Mikhail Kochukov, Snigdha Srivastava, Elizabeth H Moss, Qingchun Tong, Benjamin R Arenkiel

Faculty, Staff and Student Publications

Sensory perception is shaped by experience, giving stimuli behavioral significance. Basal forebrain (BF) cholinergic neurons in mice, which are crucial for arousal and motivation, also regulate sensory processing. Within BF nuclei, glutamatergic (vGlut2BF) neurons receive cholinergic input and modulate behaviors, but their roles in encoding sensory significance remain unclear. Using in vivo calcium imaging, we found that vGlut2BF neurons initially poorly encoded odor identity. However, their response to conditioned odors increased following associative learning, and their population activity more distinctly encoded paired stimuli, reflecting emergent value representation. Furthermore, pairing stimulation or inhibition of vGlut2BF neurons with specific odors altered odor …

Loss Of Payload Sensitivity And Other Mechanisms Of Resistance To T-Dxd In Her2-Mutant Nsclc: Implications For Subsequent Responsiveness To Her2 Tkis, Monique B Nilsson, Xiuning Le, Alissa Poteete, Xiaoxing Yu, Junqin He, Qian Huang, Yuji Shibata, Ximeng Liu, Cesar Moran, Ash A Alizadeh, Maximilian Diehn, Heather Wakelee, Diego Almanza, Scott Soltys, Takeshi Sugio, Jurik Mutter, Xiaoman Kang, Rui Wang, Soyeong Jun, Mohammad Shahrokh Esfahani, Hai Tran, Yuanxin Xi, Lingzhi Hong, Xiaofang Huo, Ashwani Kumar, Xiaoyang Ren, Kei Oguchi, Kazuhisa Minamiguchi, Caroline M Weipert, Jing Wang, Ralf Kittler, John V Heymach

Faculty, Staff and Student Publications

Introduction: Effective therapies are needed for patients with NSCLC with HER2-mutant tumors who progress on the HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd), a standard-of-care treatment. A greater understanding of mechanisms mediating acquired T-DXd resistance and whether these tumors could benefit from HER2 tyrosine kinase inhibitors (TKIs) is needed.

Methods: Using preclinical models of acquired T-DXd resistance, LentiMutate scanning mutagenesis, and clinical analyses, we investigated mechanisms mediating acquired resistance to T-DXd and assessed the impact of each of these resistance mechanisms on cross-resistance to alternative HER2-targeting approaches.

Results: We determined that acquired resistance to T-DXd could occur through multiple mechanisms including …

Aberrant Cd25 And Increased Cd123 Expression Are Common In Acute Myeloid Leukemia With Kmt2a Partial Tandem Duplication And Are Associated With Flt3 Internal Tandem Duplication, Qing Wei, Guilin Tang, Shaoying Li, Sa A Wang, Pei Lin, Wei Wang, Sanam Loghavi, Wei J Wang, L Jeffrey Medeiros, Jie Xu

Faculty, Staff and Student Publications

Background: KMT2A partial tandem duplication (PTD) occurs in approximately 5-10% of acute myeloid leukemia (AML) cases and is associated with poor prognosis. While its cytogenetic and molecular features are well described, the immunophenotypic characteristics of AML with KMT2A-PTD remain incompletely defined.

Methods: We identified 47 cases of AML with KMT2A-PTD by optical genome mapping. All cases underwent flow cytometric immunophenotypic analysis and next-generation sequencing using an 81-gene panel.

Results: The cohort included 32 men and 15 women with a median age of 67 years (range, 19-87). Thirty-eight cases were de novo AML, and nine were secondary to myelodysplastic …

Emt-Induced Stem Cell And Mesenchymal Programs Can Be Decoupled Via Cell Division And Esrp1-Dependent Mechanisms, Petra Den Hollander, Maria Castaneda, Suhas V Vasaikar, Joanna Joyce Maddela, Claire Gould, Breanna R Demestichas, Robiya Joseph, Shivangi Agarwal, Abhijeet P Deshmukh, Alvina Zia, Shruti Shah, Tieling Zhou, Geraldine Raja, Paul Allegakoen, Nick A Kuburich, Mika Pietila, Chunxiao Fu, Jeffrey Chang, Chad J Creighton, William F Symmans, Rama Soundararajan, Sendurai A Mani

