Digital Commons Network^™

Atg16l1 Controls Mammalian Vacuolar Proton Atpase, Thabata L A Duque, Masroor Paddar, Einar Trosdal, Ruheena Javed, Lee Allers, Michal H Mudd, Prithvi Akepati, Soumya R Mishra, Michelle Salemi, Brett Phinney, Shawn B Bratton, Thomas Wileman, Vojo Deretic

Faculty, Staff and Student Publications

The mechanisms governing mammalian proton pump V-ATPase function are of fundamental and medical interest. The assembly and disassembly of cytoplasmic V1 domain with the membrane-embedded V0 domain of V-ATPase is a key aspect of V-ATPase localization and function. Here, we show that the mammalian protein ATG16L1, primarily appreciated for its role in canonical autophagy and in noncanonical membrane atg8ylation processes, controls V-ATPase. ATG16L1 knockout elevated V-ATPase activity, increased V1 presence on endomembranes, and increased the number of acidified intracellular compartments. ATG16L1's ability to efficiently bind V-ATPase was required for its inhibitory role in endolysosomal acidification and for control of Mycobacterium …

Strain-Specific Variability In Viral Kinetics, Cytokine Response, And Cellular Damage In Air-Liquid Cultures Of Human Nasal Organoids After Infection With Sars-Cov-2, Gina M Aloisio, Trevor J Mcbride, Letisha Aideyan, Emily M Schultz, Ashley M Murray, Anubama Rajan, Erin G Nicholson, David Henke, Laura Ferlic-Stark, Amal Kambal, Hannah L Johnson, Elina A Mosa, Fabio Stossi, Sarah E Blutt, Pedro A Piedra, Vasanthi Avadhanula

Faculty, Staff and Students Publications

SARS-CoV-2 variants have demonstrated distinct epidemiological patterns and clinical presentations throughout the COVID-19 pandemic. Understanding variant-specific differences at the respiratory epithelium is crucial for understanding their pathogenesis. Here, we utilized human nasal organoid air-liquid interface (HNO-ALI) cell cultures to compare the viral replication kinetics, innate immune response, and epithelial damage of six different strains of SARS-CoV-2 (B.1.2, WA, Alpha, Beta, Delta, and Omicron). All variants replicated efficiently in HNO-ALIs, but with distinct replication kinetic patterns. The Delta variant exhibited delayed replication kinetics, achieving a steady state at 6 days post-infection compared to 3 days for other variants. Cytokine analysis revealed …

Practicing With Intent: How To Teach An Old Dogma New Tricks, Matthew C Phillips, Kusha Davar, Sarah Freling, Steven Y C Tong, Todd C Lee, Emily G Mcdonald, Travis B Nielsen, Noah Wald-Dickler, Alfredo J Mena Lora, Rachael A Lee, Fergus Hamilton, Daniel M Musher, Rodrigo P L Costa, Bassam Ghanem, Rachel Baden, Brad Spellberg

Faculty, Staff and Students Publications

Clinicians are constantly bombarded with an onslaught of newly published data, yet they must make clinical decisions despite a dearth of clinical data. Sometimes, they may fall back on clinical practices entrenched by experience, unaware that they are upheld by dogmatic tradition rather than robust evidence. Ideally, the totality of evidence must be assessed and utilized for clinical decision-making, irrespective of entrenched orthodoxy. Here, we explore the questions, how much evidence is needed to revise established clinical practices and, more fundamentally, can data alone truly catalyze such shifts.

Improved Allele Frequencies In Gnomad Through Local Ancestry Inference, Pragati Kore, Michael W Wilson, Grace Tiao, Katherine Chao, Philip W Darnowsky, Nicholas A Watts, Jessica Honorato Mauer, Samantha M Baxter, Genome Aggregation Database Consortium, Heidi L Rehm, Mark J Daly, Konrad J Karczewski, Elizabeth G Atkinson

Faculty, Staff and Students Publications

The Genome Aggregation Database (gnomAD) is a foundational resource for allele frequency data, widely used in genomic research and clinical interpretation. However, traditional estimates rely on individual-level genetic ancestry groupings that may obscure variation in recently admixed populations. To improve resolution, we applied local ancestry inference (LAI) to over 27 million variants in two admixed groups: Admixed American (n = 7612) and African/African American (n = 20,250), deriving ancestry-specific allele frequencies. We show that 78.5% and 85.1% of variants in these groups, respectively, exhibit at least a twofold difference in ancestry-specific frequencies. Moreover, 81.49% of variants with LAI information would …

