Digital Commons Network^™

Global Dose Prescription Variances Exemplified Through Oropharynx Cancer: When Is 70 Gray 70 Gray?, Christian Rønn Hansen, Tony Tadic, Manju Sharma, Gareth Price, Jens Petersen, Mohamed A Naser, Ying Xiao, Nataliya Kovalchuk, Pernille Lassen, Jens Overgaard, Lachlan Mcdowell, Prabhakar Ramachandran, Jun Won Kim, Clifton David Fuller, David J Thomson, Jørgen Johansen, Jeppe Friborg, Sue S Yom, Andrew Hope

Faculty, Staff and Student Publications

Purpose/objectives: Radiation therapy treatment planning hinges on a critical factor: the prescribed dose. Surprisingly, there is no consistent, standardized global approach to evaluating the dosimetry of this prescription across different centers treating head and neck cancer (HNC). This study aimed to quantify global dose variations for identical prescriptions across international centers treating oropharyngeal cancer, to establish the foundation for future outcome-based studies and improve consistency of interpretation worldwide.

Materials and methods: The study included patients with oropharyngeal cancer who were consecutively treated from 2017 onward with intensity-modulated radiation therapy or volumetric modulated arc therapy at 8 globally recognized radiation therapy …

An Application-Based Ontological Knowledge Base Of Medications To Support Health Literacy And Adherence For The Consumer Population: An Aging Population Use Case, Clifford Chen, Muhammad Amith, Kirk Roberts, Rebecca Mauldin, Renata Komalasari, Cui Tao

Faculty, Staff and Student Publications

No abstract provided.

Beyond Neurons: Impact Of Cannabidiol On Glial Cells In Ischemic Stroke, Victória Linden De Rezende, Khiany Mathias, Cinara Ludvig Gonçalves, Rafael Mariano De Bitencourt, Tatiana Barichello, Fabricia Petronilho

Faculty, Staff and Student Publications

Ischemic stroke triggers a complex cascade of events involving inflammation, oxidative stress, and glial cell dysfunction, all of which contribute to neuronal damage and impaired recovery. Glial cells (e.g., astrocytes, microglia, and oligodendrocytes) play key roles in neuroinflammatory responses, making them attractive targets for therapeutic modulation. Cannabidiol, a non-psychoactive phytocannabinoid from Cannabis sativa, exhibits anti-inflammatory, antioxidant, and neuroprotective properties. Preclinical evidence indicates that cannabidiol attenuates glial reactivity, reduces pro-inflammatory signaling, mitigates oxidative stress, and preserves blood-brain and intestinal barrier integrity in stroke models. Moreover, cannabidiol modulates key molecular pathways (e.g., nuclear factor-κB, tumor necrosis factor, and calcium-related signaling), contributing to …

Differentiation In The Human Urothelia Is Defined By Distinct Alternative Polyadenylation, Ninh B Le, Surbhi Sona, Briana Santo, Yi Zhang, Rosie Ou, R Allen Schweickart, Veena Kochat, William I Padron, Kunal Rai, Shih-Han Lee, Joo Mi Yi, Oliver Wessely, Byron H Lee, Angela H Ting

Faculty, Staff and Student Publications

Distinct epithelial cell states arise during differentiation, but mechanisms generating transcriptomic diversity among them remain poorly defined. The human ureter urothelium contains basal progenitor, intermediate cells, and terminally differentiated umbrella cells. Prior single-cell RNA sequencing revealed similar global gene expression profiles across these states, raising the question of how distinct identities emerge. Here, we show that alternative cleavage and polyadenylation (APA) introduces a major layer of transcriptomic diversity during urothelial differentiation, largely independent of changes in mRNA levels. Analysis of 13,544 urothelial cells identified hundreds of differentiation-associated APA events. Single-cell imaging revealed spatially specific APA patterns, and reporter assays demonstrated …

Differentiation In The Human Urothelia Is Defined By Distinct Alternative Polyadenylation, Ninh B Le, Surbhi Sona, Briana Santo, Yi Zhang, Rosie Ou, R Allen Schweickart, Veena Kochat, William I Padron, Kunal Rai, Shih-Han Lee, Joo Mi Yi, Oliver Wessely, Byron H Lee, Angela H Ting