Faculty, Staff and Student Publications

Epithelial-to-mesenchymal transition (EMT) is known to induce both stemness and mesenchymal properties, and our findings reveal that these two programs can be uncoupled. During EMT, epithelial cells transition from symmetric divisions producing differentiated daughter cells to self-renewing daughter cells. When we block cell division and induce EMT, cells gain mesenchymal properties but not stemness, suggesting the importance of cell division for gaining stemness. We identified ESRP1 as a key regulator of EMT-driven stemness, which get downregulated during EMT in a cell division-dependent manner. Overexpression of ESRP1 prevents the gain of stemness without affecting the mesenchymal program. Only the stemness and …

Role Of The Etv5/P38 Signaling Axis In Aggressive Thyroid Cancer Cells, Jerry H Houl, Rozita Bagheri-Yarmand, Muthusamy Kunnimalaiyaan, Paola Miranda Mendez, Joseph L Kidd, Ali Dadbin, Andrea Ruiz-Jurado, Parag A Parekh, Ying C Henderson, Nikhil S Chari, Aatish Thennavan, Reid T Powell, Clifford C Stephan, Xiao Zhao, Anastasios Maniakas, Roza Nurieva, Naifa L Busaidy, Maria E Cabanillas, Ramona Dadu, Mark Zafereo, Jennifer R Wang, Stephen Y Lai, Marie-Claude Hofmann

Faculty, Staff and Student Publications

Patients with poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) face a much poorer prognosis than those with differentiated thyroid cancers. Around 25% of PDTCs and 35% of ATCs carry the BRAFV600E mutation, which constitutively activates the MAPK pathway, a key driver of cell growth. Although combining BRAF and MEK inhibitors can shrink tumors, resistance often develops. The exact cause of this resistance remains unclear. We previously found that in PDTC and ATC cells, the BRAFV600E mutation is strongly linked to the expression of ETV5, a transcription factor downstream of the MAPK pathway. In the current study, we …

Advances In Targeting Her2 Across Cancer Subtypes: A Pan-Tumor Approach, Taiwo Adesoye, Ecaterina E Dumbrava, Kanwal P S Raghav, Aysegul A Sahin, Hui Chen, Sunyoung S Lee, Milind M Javle, Shubham Pant, Omar Alhalabi, Xiuning Le, Vicente Valero, Paula R Pohlmann, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Human epidermal growth factor receptor 2 (HER2) is an established therapeutic target in multiple solid tumors, particularly breast and gastric cancers. Significant advancements have been made in the development of HER2-targeted therapies, including monoclonal antibodies, tyrosine kinase inhibitors, antibody-drug conjugates (ADC), and novel bispecific antibodies. These agents have revolutionized the treatment landscape for HER2-positive metastatic cancers, resulting in improved progression-free and overall survival, and quality of life for patients. Beyond breast and gastric cancers, HER2 expression/amplification has been observed in other solid tumors, such as colorectal, lung, bladder, ovarian, and biliary tract cancers, offering new opportunities for personalized therapy in …

Integrative Spatial Multi-Omics Reveal Niche-Specific Inflammatory Signaling And Differentiation Hierarchies In Aml, Enes Dasdemir, Ivo Veletic, Christopher P Ly, Andres E Quesada, Christopher D Pacheco, Fatima Z Jelloul, Pamella Borges, Sreyashi Basu, Sonali Jindal, Zhiqiang Wang, Alexander Lazar, Khalida M Wani, Dinler A Antunes, Patrick K Reville, Preethi H Gunaratne, Robert J Tower, Padmanee Sharma, Hussein A Abbas

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is a clonal disorder characterized by immature blasts and arrested differentiation that primarily affects the bone marrow (BM) and occasionally presents as extramedullary (EM) disease. EM manifestations highlight AML's adaptability to distinct microenvironments, which we examined using spatial analyses of medullary and EM tissues. We describe a workflow for Visium-based spatial transcriptomics in medullary and EM AML, revealing insights into cell-cell communication and the spatial organization of AML hierarchies. In BM, monocytes and granulocyte-monocyte progenitors colocalized with leukemic populations, sharing molecular signatures with those in EM sample. CXCL12-CXCR4-mediated communication correlated with PI3K/AKT/mTOR signaling in inflammatory niches.