Causal Ai-Based Clinical And Radiomic Analysis For Optimizing Patient Selection In Combined Immunotherapy And Sabr In Early-Stage Nsclc: A Secondary Analysis Of The Phase Ii I-Sabr Trial, Maliazurina B Saad, Eman Showkatian, Vivek Verma, Qasem Al-Tashi, Muhammad Aminu, Xinyan Xu, Muhamed Qayati Mohamed, Morteza Salehjahromi, Sheeba J Sujit, Yuliya Kitsel, Steven H Lin, Zhongxing Liao, Saumil Gandhi, David Qian, David Jaffray, Caroline Chung, Natalie I Vokes, Jianjun Zhang, J Jack Lee, John V Heymach, Jia Wu, Joe Y Chang

Faculty, Staff and Student Publications

Background: The recent phase II randomized stereotactic ablative radiotherapy with and without immunotherapy (I-SABR) trial has shown improved event-free survival (EFS) when adding immunotherapy to stereotactic ablative radiotherapy (SABR) for early-stage inoperable non-small cell lung cancer (NSCLC). However, optimizing patient selection thereof is critical, because not every patient benefits from immunotherapy. Leveraging the powerful use of artificial intelligence, this secondary analysis of the I-SABR trial developed a modeling system (named "I-SABR-SELECT") based on clinical and radiomic factors to address which patients should receive additional immunotherapy.

Methods: The discovery/validation cohorts were from the I-SABR trial, with external validation from the single-arm …

Vaccine Value Profile For Schistosomiasis, Gavin Yamey, Kaci Kennedy Mcdade, Roy M Anderson, Sarah M Bartsch, Maria Elena Bottazzi, David Diemert, Peter J Hotez, Bruce Y Lee, Donald Mcmanus, Adebayo J Molehin, Meta Roestenberg, David Rollinson, Afzal A Siddiqui, Miriam Tendler, Joanne P Webster, Hong You, Raphaël M Zellweger, Caroline Marshall

Faculty, Staff and Students Publications

Schistosomiasis is caused by parasitic flatworms (Schistosoma). The disease in humans can be caused by seven different species of Schistosoma: S. mansoni, S. japonicum, S. haematobium, S. malayensis, S. mekongi, S. guineensis and S. intercalatum, as well as by hybrids between species, including livestock schistosome species. People are infected when exposed to infested water and the parasite larvae penetrate the skin. Poor and rural communities are typically the most affected, and the general population who lives in affected areas and is exposed to contaminated water is at risk. Areas with poor access to safe water and adequate sanitation are also …

Oncopacket: Integration Of Cancer Research Data Using Ga4gh Phenopackets., Michael Sierk, Daniel Danis, Sujay Patil, Nobal Kishor, Rajdeep Mondal, Abhishek Jha, Qingrong Chen, Chunhua Yan, Monica Munoz-Torres, Daoud Meerzaman, Peter N Robinson, Justin T Reese

Faculty Research 2025

SUMMARY: Lack of data integration remains a significant impediment to cancer research, and many analyses still require customized software to transform and prepare cancer data. We describe a software package to harmonize genetic and clinical cancer data into the GA4GH Phenopacket schema, an ISO standard for representing clinical case data. We integrated demographic, mutation, morphology, diagnosis, intervention, and survival data using case data from the National Cancer Institute for 12 cancer types. The Phenopacket standard provides a foundation for downstream use, including sophisticated statistical and AI/ML analyses. We demonstrate fitness for purpose by using the integrated data to recapitulate a …

Automating Candidate Gene Prioritization With Large Language Models: From Naive Scoring To Literature-Grounded Validation., Taushif Khan, Mohammed Toufiq, Marina Yurieva, Nitaya Indrawattana, Akanitt Jittmittraphap, Nathamon Kosoltanapiwat, Pornpan Pumirat, Passanesh Sukphopetch, Muthita Vanaporn, Karolina Palucka, Basirudeen Syed Ahamed Kabeer, Darawan Rinchai, Damien Chaussabel

Faculty Research 2025

MOTIVATION: Identifying promising therapeutic targets from thousands of genes in transcriptomic studies remains a major bottleneck in biomedical research. While large language models (LLMs) show potential for gene prioritization, they suffer from hallucination and lack systematic validation against expert knowledge.