Faculty, Staff and Student Publications

Distinct epithelial cell states arise during differentiation, but mechanisms generating transcriptomic diversity among them remain poorly defined. The human ureter urothelium contains basal progenitor, intermediate cells, and terminally differentiated umbrella cells. Prior single-cell RNA sequencing revealed similar global gene expression profiles across these states, raising the question of how distinct identities emerge. Here, we show that alternative cleavage and polyadenylation (APA) introduces a major layer of transcriptomic diversity during urothelial differentiation, largely independent of changes in mRNA levels. Analysis of 13,544 urothelial cells identified hundreds of differentiation-associated APA events. Single-cell imaging revealed spatially specific APA patterns, and reporter assays demonstrated …

Mechanistic Insights Into The Antimicrobial Effect Of Benzodioxane-Benzamides Against Escherichia Coli, Lorenzo Suigo, Alessia Lanzini, Valentina Straniero, William Margolin

Faculty, Staff and Student Publications

Background/Objectives: The bacterial cell division machinery is emerging as an attractive target for antimicrobial compounds. FtsZ, a highly conserved essential division protein, is the target for a number of small molecules such as benzamides. Recent studies show that benzodioxane-benzamides (BDOBs) are among the most potent inhibitors of FtsZ function in Gram-positive bacteria, although their ability to inhibit Gram-negative FtsZ, in particular Escherichia coli FtsZ, has been more controversial.

Methods: Here, we use genetic and cytological methods to demonstrate that FtsZ of efflux pump-disabled E. coli can be efficiently targeted by BDOBs.

Results: We show that engineered mutants …

Payload Diversification Overcomes Resistance And Guides Sequential Antibody-Drug Conjugate Therapy In Breast Cancer, Dileep Reddy Rampa, Minji Seo, Nanae Ogata, Zhaoxuan Yang, Nithya Sridhar, Fujii Takeo, Chalothorn Wannaphut, Jennifer A Maynard, Kyoji Tsuchikama, George W Sledge, Naoto T Ueno, Jangsoon Lee

Faculty, Staff and Student Publications

Purpose: Antibody-drug conjugates (ADCs) have transformed the treatment of breast cancer. FDA-approved ADCs such as trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd) have demonstrated clinical benefit; however, drug resistance will almost inevitably emerge in the metastatic setting, and there is no established strategy for selecting subsequent ADCs after disease progression to the first exposure to the ADC. This study aimed to define mechanisms of acquired resistance and evaluate rational sequencing approaches.

Experimental design: We generated breast cancer cell lines resistant to T-DXd (TDXd-R) and SG (SG-R). We assessed antigen expression, internalization, and resistance pathways, including efflux transporter …

The Gene Encoding Ornithine Decarboxylase For Putrescine Biosynthesis Is Essential For The Viability Of Fusobacterium Nucleatum, Shiqi Xu, Bibek G C, Alex Phan, Chenggang Wu

Faculty, Staff and Student Publications

Fusobacterium nucleatum is a Gram-negative anaerobe associated with periodontitis and colorectal cancer. It secretes putrescine, a polyamine that promotes biofilm formation by oral co-colonizers and enhances the proliferation of cancer cells. However, the physiological importance of putrescine for F. nucleatum itself remains unexplored. Here, we show that putrescine biosynthesis, mediated by the ornithine decarboxylase gene oda, is essential for F. nucleatum viability. Deletion of oda was only possible when a functional copy was provided in trans, and CRISPR interference of oda expression resulted in complete growth defects. The essentiality of oda was conserved across multiple subspecies. Supplementation with …

Qsox1: A Mysterious Golgi-Localized Disulfide Bond Catalyst And An Emerging Cancer Regulator, Shike Wang, Guan-Yu Xiao, Xiaochao Tan

Faculty, Staff and Student Publications

Quiescin sulfhydryl oxidase 1 (QSOX1) is a disulfide bond-forming enzyme with both disulfide isomerase and oxidoreductase activities. It plays an important role in protein folding, stability, and secretion. Growing evidence demonstrates that QSOX1 is upregulated in multiple cancer types and influences key behaviors of cancer cells, including proliferation, migration, invasion, and metastasis. Elevated QSOX1 expression is also associated with tumor malignancy and disease relapse. However, the molecular mechanisms by which QSOX1 drives cancer progression remain incompletely understood. In this review, we summarize current knowledge of QSOX1 expression and regulation in cancer, discuss its functional roles, and highlight key unanswered questions …

Pseudoamniotic Band Sequence Risk Factors Following Fetoscopic Laser For Twin-Twin Transfusion Syndrome, Felicia V Lemoine, Sami Backley, Gustavo Vilchez-Lagos, Jimmy Espinoza, Edgar Hernandez-Andrade, Anthony Johnson, Ramesha Papanna, Eric Bergh

Faculty, Staff and Student Publications

Introduction: Pseudoamniotic band sequence (PABS) is a rare but serious complication following fetoscopic laser photocoagulation (FLP) for twin-twin transfusion syndrome (TTTS). We aim to explore associations between perioperative factors and PABS in monochorionic, diamniotic twins undergoing FLP for TTTS.