Onset And Exacerbation Of Obsessive-Compulsive Disorder In The Perinatal Period, Jack Samuels, Mary Kimmel, Janice Krasnow, Rashelle Musci, Paul S Nestadt, Lauren M Osborne, Eric A Storch, Jonathan S Abramowitz, Gerald Nestadt

Faculty, Staff and Students Publications

Purpose: Obsessive-compulsive disorder (OCD) can emerge during pregnancy and the postpartum and may adversely affect mother and newborn. However, little is known about potential risk factors for the onset of OCD in the perinatal period. Therefore, we investigated the onset of diagnosed DSM-5 OCD in women followed from the second trimester of pregnancy to 6-months postpartum.

Methods: We followed 256 women from the 20-24th week of pregnancy to 6-month postpartum. Participants had psychiatric diagnostic interviews at baseline and 6-month postpartum and completed self-report instruments. We compared women with and without incident OCD on sociodemographic characteristics and clinical features.

Results: Of …

Effects Of Icosapent Ethyl On Risk And Duration Of Hospitalizations And Death In Reduce-It, Michael Szarek, Deepak L Bhatt, Michael Miller, Eliot A Brinton, Jean-Claude Tardif, Christie M Ballantyne, Steven B Ketchum, Mandeep R Mehra, Ph Gabriel Steg

Faculty, Staff and Students Publications

Aims: Among statin-treated participants with elevated triglycerides and known cardiovascular disease or with diabetes and other risk factors, icosapent ethyl reduced the risk of cardiovascular events in the REDUCE-IT study. In this post hoc analysis of REDUCE-IT, we quantified the effects of icosapent ethyl on total hospitalizations and days lost to hospitalization and death.

Methods: Randomization to treatment with 2 g twice daily of icosapent ethyl or matching placebo was performed among 8179 participants receiving statin therapy with established cardiovascular disease or age ≥50 years with diabetes and ≥1 additional risk factor, fasting triglyceride 1.69-5.63 mmol/L, and low-density lipoprotein cholesterol …

Rnai-Based Screen For Pigmentation In Drosophila Melanogaster Reveals Regulators Of Brain Dopamine And Sleep, Samantha L Deal, Danqing Bei, Shelley B Gibson, Harim Delgado-Seo, Yoko Fujita, Kyla Wilwayco, Elaine S Seto, Amita Sehgal, Shinya Yamamoto

Faculty, Staff and Students Publications

The dopaminergic system has a large role in behavior and neurological disease, and understanding dopamine level regulation in vivo is critical. To identify dopamine regulators, we utilized Drosophila melanogaster cuticle pigmentation, where dopamine is a precursor to melanin. We measured dopamine from known pigmentation mutants (e.g., tan, ebony, black) and performed an RNAi-based screen to identify additional regulators. We found 153 hits, enriched for developmental signaling pathways and mitochondria-associated proteins. From 35 prioritized candidates, 11 affected head dopamine levels. Effects on brain dopamine were mild, even knocking down the rate-limiting synthesis enzyme Tyrosine hydroxylase (TH), suggesting …

Associations Of Arsenic Exposure And Folate In Maternal Leukocyte Dna Methylation: A Case-Control Study Of Mothers With Spina-Bifida Affected Children, Amy M Inkster, Anne K Bozack, Bernardo Lemos, Tabitha Lumour-Mensah, Sudipta Kumar Mukherjee, Shekh Muhammad Ekramullah, D M Arman, Joynul Islam, Xingyan Wang, Liming Liang, Richard H Finnell, Maitreyi Mazumdar, Andres Cardenas

Faculty, Staff and Students Publications

No abstract provided.