RESULTS: The framework identified 609 sepsis-relevant genes with >94% filtering efficiency, demonstrating strong enrichment for inflammatory pathways including TNF-α signaling, complement activation, and interferon responses. Literature validation yielded 30 ultra-high confidence therapeutic candidates, including both established sepsis genes (IL10, TREM1, S100A9, NLRP3) and novel targets warranting investigation. Benchmark validation against expert-curated databases achieved 71.2% recall, with systematic correlation between computational …

Genome-Wide Analysis Of Dna Methylation Signatures Linking Prenatal Exposure To The Chinese Great Famine And Blood Lipids In Late Adulthood: The Genomic Research Of The Chinese Famine (Grecf) Study, Huan Wang, Luqi Shen, Tingting Liu, Ruiyuan Zhang, Zhenghe Wang, Jingkai Wei, Ye Shen, Jinzhen Guo, Toni Miles, Changwei Li, Zhiyong Zou

Faculty, Staff and Student Publications

Background/objectives: Prenatal exposure to famine can lead to lasting health effects through changes in DNA methylation. This study aims to evaluate the impact of prenatal exposure to the Chinses Great Famine (1959-1961) on human epigenome and the subsequent influence on blood lipids.

Methods: We conducted an epigenome-wide association study (EWAS) of peripheral blood-based DNA methylation and prenatal exposure to the Chinese Great Famine as well as blood lipids among eight participants exposed to famine and eight sex-matched participants (born ≤ 3 years after the famine). Genome-wide DNA methylation sites were profiled using the Illumina EPIC BeadChip, which covers 850K methylation …

A Needed Nomenclature For Nucleosomes, Michael-Christopher Keogh, Genevieve Almouzni, Andrew J Andrews, Karim-Jean Armache, Cheryl H Arrowsmith, Sung Hee Baek, Mark T Bedford, Emily Bernstein, Jacques Côté, Yael David, John M Denu, Beat Fierz, Benjamin A Garcia, Karen C Glass, Or Gozani, Kristian Helin, Steven Henikoff, Ole N Jensen, Steven Z Josefowicz, Neil L Kelleher, Tatiana G Kutateladze, Herbert H Lindner, Chao Lu, Karolin Luger, Parag Mallick, Catherine A Musselman, Tom W Muir, Ljiljana Paša-Tolić, Robert Schneider, Xiaobing Shi, Yang Shi, Simone Sidoli, Lloyd M Smith, Jessica K Tyler, Cynthia Wolberger, Jerry L Workman, Brian D Strahl, Nicolas L Young

Faculty, Staff and Student Publications

Histone post-translational modifications (PTMs) are crucial to eukaryotic genome regulation, with a range of reported functions and mechanisms of action. Though often studied individually, it has long been recognized that the modifications function by combinatorial synergy or antagonism. Interplay may involve PTMs on the same histone, within the same nucleosome (containing a histone octamer), or between nucleosomes in higher-order chromatin. Given this, the field must distinguish ever greater complexity, and the context in which it is studied, with brevity and precision. The proteoform was introduced to define individual forms of a protein by sequence and PTMs, followed by the nucleoform …

International Headache Society Evidence-Based Guidelines On The Use Of Non-Invasive Neuromodulation Devices For The Acute And Preventive Treatment Of Migraine, Hsiangkuo Yuan, Serena L. Orr, Mohammad A. M. Al-Karagholi, Messoud Ashina, Fred Cohen, Hans-Christoph Diener, David W. Dodick, Rigmor Højland Jensen, Michael J. Marmura, Daniele Martinelli, Manjit S. Matharu, Anja S. Petersen, Patricia Pozo-Rosich, Simona Sacco, Lucy Simmonds, Cristina Tassorelli, Stewart J. Tepper, Gisela M. Terwindt, Shuu-Jiun Wang, Jiunn-Tyng Yeh, Stephen D. Silberstein