Methods: A secondary analysis was conducted using a prospective cohort of 816 FLP procedures performed between 2011 and 2024 at a single fetal therapy center. All cases had confirmed absence of PABS prior to FLP via ultrasound and fetoscopic evaluation. PABS was diagnosed postnatally or suspected after FLP and confirmed after birth. Clinical and perioperative variables were compared between cases with …

Genomics Define Malignant Transformation In Myeloma Precursor Conditions, Francesco Maura, P Leif Bergsagel, Bachisio Ziccheddu, Shaji Kumar, Kylee Maclachlan, Andriy Derkach, Juan-Jose Garces, Ross Firestone, Esteban Braggio, Yan Asmann, Michael Durante, Benjamin T Diamond, Marios Papadimitriou, Malin Hultcrantz, Alessio Marella, Giancarlo Castellano, Akihiro Maeda, Marta Lionetti, Antonio Matera, Stefania Pioggia, Matteo Claudio Da Vià, Claudio De Magistris, Daniel Leongamornlert, Danny Deavila, Praneeth Reddy Sudalagunta, Rafael Renatino Canevarolo, Erin M Siegel, Phaedra Agius, Jamie Teer, Andrew Mcpherson, Yusuke Yamashita, Ariosto S Silva, Patrick Blaney, Rachid Baz, Krina K Patel, Peter Campbell, Gareth Morgan, Rafael Fonseca, Ola Landgren, Robert Z Orlowski, Kenneth H Shain, Niccolo Bolli, Saad Usmani, S Vincent Rajkumar

Faculty, Staff and Student Publications

Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). While these precursor conditions are asymptomatic, they are not entirely benign and carry a lifelong risk of progression to MM. Unlike other cancers defined by pathology, malignant transformation from MGUS or SMM to MM has so far relied on demonstration of clinical end-organ damage as morphology and cytogenetics cannot reliably distinguish them. In this study, using genomic data from 374 patients with MGUS or SMM (277 training, 97 validation), to our knowledge, we demonstrate for the first time the ability to identify …

The Influence Of Bapineuzumab And Semagacestat On Rapid Progressors: A Retrospective Cohort Study, Kristofer Harris, Madison Shyer, Dulin Wang, Elizabeth He, Matias Cattani, Catherine Zhang, Christine M Farrell, Xiaoqian Jiang, Yejin Kim, Paul E Schulz

Faculty, Staff and Student Publications

Background: A subset of Alzheimer's disease patients progresses much more rapidly than average. These rapid progressors exhibit accelerated cognitive and functional decline. Potential differences in Alzheimer's biomarkers for rapid progressors and their responses to disease-modifying treatments remain poorly understood, with previous clinical trials and studies producing limited biomarker data and inconsistent results.

Objectives: Examine differences in rapid progressor versus non-rapid progressor outcomes in two AD treatment trials (bapineuzumab and semagacestat) and investigate cognitive and biomarker progression in the placebo groups.

Design: Retrospective cohort study.

Setting: Four randomized, double-blind, phase 3 clinical trials from the Center for Global Clinical Research Data …

Ionic Mechanisms Of Two-Pore Channel Regulation Of Vesicle Trafficking, Heng Zhang, Michael X Zhu

Faculty, Staff and Student Publications

The endolysosomal system plays a pivotal role in cellular function. Before reaching lysosomes for degradation, the endocytosed cargoes are sorted at various stages of endosomal trafficking for recycling and/or rerouting. The proper execution of these processes depends on tightly regulated ion fluxes across endolysosomal membranes. Recent studies have demonstrated the importance of two-pore channels (TPCs), including TPC1 and TPC2, in endolysosomal trafficking. These channels are expressed in the membranes of distinct populations of endosomes and lysosomes, where they respond to nicotinic acid adenine dinucleotide phosphate (NAADP) and phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] to conduct Ca2+ and Na+ release from these acidic organelles. …

Simulated Complex Cells Contribute To Object Recognition Through Representational Untangling, Mitchell B Slapik, Harel Z Shouval