Rare Heterozygous De Novo Variants In Rapgef2 Are Associated With A Neurodevelopmental Disorder, Ali H Bereshneh, Kirkland A Wilson, Xueyang Pan, Shabab B Hannan, Megan A Cooper, Jullianne Diaz, Eyby Leon, Tiana M Moses, Mahshid S Azamian, Daryl A Scott, Ping Yee Billie Au, Juan Pablo Appendino, Ingrid E Scheffer, Antony Kaspi, Melanie Bahlo, Michael S Hildebrand, Angela T Morgan, Ekanem Ekure, Joshua M Shulman, Friedhelm Hildebrandt, Jennifer E Posey, Paul Kruszka, Eric Vilain, Shinya Yamamoto, Oguz Kanca, Seth Berger, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Purpose: RAPGEF2 encodes a guanine nucleotide exchange factor (GEF) that activates small GTPases and has not been linked to a Mendelian disorder. RAPGEF2 is highly intolerant to loss-of-function variants. We report 5 de novo heterozygous variants in RAPGEF2 in unrelated individuals with developmental delay, attention deficit hyperactivity disorder, epilepsy, dysmorphic features, or other manifestations. We used a Drosophila model to assess the functional impact of the identified human variants.

Methods: We generated a Kozak-GAL4 null allele of the Drosophila ortholog of RAPGEF2, PDZ-GEF, and used the allele to determine the gene expression pattern as well as the loss-of-function phenotypes. We …

Combining Dna Methylation Features And Clinical Characteristics Predicts Ketamine Treatment Response For Ptsd, Amir Valizadeh, John D Roache, Xinyu Zhang, Ying Hu, Ralitza Gueorguieva, Lynnette A Averill, Mohini Ranganathan, Zuoheng Wang, Douglas E Williamson, Paulo R Shiroma, Matthew J Girgenti, Ismene L Petrakis, Argelio L López-Roca, Stacey Young-Mccaughan, Terence M Keane, Alan L Peterson, Chadi G Abdallah, John H Krystal, Ke Xu

Staff and Researcher Publications

Post-traumatic stress disorder (PTSD) exhibits extensive clinical and biological variability, making treatment challenging. The Consortium to Alleviate PTSD (CAP)-ketamine trial, the largest randomized study of ketamine for PTSD, found no overall benefit of ketamine over placebo, underscoring the necessity to identify responsive subgroups. Using pre-treatment blood DNA methylation profiles and clinical measures from the CAP-ketamine trial, we applied machine learning to predict treatment response. A model based on 1,208 methylation sites achieved higher predictive accuracy than models using clinical variables alone, and combining both data types further improved performance. The methylation-derived score distinguished responders with 92.9% accuracy. The predictive CpGs …

Whole Genome Sequence Analysis Of Pulmonary Function And Copd In 44,287 Multi-Ancestry Participants, Wonji Kim, Xiaowei Hu, Kangjin Kim, Sung Chun, Peter Orchard, Dandi Qiao, Ingo Ruczinski, Aabida Saferali, Francois Aguet, Lucinda Antonacci-Fulton, Pallavi P Balte, Traci M Bartz, Wardatul Jannat Anamika, Xiaobo Zhou, Junyi Duan, Jennifer A Brody, Brian E Cade, Martha L Daviglus, Harshavadran Doddapaneni, Shannon Dugan-Perez, Susan K Dutcher, Christian D Frazar, Stacey B Gabriel, Sina A Gharib, Namrata Gupta, Brian D Hobbs, Silva Kasela, Laura R Loehr, Ginger A Metcalf, Donna M Muzny, Elizabeth C Oelsner, Laura J Rasmussen-Torvik, Colleen M Sitlani, Joshua Smith, Tamar Sofer, Hanfei Xu, Bing Yu, David Zhang, John Ziniti, R Graham Barr, April P Carson, Myriam Fornage, Lifang Hou, Ravi Kalhan, Robert Kaplan, Tuuli Lappalainen, Stephanie J London, Alanna C Morrison, George T O'Connor, Bruce M Psaty, Laura M Raffield, Susan Redline, Stephen S Rich, Jerome I Rotter, Edwin K Silverman, Ani Manichaikul, Michael H Cho

Faculty, Staff and Student Publications

Background: Whole genome sequence (WGS) data in multi-ancestry samples supports discovery of low-frequency or population-specific genetic variants associated with chronic obstructive pulmonary disease (COPD) and lung function.