Department of Jefferson Headache Center Papers and Presentations

ObjectiveTo develop evidence-based clinical practice guidelines for non-invasive neuromodulation devices in acute and preventive migraine treatment.MethodsA systematic review was conducted across six databases from 1946 to April 2025. Randomized controlled trials evaluating Food and Drug Administration-cleared or Conformité Européenne (CE)-marked non-invasive neuromodulation devices were included. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, and recommendations were developed through consensus following GRADE Evidence-to-Decision frameworks. The working group comprised 15 senior members and six junior members.ResultsFrom 1536 initial records, 15 studies met the inclusion criteria and were finally used to develop evidence-based recommendations. …

Humanized Mouse Models For Type 1 Diabetes., David V. Serreze, Marissa Tousey-Pfarrer, Jeremy Racine

Faculty Research 2025

T cell-mediated autoimmune type 1 diabetes (T1D) is under complex polygenic control in both humans and the NOD mouse model. However, in both species, particular major histocompatibility complex (MHC; designated HLA in humans) haplotypes provide the primary T1D risk factor. Both MHC/HLA class I and II variants interactively contribute to T1D by respectively driving autoreactive CD8 and CD4 T cell responses that cooperatively destroy insulin-producing pancreatic β cells. While NOD mice have provided important insights to the pathogenic basis of T1D, the model has so far provided only a limited means to identify possible clinically translatable disease intervention approaches. This …

Evaluation Of Hippocampal Dlgap2 Overexpression On Cognition, Synaptic Function, And Dendritic Spine Structure In A Translationally Relevant Ad Mouse Model., Andrew R Ouellette, Kristen M S O'Connell, Catherine Kaczorowski

Faculty Research 2025

INTRODUCTION: Developing effective therapeutics for Alzheimer's disease (AD) requires a better understanding of the molecular drivers of the disease. Our previous work nominated DLGAP2 as a modifier of age-related cognitive decline and risk for AD. We tested the hypothesis that overexpression of DLGAP2 in the hippocampus would protect against cognitive and synaptic deficits in a susceptible F1 5XFAD model.

METHODS: DLGAP2 was overexpressed in the hippocampus of F1 hybrid 5XFAD and non-transgenic littermates using a viral approach. Cognitive function, electrophysiological properties, and dendritic spine morphology were assessed at 6 and 14 months of age.

RESULTS: DLGAP2 overexpression impaired synaptic plasticity …

Genetic And Epigenetic Screens In Primary Human T Cells Link Candidate Causal Autoimmune Variants To T Cell Networks., Ching-Huang Ho, Maxwell A Dippel, Meghan S Mcquade, Leann P Nguyen, Arpit Mishra, Stephan Pribitzer, Samantha Hardy, Harshpreet Chandok, Florence M Chardon, Troy A Mcdiarmid, Hannah A Deberg, Jane H Buckner, Jay Shendure, Carl G De Boer, Michael H Guo, Ryan Tewhey, John P Ray

Faculty Research 2025

Genetic variants associated with autoimmune diseases are highly enriched within putative cis-regulatory regions of CD4⁺ T cells, suggesting that they could alter disease risk through changes in gene regulation. However, very few genetic variants have been shown to affect T cell gene expression or function. Here we tested >18,000 autoimmune disease-associated variants for allele-specific effects on expression using massively parallel reporter assays in primary human CD4⁺ T cells. We find 545 variants that modulate expression in an allele-specific manner (emVars). Primary T cell emVars greatly enrich for likely causal variants, are mediated by common upstream pathways and …

Expanding And Refining The Mammalian Phenotype Ontology To Enhance Disease Model Discovery., Susan M. Bello, Anna V Anagnostopoulos, Leigh Carmody, Nicolas Matentzoglu, Cynthia Smith

Faculty Research 2025

The mouse is a premier model system for investigating gene function and modeling human disease. For almost 40 years, Mouse Genome Informatics has worked to capture and integrate the data generated from mouse studies. A critical component of this integration is the development and use of the Mammalian Phenotype (MP) Ontology to capture the morphological and physiological effects of alterations to gene function in the mouse. As the wealth of phenotype data captured using the MP has expanded, its utility in the diagnosis of human disease has increased. Tools have been developed to use mouse and human phenotypes in variant …

