Digital Commons Network^™

Circulating Fatty Acid Binding Protein 4 (Fabp-4) Concentrations And Mortality In Individuals With Colorectal Cancer In The European Prospective Investigation Into Cancer And Nutrition Study, Thu Thi Pham, Katharina Nimptsch, Krasimira Aleksandrova, Mazda Jenab, Veronika Fedirko, Anja Olsen, Anne Tjønneland, Claire Cadeau, Gianluca Severi, Matthias B Schulze, Renée Turzanski Fortner, Verena Katzke, Claudia Agnoli, Carlotta Sacerdote, Rosario Tumino, Simona Signoriello, Camino Trobajo-Sanmartín, Jesús-Humberto Gómez, María-Dolores Chirlaque, Maria-Jose Sánchez, Marta Crous-Bou, Anne May, Alicia Heath, Dagfinn Aune, Elisabete Weiderpass, Tobias Pischon

Faculty, Staff and Student Publications

Human fatty acid binding protein‐4 (FABP‐4), a protein elevated in obesity that promotes colon cancer cell invasiveness and metastasis, may be associated with higher mortality in individuals with colorectal cancer (CRC) and may serve as a mediator of the obesity–mortality association in these individuals. We used a causal diagram to inform covariate selection and applied Cox proportional hazards models to estimate hazard ratios (HRs) for CRC‐specific, non‐CRC‐specific, and all‐cause mortality by FABP‐4 levels measured in baseline blood samples from 1371 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. Competing risk analyses were adapted for CRC …

Hypoglossal Neuropathy In The Pathogenesis Of Fibrosis-Related Late-Radiation Associated Dysphagia: A Correlative Analysis Utilizing Electromyography To Explore The Frequency Of Clinical And Subclinical Neuropathy In A Pilot Dysphagia Trial, Holly Mcmillan, Christine Okoro, Sheila Buoy, Karin Woodman, Nicolaas Anderson, Clifton Fuller, Stephen Y Lai, Katherine Hutcheson

Faculty, Staff and Student Publications

Background: Late radiation-associated dysphagia (late-RAD) commonly presents in patients with signs of hypoglossal neuropathy, with hallmark clinical features including lingual atrophy, deviation, and fasciculation. Gold-standard electromyography (EMG) has not been used to explore the frequency of hypoglossal neuropathy in patients with late-RAD.

Methods: Exploratory post hoc secondary analysis of MANTLE trial (NCT03612531) was completed. The presence of cranial nerve XII (CN XII) neuropathy was classified by (1) features of clinical assessment as well as (2) intramuscular genioglossus EMG pre-MANTLE intervention in disease-free HNC survivors ≥ 2 years post-radiotherapy (RT) with grade ≥ 2 fibrosis and dysphagia.

Results: All …

Impact Of Treatment Interruption On Outcomes In Head And Neck Cancer: Nrg/Rtog Secondary Analysis, Laila A Gharzai, Emily Morris, Matthew J Schipper, Kelley M Kidwell, Phuc Felix Nguyen-Tân, David I Rosenthal, Maura L Gillison, Richard C Jordan, Adam S Garden, Shlomo A Koyfman, Jimmy J Caudell, Dukagjin M Blakaj, Neal E Dunlap, Greg A Krempl, John M Longo, Christopher U Jones, Michael F Gensheimer, Thomas J Galloway, Lyudmila Demora, Quynh-Thu Le, Jennifer L Shah, Krithika Suresh, Michelle Mierzwa

Faculty, Staff and Student Publications

Importance: Historical evidence demonstrated that delays or interruptions in radiotherapy (RT) are associated with poorer oncologic outcomes in head and neck squamous cell carcinoma (HNSCC). Substantial concerns arose during the COVID-19 pandemic, when treatment schedules were frequently disrupted.

Objective: To determine the association of RT interruptions with locoregional failure (LRF) and overall survival (OS).