Results: We performed single variant, structural variant, and gene-based analysis of pulmonary function (FEV1, FVC and FEV1/FVC) and COPD case-control status in 44,287 multi-ancestry participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We validated findings using the UK Biobank and assessed implicated genes using lung single-cell RNA-seq (scRNA-seq) data sets. Applying a genome-wide significance threshold (P < 5 × 10-9), we replicated known loci and identified novel associations near LY86, MAGI1, GRK7, and LINC02668. Colocalization with gene expression quantitative trait loci (eQTL) from the Lung Tissue Research Consortium highlighted known candidate genes including ADAM19, THSD4, C4B, and PSMA4, which were not identified through other eQTL sources. Multi-ancestry analysis improved fine-mapping resolution (e.g., HTR4 and RIN3). Gene-based analysis identified and replicated HMCN1. In human lung scRNA-seq data sets, lung epithelial cells and immune cell types showed enriched expression, while fibroblasts showed higher expression for HMCN1. CRISPR targeting HMCN1 in IMR90 demonstrated reduced expression of collagen genes.

Conclusions: Large-scale multi-ancestry WGS analysis improves variant discovery and fine-mapping resolution for lung function and …

Rab5c Increases Endothelial Release Of Vwf By Regulating Vesicle Trafficking, Paula Reventun, Pablo Toledano-Sanz, Maria Delgado-Marin, Maria Viskadourou, D Brian Foster, Paul S De Vries, Maria Sabater-Lleal, Nunzio Alcharani, Claudia Gonzalez-Cucharero, William O Osburn, Alanna C Morrison, Alisa S Wolberg, Nicholas L Smith, Marios Arvanitis, Charles J Lowenstein

Faculty, Staff and Student Publications

Background: Abnormal levels of VWF (von Willebrand Factor) are a risk factor for venous thromboembolism (VTE) and bleeding. Genome-wide association studies for VWF have identified novel candidate genes that may regulate VWF levels in humans, including RAB5C (RAS-associated protein RAB5C). We hypothesized that RAB5C regulates VWF release from endothelial cells.

Methods: We studied the effect of RAB5C on vesicle trafficking in human endothelial cells. We performed CRISPR (clustered regularly interspaced short palindromic repeats) interference targeting 2 genetic variants linked to altered VWF levels and evaluated RAB5C expression by reverse transcription-quantitative polymerase chain reaction. We silenced RAB5C or overexpressed RAB5C wild-type, …

Epigenome-Wide Association Study Meta-Analysis Of Bmi In African Americans, Kendra Ferrier, Mariaelisa Graff, Iain R Konigsberg, Maggie Stanislawski, Heather M Highland, Laura M Raffield, April P Carson, Eric Boerwinkle, Jill M Norris, Chris R Gignoux, Audrey E Hendricks, Sridharan Raghavan, Kari E North, Kristin L Young, Anne E Justice, Matthew A Allison, Mathew J Budoff, Silva Kasela, François Aguet, Joshua J Joseph, Charles Kooperberg, Stephen S Rich, Jerome I Rotter, Ethan M Lange, Leslie A Lange

Faculty, Staff and Student Publications

Despite considerable advances in identifying risk factors for obesity, gaps remain in our understanding about its etiology. Genetic variants explain only a small portion of variation in obesity-related traits such as body mass index (BMI). Epigenetic regulation, which controls gene expression and is influenced by environmental and genetic factors, may account for additional variability in BMI. Epigenetic studies of BMI have largely been conducted in European ancestry populations, despite the disproportionate burden of obesity in African Americans (AAs). We conducted a sex-stratified BMI epigenome-wide association study meta-analysis in AA participants from the Jackson Heart Study (n = 1,604) and …

Dna Methyltransferase Inhibitors In Hematological Malignancies And Solid Tumors, Valentin Wenger, Guillermo Garcia-Manero, Robert Zeiser, Michael Lübbert

Faculty, Staff and Student Publications

Epigenetic modifications such as DNA methylation play a fundamental role in oncogenesis and the progression of neoplasms neoplasias. DNA methyltransferase inhibitors (DNMTi) constitute a family of therapeutic agents that impede the methylation at the 5-position on cytosine nucleotides, thereby modulating the epigenetic regulation of tumor suppressor genes, oncogenes, and other key regulatory genes. The first-generation DNMTi azacitidine and decitabine have demonstrated substantial efficacy in the treatment of medically non-fit, older patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy (IC), by virtue of their favorable safety profile. Despite these clinical achievements, however, single-agent DNMTi treatment …