Neuronal Activity-Dependent Gene Dysregulation In C9orf72 I3neuronal Models Of Als/Ftd Pathogenesis, Layla T. Ghaffari, Emily A. Welebob, Sarah E. Bond Newton, Ashley V. Boehringer, Kelly L. Cyliax, Piera Pasinelli, Davide Trotti, Aaron R. Haeusler

Farber Institute for Neuroscience Faculty Papers

The GGGGCC nucleotide repeat expansion (NRE) mutation in the C9ORF72 (C9) gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal activity plays an essential role in shaping biological processes within both healthy and neurodegenerative disease scenarios. Here, we show that at baseline conditions, C9-NRE-induced pluripotent stem cell-cortical neurons display aberrations in several pathways, including synaptic signaling and transcriptional machinery, potentially priming diseased neurons for an altered response to neuronal stimulation. Indeed, exposure to two pathophysiologically relevant stimulation modes, prolonged membrane depolarization or a blockade of K⁺ channels, followed by RNA sequencing, induces …

Role Of Growth Factors In The Pathogenesis Of Systemic-Sclerosis-Associated Fibrosis, Fabian A. Mendoza, Sonsoles Piera-Velazquez, Sergio A. Jimenez

Jefferson Institute of Molecular Medicine Papers and Presentations

Systemic Sclerosis (SSc) is a systemic autoimmune disease of unknown etiology characterized by a severe fibroproliferative vasculopathy and frequently progressive cutaneous and internal organ fibrosis. The small-vessel vasculopathy and the tissue fibrotic alterations are responsible for the most serious clinical and pathological manifestations of the disease and for its high mortality. Despite the high severity and frequent mortality, there are currently no optimal therapeutic approaches for SSc, and its complex pathogenesis has not been fully elucidated. Numerous studies have suggested that growth factors and related regulatory macromolecules released from inflammatory and other cells present in the affected tissues play a …

Concurrent Local Therapy Extends Clinical Benefit Of Tebentafusp In Metastatic Uveal Melanoma Patients, Tristan L. Lim, Kamaneh Montazeri, Eric Wehrenberg-Klee, Antoine Desilets, Rino S. Seedor, Marlana Orloff, Takami Sato, Michael Caplan, Mariam El-Ashmawy, Benjamin Izar, Shaheer Khan, Inderjit Mehmi, Aleigha Lawless, Theodore S. Hong, Omid Hamid, Richard D. Carvajal, Alexander Shoushtari, Ryan J. Sullivan

Kimmel Cancer Center Faculty Papers

BACKGROUND: Tebentafusp has significantly improved overall survival in HLA-A*02:01+ metastatic uveal melanoma (mUM) patients even in those with a best objective response of progressive disease. Thus, strategies to maintain tebentafusp therapy are critical. Here, we examine the efficacy and safety of adding concurrent local therapy (CLT) to tebentafusp upon radiological progression with tebentafusp alone.

PATIENTS AND METHODS: This multicenter retrospective study included mUM patients treated with tebentafusp and CLT, consisting of extrahepatic soft tissue irradiation and liver-directed therapies (LDTs). Efficacy of target and nontarget sites were assessed per RECIST version 1.1. PFS with tebentafusp alone (PFS1) was compared to that …

Hydrogen Sulfide Inhibits Recruitment Of Monocyte-Derived Tumor Associated Macrophages In Glioblastoma By Downregulating Cxcl12, Joseph Camarano, Morgan Roque, Gabrielle Gahn, Stephen Garrett Whipple, Danielle Terrell, Charles Ronkon, Jamie Toms, Anthony Sin, Bharat Guthikonda, Khatri Latha, Yuhui Yang, Xinggui Shen, Christopher G Kevil, Ganesh Rao, Sungho Lee

Faculty, Staff and Students Publications

Tumor associated macrophages (TAMs) directly contribute to the dismal prognosis of glioblastoma by preventing anti-tumor immunity and promoting tumor invasion and angiogenesis. Inhibiting TAM infiltration is a potential therapeutic strategy in glioblastoma, with several chemokine antagonists in early clinical development. Hydrogen sulfide, a gasotransmitter that regulates microglial accumulation in a wide range of CNS diseases, may be a novel therapeutic target to prevent TAM recruitment in glioblastoma. In this study, hydrogen sulfide concentrations were directly measured from 14 isocitrate dehydrogenase (IDH)-wildtype glioblastoma surgical samples and compared against overall survival as well as expression of TAM markers and chemokines. Effects of …