Design, setting, and participants: This retrospective review and secondary analysis of 3 randomized clinical trials (NRG/RTOG 0129, 0522, and 1016) included patients enrolled in the trials who were treated with RT. Patients with HNSCC were grouped as (1) p16-positive oropharynx (p16+ OPSCC) and (2) p16-negative oropharynx …

A Step-By-Step Guide To Performing Cancer Metabolism Research Using Custom-Made Media, Sophie Seifert, Francisco Yanqui-Rivera, Tim Kühn, Lena Elise Høyland, Toman Borteçen, Bella Agranovich, Lara Elea Eckhardt, Martin Herdt, Alessa Henneberg, Verena Panitz, Faisal Hayat, Marie Migaud, Gernot Poschet, Ifat Abramovich, Eyal Gottlieb, Jeroen Krijgsveld, Mathias Ziegler, Mirja Tamara Prentzell, Christiane A Opitz

Faculty, Staff and Student Publications

The preparation of custom-made media offers precise control over nutrient composition, enabling detailed studies of cellular metabolism. We demonstrate how self-made media formulations enable diverse assay designs and readouts to assess cancer metabolism. Self-made media can be used in Seahorse assays to measure mitochondrial respiration under defined conditions. In nutrient deprivation experiments, amino acid or vitamin removal can uncover how cancer cells adapt to metabolic stress. Using labeled amino acids enables analysis of nascent protein synthesis and translational regulation, while stable-isotope tracing reveals metabolic fluxes through key pathways. This guide presents a suite of metabolic assays using custom-made media, covering …

Acta2 Pathogenic Variants Activating Heat Shock Factor 1 And Increasing Cholesterol Biosynthesis In Smooth Muscle Cells Predispose To Early Onset Atherosclerosis, Maura L Boerio, Abhijnan Chattopadhyay, Xue-Yan Duan, Aamuktha Karla, Ernesto Calderon Martinez, Amelie Pinard, Andrew K Morse, Darshan Reddy, Sree Dharma, Walter Velasco-Torrez, Julien Marcadier, Siddharth K Prakash, Sherene Shalhub, Julie De Backer, Richmond Jeremy, Shaine A Morris, Anji T Yetman, Alan C Braverman, Dianna M Milewicz

Faculty, Staff and Student Publications

Background: ACTA2 pathogenic variants predispose to thoracic aortic disease, and a subset of variants lead to early onset atherosclerotic cardiovascular disease (ASCVD). The molecular pathway linking misfolded SMA (α-smooth muscle actin) monomers to augmented atherosclerosis-associated smooth muscle cell phenotypic modulation can be modeled in vitro by stably expressing the ACTA2 p.R149C variant in Acta2-/- smooth muscle cells.

Methods: The Montalcino Aortic Consortium patient registry was used to identify cases with ACTA2 pathogenic/likely pathogenic missense variants. These patients were surveyed, and medical records were reviewed, to identify cases with early onset ASCVD. The variants for these cases, as well as …

Quantitative Analysis Of Robustness-Based Versus Let-Based Optimization In Intensity-Modulated Proton Therapy For Pediatric Brain Tumors, Fariha Kabir Torsha, Gino Lim, Hadis Moazami Goudarzi, Radhe Mohan, David Grosshans, Wenhua Cao

Faculty, Staff and Student Publications

Purpose: To perform a quantitative analysis of the trade-off between robustness-based and linear energy transfer (LET)-based optimization of intensity-modulated proton therapy for anatomically challenging pediatric brain tumor cases.

Methods: Three pediatric brain tumor patients were included in this study. Three plans were generated for each case based on: (1) nominal optimization, without considering uncertainties and LET; (2) robust optimization, including proton range and patient setup uncertainties; and (3) LET optimization, considering increasing LET in the target and reducing LET in normal tissues. All plans were optimized with individually fine-tuned objective weighing to obtain highest achievable target coverage and meet dose …

Presenilin L166p Mutation, A Model Of Familial Alzheimer's Disease, Leads To Early Onset Bone Loss, Vidyani Suryadevara, Connor J Krehbial, Anuradha K Valiya, Melinda Vang, Julian Balanta-Melo, Pierre P Eleniste, Sumana Posritong, Jung Min Hong, Katie Chester, Gabriel M Pagnotti, Teresita Bellido, Monte S Willis, Angela Bruzzaniti