Faculty, Staff and Student Publications

The visual system performs a remarkable feat: it takes complex retinal activation patterns and decodes them for object recognition. This operation, termed "representational untangling," organizes neural representations by clustering similar objects together while separating different categories of objects. While representational untangling is usually associated with higher-order visual areas like the inferior temporal cortex, it remains unclear how the early visual system contributes to this process-whether through highly selective neurons or high-dimensional population codes. This article investigates how a computational model of early vision contributes to representational untangling. Using a computational visual hierarchy and two different data sets consisting of numerals …

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. …

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 …

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, …

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 …

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, …

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 …

Serendipity In Psychiatric Discoveries: Historical Lessons And Future Imperatives For Clinical Observation, Stanley Lyndon, Vineeth P John

Faculty, Staff and Student Publications

Aims and method: Serendipity has driven many of psychiatry's most important treatments, yet contemporary systems may undermine clinicians' ability to notice and develop unexpected therapeutic effects. This selective narrative review synthesises landmark discovery stories, conceptual accounts of serendipity and contemporary case examples to clarify how chance observations become robust advances.

Results: Across historical and modern examples, serendipitous discoveries consistently reflected the interaction of unexpected events with prepared observers working in supportive institutional and research systems. We identify current barriers created by standardised care, funding and trial structures, and professional fragmentation, and outline a multi-level framework for cultivating serendipity through phenomenological …

Bridging Hypoxia And Vision Loss: The Emerging Role Of Connexins In Local And Systemic Eye Diseases, Xianping Zhang, Yalong Cheng, Jean X Jiang, Yuting Li

Faculty, Staff and Student Publications

Hypoxic eye diseases represent a pivotal yet often underappreciated contributor to the onset and progression of many retinal disorders. When hypoxia persists or exceeds the tissue's compensatory capacity, it triggers pathological retinal neovascularization, blood-retinal barrier disruption, and neuronal apoptosis, ultimately resulting in irreversible visual impairment. Connexins (Cxs) form gap junction channels and hemichannels and regulate retinal cell proliferation, differentiation, and survival, thereby playing a central regulatory role in the pathogenesis of hypoxic ocular diseases. In addition to gap junctions, Cx hemichannels promote transmission of molecules between intra- and extracellular environments, further influencing retinal homeostasis under hypoxic stress. This review synthesizes …

Epilepsy Disease Classification: A Community Effort To Enhance The Mondo Disease Ontology, Nicole Vasilevsky, Sarah Gehrke, Kathleen Mullen, Subit Barua, Ian Braun, Tobias Brünger, Curtis Coughlin, Alina Ivaniuk, Daniel Korn, Dennis Lal, Stephanie Marsh, Elaine O'Loughlin, Daniel Olson, Yousif Shwetar, Christalena Sofocleous, Vanessa Vogel-Farley, Heidi Grabenstatter, Melissa Haendel, Christopher Mungall, Sabrina Toro

Faculty, Staff and Student Publications

Motivation: Epilepsy is a diverse group of neurological disorders affecting over 50 million people worldwide. While common epilepsy types are well studied, rare epilepsies-often severe and genetically complex-pose significant challenges in diagnosis, research, and treatment. Accurate and interoperable etiology and disease classifications are critical for improving data sharing, supporting clinical decision-making, and advancing rare disease research.

Results: To enhance the accuracy of epilepsy-related disease concept representation within the Mondo Disease Ontology (Mondo), we conducted a series of expert-driven workshops in collaboration with the team from the Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP). Specialists in epileptology, genetics, neurodevelopment, biomedical …

Autograft Enlargement After The Ross Procedure In Pediatric Patients: Somatic Growth Or Pathologic Dilatation?, Ioannis Zoupas, Alexander C Mills, Scott D Olson, Damien J Lapar

Faculty, Staff and Student Publications

Purpose of ReviewPulmonary autograft autotransplantation represents a popular surgical approach for pediatric patients requiring aortic valve replacement due to the potential for autograft enlargement to accommodate somatic growth. Nevertheless, autograft dilatation and the subsequent need for reintervention are quite common. Published data suggest that autograft enlargement may result from pathological passive remodeling rather than active somatic growth and vice versa. The present review serves to comprehensively evaluate available evidence related to the fate of the pulmonary autograft after the Ross procedure as it relates to the etiology, risk factors and patterns of autograft failure.ResultsStudies present conflicting results supporting both pathological …