All-Cause And Cause-Specific Mortality Among Patients With Narcolepsy., Chih-Wei Hsu, Yen-Shan Yang, Yang-Chieh Brian Chen, Liang-Jen Wang, Mu-Hong Chen, Yao-Hsu Yang, Chih-Sung Liang, Edward Chia-Cheng Lai

Children’s Nutrition Research Center Staff Publications

Importance: Narcolepsy is a sleep disorder potentially affecting mortality, yet evidence on this association remains sparse.

Objective: To examine whether narcolepsy is associated with an increased risk of all-cause and cause-specific mortality.

Design, setting, and participants: This retrospective cohort study used data from the Taiwan National Health Insurance Research Database (NHIRD) from 2001 to 2021, with patients followed up until death or December 31, 2022. Patients were aged 6 years or older with 2 or more narcolepsy diagnoses from psychiatrists or neurologists. Controls were selected from the NHIRD as a population-based sample. Controls without narcolepsy were matched in a 1:4 …

The Effect Of Chronic Azithromycin Use In Winter On Health Care Utilization For Children With Bronchopulmonary Dysplasia: A Double Blind Randomized Controlled Study (Rct), Ricardo A Mosquera, Aravind Yadav, Maria Del Mar Romero-Lopez, Ivan G Magana-Ceballos, S Shahrukh Hashmi, Wilfredo De Jesus Rojas, Maria E Tellez, Kaleigh Riggs-Harpur, Fatima M Boricha, Tina S Reddy, Janice L John, Tomika S Harris, Carlos E Rodriguez-Martinez, Jefferson Buendia, Katrina E Mcbeth, Cindy K Jon, James M Stark, Giuseppe N Colasurdo

Faculty, Staff and Student Publications

Background: Bronchopulmonary dysplasia (BPD), a chronic lung disease in preterm infants, often leads to acute respiratory exacerbations triggered by infections. Our previous mouse study suggested that azithromycin's anti-inflammatory properties may benefit virus-induced respiratory illnesses prophylactically.

Methods: In this single-center, double-blind RCT, 60 children (6 months to 6 years) with BPD received azithromycin (5 mg/kg three times weekly; n = 30) or placebo (n = 30) for one winter season (October to March). Primary outcome was the total number of days of unscheduled healthcare clinic visits, ER visits, and hospital days. Secondary outcomes comprised clinic visits, ER visits, hospital admissions, hospital …

Bone Marrow Endosteum In Homeostasis And Metastasis, Yuta Nakai, Wanida Ono, Noriaki Ono

Faculty, Staff and Student Publications

The endosteum is a thin layer of connective tissue lining the inner surfaces of bones adjoining the medullary cavity. The endosteum houses a variety of cells crucial for bone growth, repair and remodelling, including bone-forming osteoblasts, bone-resorbing osteoclasts and their precursor cells. Historically, the endosteum has been extensively studied as a key site for haematopoiesis by which blood cells are incessantly produced. However, recent studies have defined the endosteum as a niche for skeletal stem cells, underscoring the importance of the harmony between the inner endosteum and the outer periosteum in maintaining bone homeostasis. The endosteum also plays a significant …

Slb-Mssim: A Spectral Library-Based Multiplex Segmented Sim Platform For Single-Cell Proteomic Analysis, Lakmini Senavirathna, Cheng Ma, Van-An Duong, Hong-Yuan Tsai, Ru Chen, Sheng Pan

The Brown Foundation: Institute of Molecular Medicine

Mass spectrometry (MS)-based single-cell proteomics, while highly challenging, offers unique potential for a wide range of applications to interrogate cellular heterogeneity, trajectories, and phenotypes at a functional level. We report here the development of the spectral library-based multiplex segmented selected ion monitoring (SLB-msSIM) method, a conceptually unique approach with significantly enhanced sensitivity and robustness for single-cell analysis. The single-cell MS data is acquired by a multiplex segmented selected ion monitoring (msSIM) technique, which sequentially applies multiple isolation cycles with the quadrupole using a wide isolation window in each cycle to accumulate and store precursor ions in the C-trap for a …