Faculty, Staff and Student Publications

Accelerated bone loss has been reported in the early stages of Alzheimer's disease (AD) as indicated by reduced bone mineral density and increased fracture risk in these patients, compared to healthy individuals. In the present study, we investigated bone loss in mouse models of familial Alzheimer's disease harboring the Presenilin 1 (L166P) knock-in mutation (PSEN1 KI), with or without the human amyloid precursor protein transgene (hAPP Tg+) known to induce brain amyloid pathology by 6 months. Female and not male 12-month PSEN1/hAPP Tg+ mice exhibited reduced whole-body bone mineral density and bone mineral content, compared to sex-matched controls. Consistent with …

Prism-Xqtl: Pleiotropic Relationships Integrated With System-Level Multiomic Qtl Analysis For Causal Genes And Molecular Mediators In Alzheimer’S Disease, Nitesh Enduru, Zhongming Zhao

Faculty, Staff and Student Publications

Introduction: Most Alzheimer's disease (AD) risk variants identified by genome-wide association studies (GWAS) reside in noncoding regions, complicating causal interpretation.

Methods: We developed PRISM-xQTL (Pleiotropic Relationships Integrated with System-level Multiomic QTL), integrating pleiotropy, co-localization, Mendelian randomization, and mediation analyses across multiomic quantitative trait loci (QTLs; expression QTL [eQTL], methylation QTL [meQTL], splicing QTL [sQTL], proteomic [pQTL], single-cell [sc-eQTL]). Seventy pleiotropic single-nucleotide polymorphisms (SNPs) shared between AD and 11 immune disorders were analyzed. AlphaGenome assessed functional regulation, and The Alzheimer's Cell Atlas (TACA) database was used for drug-target relevance of FCER1G.

Results: Across 54 Genotype-Tissue Expression (GTEx) tissues, 410 SNP-gene-tissue co-localizations …

A Guide To Transcriptomic Deconvolution In Cancer, Yaoyi Dai, Shuai Guo, Yidan Pan, Carla Castignani, Matthew D Montierth, Peter Van Loo, Wenyi Wang

Faculty, Staff and Student Publications

Cancer tissues are heterogeneous mixtures of tumour, stromal and immune cells, where each component comprises multiple distinct cell types and/or states. Mapping this heterogeneity and understanding the unique contributions of each cell type to the tumour transcriptome is crucial for advancing cancer biology, yet high-throughput expression profiles from tumour tissues only represent combined signals from all cellular sources. Computational deconvolution of these mixed signals has emerged as a powerful approach to dissect both cellular composition and cell-type-specific expression patterns. Here, we provide a comprehensive guide to transcriptomic deconvolution, specifically tailored for cancer researchers, presenting a systematic framework for selecting and …

Stimulated Cytokine Production, Attachment, And Emotional Well-Being In Dementia Spousal Caregivers, Daniel L Argueta, Sarah Roberts, Kelly N Brice, E Lydia Wu-Chung, Vincent D Lai, Jensine Paoletti-Hatcher, Bryan T Denny, Charles Green, Samantha Henry, Luis D Medina, Paul E Schulz, Jennifer Stinson, Cobi Heijnen, Christopher P Fagundes

Faculty, Staff and Student Publications

Background: Proinflammatory cytokine production may be related to poor emotional adjustment in dementia spousal caregivers. People who display attachment insecurity may be at increased risk for adverse caregiving experiences and poor psychosocial outcomes.

Objective: This study aimed to understand whether proinflammatory cytokine production was associated with anticipatory grief, caregiver burden, and depressive symptoms and whether those relationships were stronger for caregivers higher on attachment anxiety or avoidance.