Sleep Eeg And Respiratory Biomarkers Of Sudden Unexpected Death In Epilepsy (Sudep): A Case-Control Study, Oman Magana-Tellez, Rama Maganti, Norma J Hupp, Xi Luo, Sandhya Rani, Johnson P Hampson, Manuela Ochoa-Urrea, Sudha S Tallavajhula, Rup K Sainju, Daniel Friedman, Maromi Nei, Brian K Gehlbach, Stephan Schuele, Ronald M Harper, Beate Diehl, Lisa M Bateman, Orrin Devinsky, George B Richerson, Samden D Lhatoo, Nuria Lacuey

Faculty, Staff and Student Publications

Background: Sudden unexpected death in epilepsy (SUDEP) is the most common category of epilepsy-related mortality. Centrally mediated respiratory dysfunction has been observed to lead to death in the majority of cases of SUDEP. SUDEP also mainly occurs during nighttime sleep. This study seeks to identify sleep EEG and sleep-related respiratory biomarkers of SUDEP risk.

Methods: In this case-control study, we compared demographic, clinical, EEG, and respiratory data from people with epilepsy who later died of SUDEP (the SUDEP group) with data from age and sex-matched living people with epilepsy, classified as high risk of SUDEP (with ≥1 generalised tonic-clonic seizure …

Mitochondrial Haplogroups, But Not Heteroplasmy, Are Associated With Midlife Cognitive Function, Nien Yeh Daphne Yu, Shea J Andrews, Lifang Hou, Myriam Fornage, Kristine Yaffe

Faculty, Staff and Student Publications

Introduction: Mitochondrial DNA (mtDNA) variation may influence cognitive performance, but prior findings are inconsistent.

Methods: We analyzed data from 2308 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study, assessing heteroplasmy (mtHz) burden and haplogroups (mtHg) from blood-derived mtDNA at three timepoints and cognitive function across multiple domains. Multivariate linear regression models and multivariate linear mixed models adjusted for age, sex, education, and race.

Results: MtDNA heteroplasmy burden and count were not associated with cognitive performance. However, mtHgs in macro-mtHg L were linked to poorer cognitive outcomes, particularly in processing speed and global cognition in cross-sectional and …

Three-Dimensional Human Mucopolysaccharidosis Iva Chondrocyte Culture Reveals Significant Impairments In The Lysosomal-Mitochondrial Crosstalk, Andrés Felipe Leal, Sampurna Saikia, Shaukat A. Khan, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder (LSD) caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase enzyme. MPS IVA patients suffer from skeletal dysplasia due to the abnormal function of chondrocytes. Given the interactions of lysosomes with various intracellular organelles, it is not surprising that lysosomal dysfunction can lead to improper functioning of lysosome-interacting organelles such as mitochondria. Mitochondrial alterations have been evaluated in several LSDs; nevertheless, they have not been fully addressed in MPS IVA. In this study, we assessed the mitochondrial alterations in MPS IVA chondrocytes using a three-dimensional culture approach. Our findings revealed that MPS IVA …

Recapitulating The Immune Microenvironment In Pediatric Brain Cancer: Preclinical Modeling Strategies., Adip G. Bhargav, Joseph S. Domino, David Akhavan, Jo Ling Goh

Manuscripts, Articles, Book Chapters and Other Papers

Primary brain and CNS tumors comprise the most common tumors in children and are the most common cause of cancer deaths in this population. Pediatric primary malignant brain tumors including high-grade glioma and medulloblastoma account for a significant proportion of these cancer deaths. Advances in the surgical management and adjuvant treatment paradigms have improved the prognosis of many patients with these tumors, but there remains a subset of treatment-resistant tumors or tumors with unique genetics aberrations and aggressive phenotypes that confer a poor prognosis. Immunotherapeutic strategies have demonstrated promise in pre-clinical studies and early clinical trials. However, high-fidelity evaluation of …