Method: A sample of 103 dementia spousal caregivers provided self-report data on demographics, health information, and psychosocial outcomes. We also determined lipopolysaccharide-induced whole-blood interleukin-6, interleukin-1β, tumor necrosis factor-α, and interleukin-10 production and combined …

Decellularized Extracellular Matrix Scaffolds To Engineer The Dormant Landscape Of Microscopic Colorectal Cancer Liver Metastasis, Sabrina N Vandenheuvel, Lucia L Nash, Abigail J Clevenger, Claudia A Collier, Oscar R Benavides, Sanjana Roy, Brinlee Goggans, Aelita Salikhova, Anvitha Tharakesh, Svasti Haricharan, Amber N Stratman, Scott Kopetz, Alex J Walsh, Shreya A Raghavan

Faculty, Staff and Student Publications

Recurrent liver-metastatic colorectal cancer contributes to high mortality. Recurrence occurs when dormant, microscopic residual disease survives initial treatment to escape dormancy. In their dormant, microscopic state within the liver, these metastatic lesions are undetectable by clinical diagnostic imaging until they form overt, chemoresistant metastases. Therefore, understanding the molecular mechanisms underlying dormancy in colorectal cancer liver metastases is a significant knowledge gap, motivating the engineering of nuanced in vitro models of disease. The current work presents an engineered model of liver-metastatic colorectal cancer dormancy. Decellularized extracellular matrix (dECM) scaffolds are used to provide microscopic colorectal cancer cell clusters with a biomimetic, …

Local Delivery Of Mir-27a* Using Ultrasound-Targeted Microbubble Cavitation Inhibits Squamous Cell Carcinoma Growth, Nikhil S Chari, Cheng Chen, Thiruganesh Ramasamy, Xucai Chen, Geetika Wadhwa, Anurag N Paranjape, Stephen Y Lai, Flordeliza S Villanueva

Faculty, Staff and Student Publications

Objective: Ultrasound-targeted microbubble (MB) cavitation (UTMC) is an image-guided therapeutic oligonucleotide delivery platform utilizing intravenously injected gas-filled ultrasound contrast agents, which carry the therapeutic on the MB shell. During transit of MBs in the microcirculation of target tissue, ultrasound causes MB oscillation, facilitating endocytosis-independent payload uptake within insonified cells. Here, we tested the hypothesis that UTMC-mediated miR-27a* delivery will reduce tumor growth rate and result in accumulation of miR-27a* within tumor cells and the tumor microenvironment.

Methods: We used UTMC to deliver miR-27a* to SCC-VII cells in vitro and in SCC-VII mouse tumor models. Pulsed ultrasound was delivered during intravenous …

Who Classification Of Skin Tumours: Key Updates In The Fifth Edition, Gabrielle Goldman-Lévy, Raymond Barnhill, Boris C Bastian, Werner Kempf, David Elder, Pedram Gerami, Wayne Grayson, Dmitry Kazakov, Daniela Massi, Jane Messina, Arnaud De La Fouchardière, Alexander J Lazar, Thomas Brenn, Brian Rous, Andrew Field, Anthony Gill, Jennelle C Hodge, Joseph D Khoury, Katia Leite, Shahin Sayed, Puay Hoon Tan, Rosalie Elenitsas, Eduardo Calonje, Lyn M Duncan, Liang Zhiyong, Holger Moch, Rajendra Singh, Harshima Wijesinghe, Ian Cree, Dilani Lokuhetty

Faculty, Staff and Student Publications

The 5th edition of the World Health Organization Classification of Tumours (WCT) serves as a foundation for global diagnostic standards in tumour pathology. Similar to other volumes in this series, the Skin Tumours (Skin5) edition follows a standardized approach. This edition introduces two new chapters: 'Tumours of the nail unit' and 'Metastases to skin', along with new entities across relevant chapters. This review article provides an overview of the updates in Skin5 based on currently published evidence, with emphasis on newly introduced chapters and newly described entities that involve the skin, in particular, epidermal, melanocytic and appendageal tumours.

A Comparative Study Of Statistical Methods For Identifying Differentially Expressed Genes In Spatial Transcriptomics, Yishan Wang, Chenxuan Zang, Ziyi Li, Charles C Guo, Dejian Lai, Peng Wei

Faculty, Staff and Student Publications

Spatial transcriptomics (ST) provides unprecedented insights into gene expression patterns while retaining spatial context, making it a valuable tool for understanding complex tissue architectures, such as those found in cancers. Seurat, by far the most popular tool for analyzing ST data, uses the Wilcoxon rank-sum test by default for differential expression analysis. However, as a nonparametric method that disregards spatial correlations, the Wilcoxon test can lead to inflated false positive rates and misleading findings. This limitation highlights the need for a more robust statistical approach that effectively incorporates spatial correlations. To this end, we propose a Generalized Estimating Equations (GEE) …