Consensus Recommendations For Hyperpolarized [1- 13c]Pyruvate Mri Multi-Center Human Studies, Shonit Punwani, Peder E Z Larson, Christoffer Laustsen, Jan Vandermeulen, Jan Henrik Ardenkjær-Larsen, Adam W Autry, James A Bankson, Jenna Bernard, Robert Bok, Lotte Bonde Bertelsen, Jenny Che, Albert P Chen, Rafat Chowdhury, Arnaud Comment, Charles H Cunningham, Duy Dang, Ferdia A Gallagher, Adam Gaunt, Yangcan Gong, Jeremy W Gordon, Ashley Grimmer, James Grist, Esben Søvsø Szocska Hansen, Mathilde Hauge Lerche, Richard L Hesketh, Jan-Bernd Hoevener, Ching-Yi Hsieh, Kayvan R Keshari, Sebastian Kozerke, Titus Lanz, Dirk Mayer, Mary Mclean, Jae Mo Park, Jim Slater, Damian Tyler, Jean-Luc Vanderheyden, Cornelius Von Morze, Fulvio Zaccagna, Vlad Zaha, Duan Xu, Daniel Vigneron

Faculty, Staff and Student Publications

MRI of hyperpolarized (HP) [1‐13C]pyruvate allows in vivo assessment of metabolism and has translated into human studies across diseases at 15 centers worldwide. To determine consensus on best practice for multi‐center studies for development of clinical applications. This paper presents the results of a two‐round formal consensus building exercise carried out by experts with HP [1‐13C]pyruvate human study experience. Twenty‐nine participants from 13 sites brought together expertise in pharmacy methods, MR physics, translational imaging, and data analysis with the goal of providing recommendations and best practice statements on conduct of multi‐center human studies of HP [1‐13C]pyruvate MRI. Overall, the group …

Pan-Uk Biobank Genome-Wide Association Analyses Enhance Discovery And Resolution Of Ancestry-Enriched Effects, Konrad J Karczewski, Rahul Gupta, Masahiro Kanai, Wenhan Lu, Kristin Tsuo, Ying Wang, Raymond K Walters, Patrick Turley, Shawneequa Callier, Nirav N Shah, Nikolas Baya, Duncan S Palmer, Jacqueline I Goldstein, Gopal Sarma, Matthew Solomonson, Nathan Cheng, Sam Bryant, Claire Churchhouse, Caroline M Cusick, Timothy Poterba, John Compitello, Daniel King, Wei Zhou, Cotton Seed, Hilary K Finucane, Mark J Daly, Benjamin M Neale, Elizabeth G Atkinson, Alicia R Martin

Faculty, Staff and Students Publications

Large biobanks, such as the UK Biobank (UKB), enable massive phenome by genome-wide association studies that elucidate genetic etiology of complex traits. However, individuals from diverse genetic ancestry groups are often excluded from association analyses due to concerns about population structure introducing false positive associations. Here, we generate mixed model associations and meta-analyses across genetic ancestry groups, inclusive of a larger fraction of the UKB than previous efforts, to produce freely-available summary statistics for 7,266 traits. We build a quality control and analysis framework informed by genetic architecture. Overall, we identify 14,676 significant loci (p < 5 × 10−8) in the meta-analysis that were not found in the EUR genetic ancestry group alone, including novel associations for example between CAMK2D and triglycerides. We also …

Ideate-Lung02: A Phase 3 Study Of Second-Line Ifinatamab Deruxtecan In Patients With Relapsed Small Cell Lung Cancer, Taofeek K Owonikoko, Lauren Byers, Ying Cheng, Hidetoshi Hayashi, Luis Paz-Ares, Maurice Pérol, Haichuan Hu, Meng Qian, Cecilio Roi Garcia, Juliette Godard, Mei Tang, Charles M Rudin

Faculty, Staff and Student Publications

Patients with small cell lung cancer (SCLC) have poor prognosis and limited treatment options beyond first-line therapy. B7 homolog 3 (B7-H3) is minimally expressed in normal tissues but highly expressed in SCLC. Ifinatamab deruxtecan (I-DXd), a B7-H3-directed antibody-drug conjugate, has demonstrated promising efficacy and a manageable safety profile in various tumours, including SCLC. IDeate-Lung02 is a global, randomized, open-label Phase 3 study of ~540 patients with relapsed SCLC. Adults with one prior line of platinum-based systemic therapy, ECOG performance status 0-1, and ≥1 measurable lesion (per RECIST 1.1) are eligible for study participation. Patients with asymptomatic untreated or previously treated …