Melody: Mediation Analysis In Logistic Regression For High-Dimensional Mediators And A Binary Outcome, Sunyi Chi, Xingyu Li, Peng Wei, Xuelin Huang

Faculty, Staff and Student Publications

Mediation analysis is a pivotal tool for elucidating the indirect effect of an environmental factor or treatment on disease through potentially high‐dimensional omics data, such as gene expression profiles. However, traditional mediation analysis methods tailored for binary outcomes often rely on the rare disease assumption in logistic regression and provide inadequate measures of total mediation effect when multiple mediators have effects in different directions. In this paper, we develop a MEdiation analysis framework in LOgistic regression for high‐Dimensional mediators and a binarY outcome (MELODY). It leverages a second‐moment‐based measure analogous to the ��2 for linear models to quantify the total …

The Concept Of Environmental Injustice In Allergy And Asthma, Ekta Perera, Christopher Codispoti, Mahboobeh Mahdavinia

Faculty, Staff and Student Publications

Purpose of review: This review examines how environmental injustice contributes to disparities in allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis. It focuses on the role of social, geographic, and economic inequities in shaping disease prevalence, severity, and access to care among underrepresented racial and ethnic communities.

Recent findings: Recent studies emphasize the persistent exposure of low-income and racially marginalized populations to environmental hazards such as air pollution, substandard housing, and climate-related changes, factors that are linked to increased prevalence and severity of allergic diseases. While environmental policies have led to overall improvements in air quality, disparities in exposure …

Investigating The Oxygen Dependence Of Flash-Rt Using Electron Paramagnetic Resonance Imaging, Trey Waldrop, Grace Murley, Brett Velasquez, Elise Konradsson, Denae Neill, Luke Connell, Alan Lopez Hernandez, Abagail Delahoussaye, F William Schuler, Jorge De La Cerda, Ziyi Li, Mark D Pagel, Emil Schüler

Faculty, Staff and Student Publications

Purpose: The FLASH effect occurs when radiation given at ultra-high dose rates spares healthy tissue while achieving isoeffective tumor control relative to conventional (CONV) dose rate irradiation. Limited data has implicated oxygen in the FLASH effect. This study investigated the effect of tissue oxygen tension (pO2) on gastrointestinal (GI) FLASH sparing in mice.

Methods: pO2 was quantified in vivo by electron paramagnetic resonance imaging (EPRI)- noninvasive oximetry through spin probe injection and magnetic resonance co-registration- and a phosphorescent quenching microsensor. B6(Cg)-Tyrc-2 J/J female mice were imaged while breathing 10%, 21%, and 95% oxygen. C57BL/6 mice of both sexes underwent microsensor …

Tbr2-Dependent Parallel Pathways Regulate The Development Of Distinct Iprgc Subtypes, Takae Kiyama, Ching-Kang Chen, Halit Y Altay, Yu-Jiun Chen, Leviette Sigala, Dan Su, Steven Eliason, Brad A Amendt, Chai-An Mao

Faculty, Staff and Student Publications

The intrinsically photosensitive retinal ganglion cells (ipRGC) are the conduit between the retina and brain regions responsible for non-image-forming and image-forming vision. In mice, six ipRGC subtypes have been discovered based on morphological characteristics, functions, and molecular profiles. All ipRGCs arise from Tbr2-expressing RGCs during developmental stages and subsequently diverge and differentiate into the six mature, distinct subtypes in adult retinas. However, the cellular and molecular mechanisms controlling the formation and maturation of the six ipRGC subtypes remain elusive. Here, we demonstrate that two Tbr2-dependent transcription factors, Iroquois‑related homeobox 1 (Irx1) and T-box containing factor 20 (Tbx20), are key downstream …

Leveraging Large Language Models For Heuristic Usability Assessment Of Medical Software: Insights With The Radiation Planning Assistant, Laurence E Court, Jacobus Smit, Lourens Strauss, William Shaw, Andrea Marais, Christoph Trauernicht, Nanette Joubert, Elaine Smith, Shona Badre, Graeme L Lazarus, Thekiso Khotle, Lauren Netherton, Wanda Van Heerden, Carlos Cardenas, Monica Serban, Jan Seuntjens, Christine V Chung, Pavel Govyadinov, Meena Khan, Saurabh Nair, Tucker Netherton, Lifei Zhang

Faculty, Staff and Student Publications

Background: Usability engineering is essential for ensuring the safety and effectiveness of medical software, as design-related issues are a leading cause of use errors in clinical settings. Heuristic evaluation provides a practical approach to identifying usability problems, but its outcomes depend heavily on expert interpretation. Large Language Models (LLMs), such as ChatGPT, offer a potential means to augment heuristic evaluation by generating structured, context-aware usability feedback. This study explored the use of ChatGPT to support heuristic assessment of the Radiation Planning Assistant (RPA), a web-based radiotherapy planning tool designed to support clinical teams in low- and middle-income countries.

Methods: ChatGPT …

Neurological Recovery After Ich Is Mediated By The Aryl Hydrocarbon Receptor-Bilirubin Interplay Through Improved Erythrophagocytosis, Xiurong Zhao, Shun-Ming Ting, Guanghua Sun, Jaroslaw Aronowski

Faculty, Staff and Student Publications

Hematoma clearance after ICH is a pro-hemostatic process aiming at repair/recovery and is achieved through microglia/macrophages (MMΦ)-mediated erythrophagocytosis. Upon the engulfment of masses of erythrocytes and toxic hemolysis products, hemoglobin and heme, phagocytes convert them to bilirubin (BrB). Bilirubin is essentially not soluble in water and when overproduced, it precipitates within the cell causing injury. Thus, keeping bilirubin soluble and at a low intracellular level is needed for proper function of MMΦ. Here, using cultured microglia (MG), we found that intracellular formation of BrB in microglia during erythrophagocytosis coincides with the activation of transcription factor AhR, and AhR target genes …

Venous Thromboembolism In Aggressive B-Cell Lymphoma Patients Treated With Cd19 Car-T Therapy: Single-Institution Study, Neha Venkatesh, Kevin Milligan, Julia Parrish, Yun Qing, Ryan Sun, Paolo Strati, Jeremy Ramdial, Amy Ayers, Sairah Ahmed, Cristhiam Rojas Hernandez

Faculty, Staff and Student Publications

Background: Large B-cell lymphomas (LBCLs) are a common subtype of non-Hodgkin lymphomas. CD19 chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized LBCL treatment, with high remission rates but also significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Venous thromboembolism (VTE) in CAR-T therapy patients is understudied.

Objective: This study aims to determine the incidence and characteristics of acute VTE in LBCL patients treated with CAR-T therapy and identify baseline clinical features associated with VTE. Methods: We retrospectively reviewed 172 adult LBCL patients treated with CAR-T therapy from January 2018 to November 2019 at MD …

An Examination Of Racial Bias In Scoring The Autism Diagnostic Observation Schedule (Ados) Module 3: An Item Response Theory Analysis, Yuen Yvonne Yu, Austin Wyman, Calliana J Faulk, Lizzy J Fulop, Rebecca L Greenberg, Rachel M Benecke, Lauren K Steinbeck, Jessica Foy, Caitlyn Kim, George O Emory, Eric A Storch, Casey J Zampella, Benjamin E Yerys, Robert T Schultz, Julia Parish-Morris, John D Herrington, Caitlin C Clements

Faculty, Staff and Students Publications

Given the rising prevalence of autism among racial minority children in the United States, but persistent service use disparities, this study examines potential bias in specific items from the autism diagnostic observation schedule (ADOS), a highly regarded autism evaluation. We leveraged unidimensional item response theory graded response models and a sample of 735 children to analyze the differential item functioning (DIF) of items within ADOS Module 3. Three items showed significant signs of racial bias: A1 (overall language level), A5 (offers information), and D5 (compulsions and rituals). On these items, Black/African American and Asian children were usually more likely to …

Rethinking The Centrality Of Brain Areas In Understanding Functional Organization, Benjamin Yost Hayden, Sarah R Heilbronner, Seng Bum Michael Yoo

Faculty, Staff and Students Publications

Parcellation of the cerebral cortex into functionally modular brain areas is foundational to cognitive and systems neuroscience. Here, we question the central status of brain areas from the perspectives of neuroanatomy and electrophysiology. We argue that the major ostensible determinants of brain function, such as cytoarchitecture and connectivity, seldom produce convergent parcellations. Brain areas themselves are just one of several equally important organizing principles; others include macroscale gradients, distributed networks, layers, columns and patches. We further argue that the evidence for a close correspondence between areal parcellation and cognitive function is weaker than is generally supposed. Indeed, many important cognitive …

Multi-Trait And Multi-Ancestry Genetic Analysis Of Comorbid Lung Diseases And Traits Improves Genetic Discovery And Polygenic Risk Prediction, Yixuan He, Wenhan Lu, Yon Ho Jee, Mu-Yi Shih, Ying Wang, Kristin Tsuo, David C Qian, James A Diao, Hailiang Huang, Chirag J Patel, Jinyoung Byun, Bogdan Pasaniuc, Elizabeth G Atkinson, Christopher I Amos, Yen-Chen Anne Feng, Matthew Moll, Michael H Cho, Alicia R Martin

Faculty, Staff and Students Publications

While respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma share many risk factors, most studies investigate them in isolation and in predominantly European-ancestry populations. Here, we conducted the most powerful multi-trait and multi-ancestry genetic analysis of respiratory diseases and auxiliary traits to date, identifying 25 new loci associated with lung function in individuals of East Asian ancestry. Using these results, we developed PRSxtra (cross-trait and cross-ancestry), a multi-trait and multi-ancestry polygenic risk score (PRS) approach that leverages shared components of heritable risk via pleiotropic effects. PRSxtra significantly improved the prediction of asthma, COPD and lung cancer compared …

13 C-Spirulina Gastric Emptying Breath Test Normative Values In Healthy Children: A Multicenter Study With Comparison To Symptomatic Children, Katja Karrento, Bruno P Chumpitazi, Liyun Zhang, Pippa Simpson, Robert J Shulman

Faculty, Staff and Students Publications

Introduction: Diagnosing pediatric gastroparesis presents a significant challenge due to lack of normative data in children. We aimed to determine normative values for gastric emptying using the nonradioactive 13 C-Spirulina gastric emptying breath test ( 13 C-GEBT) in a large cohort of healthy children (HC) and examine differences compared to children with gastroparesis-like symptoms (GLS).

Methods: A total of 301 HC ages 7-18 years completed the 13 C-GEBT with 10 different breath samples × 4 hours. 13 CO 2 excretion rate (kPCD) was determined by change in 13 CO 2 / 12 CO 2 . Outcome variables included: kPCD at …

Single-Cell Atlas Of The Transcriptome And Chromatin Accessibility In The Human Retina, Jin Li, Jun Wang, Ignacio L Ibarra, Xuesen Cheng, Malte D Luecken, Jiaxiong Lu, Aboozar Monavarfeshani, Wenjun Yan, Yiqiao Zheng, Zhen Zuo, Samantha Lynn Zayas Colborn, Berenice Sarahi Cortez, Leah A Owen, Brittney Wick, Xuan Bao, Jongsu Choi, Maximilian Haeussler, Nicholas M Tran, Karthik Shekhar, Joshua R Sanes, J Timothy Stout, Shiming Chen, Yumei Li, Margaret M Deangelis, Fabian J Theis, Rui Chen

Faculty, Staff and Students Publications

Single-cell sequencing has revolutionized the scale and resolution of molecular profiling of tissues and organs. Here we present an integrated dual-modal reference atlas of the most accessible portion of the mammalian central nervous system, the retina. We compiled around 3.9 million cells from 125 donors of diverse ancestral backgrounds, including 8 published studies and 2.7 million unpublished data points, to create a comprehensive human retina cell atlas (HRCA) with more than 130 cell types identified. We annotated each cluster, identified marker genes and characterized cis-regulatory elements and gene regulatory networks. Our analysis uncovered differences in transcriptome, chromatin and gene regulatory …

Hyperglycemia, Receptor For Advanced Glycation End Products, And Small Airways Dysfunction In Asthma, Paula Sierra Salas, Dennis T Villareal, Vickram Tejwani, Amrit Koirala, Cristian Coarfa, Meredith C Mccormack, Nicola A Hanania, Tianshi David Wu

Faculty, Staff and Students Publications

Background: Diabetes and insulin resistance are associated with higher risk of asthma exacerbation and preserved ratio impaired spirometry (PRISm), but the pathophysiology is unclear. These conditions may cause small airways dysfunction (SAD), which is an under-recognized cause of PRISm.

Objective: To determine whether insulin resistance and poor glucose control associate with SAD and to explore whether proteins prognostic of diabetes end-organ complications predict lung function abnormalities.

Methods: We recruited a prospective cohort of adults with physician-diagnosed asthma. Fasting insulin, glucose, hemoglobin A1c, and concentrations of 13 proteins prognostic of diabetes end-organ complications were measured. Static insulin resistance was calculated by …

Induction Of Yin Yang 1 (Yy1) Overexpression In Mature Adipocytes Promotes Dysfunctional Adipose Tissue And Systemic Insulin Resistance In Mice, Line Pedersen, Christy M Gliniak, Thomas Myhre Dale, Qingzhang Zhu, Chao Li, Jan-Bernd Funcke, Clair Crewe, Jiahui Luo, Lauren Palluth, Yi Zhu, Philipp E Scherer

Faculty, Staff and Students Publications

The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been linked to controlling mitochondrial gene expression and regulating cellular oxidative respiration, protecting against diet-induced obesity and alterations in energy balance. The role of YY1 in non-thermogenic, white adipose tissue, on the other hand, remains largely unknown. Here, we show that adipocyte-specific induction of YY1 promotes dysfunctional adipose tissue and systemic insulin resistance in mice. Long-term YY1 induction in mature adipocytes leads to reduced …

Participant Retention In A Prospective Multicenter Cohort Of Participants With Pancreatitis And Factors Associated With Attrition, Radmila Choate, Jun Xu, Jeffrey J Easler, Samuel Han, Anna E Phillips, Melena D Bellin, William E Fisher, Evan L Fogel, Chris Forsmark, Phil A Hart, Stephen J Pandol, Walter G Park, Jose Serrano, Stephen K Van Den Eeden, Santhi Swaroop Vege, Liang Li, Darwin L Conwell, Dhiraj Yadav

Faculty, Staff and Students Publications

Objectives: Participant retention is essential in prospective studies to minimize bias and maintain validity. This study aimed to estimate retention rates and identify factors influencing attrition in a multicenter cohort (PROCEED) of US adults with acute/recurrent acute pancreatitis (AP/RAP) and chronic pancreatitis (CP).

Methods: Participants from the PROCEED study with AP/RAP or CP eligible for follow-up within the designated visit window were included. Retention was defined as completing at least one follow-up visit during the observation period. Retention was analyzed by follow-up mode (in-person and/or medical record review) and disease type (AP/RAP and CP). Retention factors were assessed using univariate …

Validation Of The French Translation Of The Movement Disorder Society Non-Motor Symptoms Scale (Mds-Nms) In Parkinson's Disease, Clément Desjardins, Stéphan Grimaldi, Sheng Luo, Luowen Yu, Christopher G Goetz, Glenn T Stebbins, Pablo Martinez-Martin, Monica M Kurtis, Tiago A Mestre, Alvaro Sanchez-Ferro, Michelle H S Tosin, Roberta Balestrino, Chi-Ying R Lin, Carmen Gasca-Salas, Tatiana Witjas, Olivier Colin, David Maltete, Luc Defebvre, Caroline Giordana, Mahmoud Charif, Claire Thiriez, Chloé Laurencin, Mélissa Tir, Gwendoline Dupont, Philippe Remy, Christine Tranchant, Sophie Drapier, Alexandra Samier, Isabelle Benatru, Sara Sambin, Jean-Christophe Corvol, Fatma Khelifi, Margherita Fabbri, Olivier Rascol, Ns‐Part Cohort Study Group And The Mds Coa Translation Steering Committee

Faculty, Staff and Students Publications

No abstract provided.