Digital Commons Network^™

Prevalence And Outcomes Of Her2-Low Versus Her2-0 Status In Patients With Metastatic Breast Cancer, Akshara Singareeka Raghavendra, Diane D Liu, Senthil Damodaran, Sarah Pasyar, Yu Shen, Jason A Mouabbi, Carlos H Barcenas, Kelly K Hunt, Debu Tripathy

Faculty, Staff and Student Publications

Background: HER2-low breast cancer (HER2 immunohistochemical [IHC] score 1+, or IHC 2+ without HER2 gene amplification) is distinct from HER2-positive and HER2-0 breast cancer (IHC 0), with a differing prognosis and specific therapeutic options. The DESTINY-Breast04 trial demonstrated notable efficacy of the HER2 antibody-drug conjugate trastuzumab deruxtecan over standard chemotherapy in patients with metastatic breast cancer (MBC) defined as HER2-low. More recently, the DESTINY-Breast06 trial confirmed this benefit in hormone receptor-positive and HER2-ultralow (less than 1+, but with ≤10% of infiltrating cancer cells showing incomplete and faint/weak membrane staining) cases, prompting re-evaluation of HER2 diagnostic thresholds and treatment strategies.

Methods …

Diet-Responsive Genetic Determinants Of Intestinal Colonization In The Yeast Candida Albicans, Musfirat Shubaita, Mazen Oneissi, Elena Lindemann-Pérez, Cecilia Fadhel Alvarez, Anne-Marie Krachler, Diana M Proctor, J Christian Pérez

Faculty, Staff and Student Publications

Dietary components influence microbial composition in the digestive tract. Although often viewed as energy sources, dietary components are likely to shape microbial determinants of intestinal colonization beyond metabolism. Here, we report that a dietary long-chain fatty acid enhances the yeast Candida albicans colonization of the murine gut partly by eliciting modifications to the fungal cell surface. Mice fed an oleic acid-rich diet were readily colonized by C. albicans and exhibited higher fungal load in feces compared with rodents fed an isocaloric control diet. Surprisingly, β-oxidation, a catabolic process to break down fatty acids for energy production, was dispensable for C. …

Genomics Reveal Staphylococcus Aureus Persists During Long-Term Urinary Catheterization Despite Antimicrobial Therapy And Catheter Exchanges, Jesus M Duran Ramirez, Chelsie E Armbruster, Blake M Hanson, Jennifer N Walker

Faculty, Staff and Student Publications

Urinary catheters, the most frequently placed medical devices in the US, increase the risk of developing symptomatic catheter-associated urinary tract infection (CAUTI) and asymptomatic bacteriuria (ASB) - the presence of bacteria in the urine - with those requiring long-term urinary catheters (LTUCs) at highest risk. While ASB and CAUTI are caused by a broad range of uropathogens, most remain understudied. We use whole-genome sequencing to investigate the understudied uropathogen, Staphylococcus aureus. Analysis of 153 longitudinal S. aureus isolates previously collected from urinary catheter or urine samples from 20 individuals with LTUCs (average of 8 longitudinal isolates/person) demonstrates that most strains …

Genome-Wide Gene By Sleepiness Interaction Analysis For Sleep Apnea, Pavithra Nagarajan, Nuzulul Kurniansyah, Jiwon Lee, Sina A Gharib, Yushan Xu, Yiyan Zhang, Brian Spitzer, Tariq Faquih, Hufeng Zhou, Eric Boerwinkle, Han Chen, Daniel J Gottlieb, Xiuqing Guo, Nancy L Heard-Costa, Bertha A Hidalgo, Daniel Levy, Peter Y Liu, Hao Mei, Rebecca Montalvan, Sutapa Mukherjee, Kari E North, George T O'Connor, Lyle J Palmer, Sanjay R Patel, Bruce M Psaty, Shaun M Purcell, Laura M Raffield, Stephen S Rich, Jerome I Rotter, Richa Saxena, Albert V Smith, Katie L Stone, Xiaofeng Zhu, Topmed Sleep Trait Working Group, Brian E Cade, Tamar Sofer, Susan Redline, Heming Wang

Faculty, Staff and Student Publications

Study objectives: Excessive daytime sleepiness (EDS), influenced by environmental and social-behavioral factors, is reported by a subset of patients with sleep apnea-a group that may be at elevated cardiovascular risk. However, it is unclear whether sleep apnea with and without EDS have distinct genetic underpinnings. In this study, we perform gene-by-EDS interaction analyses for apnea hypopnea index, a diagnostic marker of sleep apnea severity, to understand EDS's influence on its underlying genetic risk.

Methods: Discovery interaction analyses for common variants and gene-based rare variants were conducted respectively using multi-ethnic Trans-Omics for Precision Medicine (N = 11 619) data, followed by …

Self-Efficacy Change Among Diverse Family Caregivers In Dementia Care, Deborah M Oyeyemi, Erich J Greene, Yunshan Xu, David R Lee, Rafael Samper-Ternent, Maya L Lichtenstein, Alan Stevens, Jeff D Williamson, Arun S Karlamangla, Debra Saliba, David B Reuben

Faculty, Staff and Student Publications

Objectives: To determine whether changes in caregiver self-efficacy (beliefs about one's ability to manage dementia-related problems and access help) differed by caregiver race and ethnicity across all participants enrolled in a large pragmatic trial of comprehensive dementia care.

Methods: In the Dementia Care Study (D-CARE), community-dwelling older adults with dementia and their unpaid family caregivers were randomized to receive usual care, community-based, or health system-based comprehensive dementia care. Caregiver self-efficacy was assessed at baseline, 6 months, and 18 months using a 4-item scale (range 4-20, higher scores indicate greater self-efficacy). Among all caregivers, we compared least squares means for overall …

Tumor-Infiltrating Bacteria Disrupt Cancer Epithelial Cell Interactions And Induce Cell-Cycle Arrest, Jorge Luis Galeano Niño, Falk Ponath, Victor A Ajisafe, Clara R Becker, Andrew G Kempchinsky, Martha A Zepeda-Rivera, Javier A Gomez, Hanrui Wu, Jessica G Terrazas, Heather Bouzek, Elizabeth Cromwell, Pritha Chanana, Matthew Wong, Ashish Damania, Michael G White, Y Nancy You, Scott Kopetz, Nadim J Ajami, Jennifer A Wargo, Christopher D Johnston, Susan Bullman

Faculty, Staff and Student Publications

Tumor-infiltrating bacteria are increasingly recognized as modulators of cancer progression and therapy resistance. We describe a mechanism by which extracellular intratumoral bacteria, including Fusobacterium, modulate cancer epithelial cell behavior. Spatial imaging and single-cell spatial transcriptomics show that these bacteria predominantly localize extracellularly within tumor microniches of colorectal and oral cancers, characterized by reduced cell density, transcriptional activity, and proliferation. In vitro, Fusobacterium nucleatum disrupts epithelial contacts, inducing G0-G1 arrest and transcriptional quiescence. This state confers 5-fluorouracil resistance and remodels the tumor microenvironment. Findings were validated by live-cell imaging, spatial profiling, mouse models, and a 52-patient colorectal cancer cohort. Transcriptomics reveals …

Spatial Omics At The Forefront: Emerging Technologies, Analytical Innovations, And Clinical Applications, Yunhe Liu, Yibo Dai, Linghua Wang

Faculty, Staff and Student Publications

Spatial omics transforms our understanding of cancer by revealing how tumor cells and the microenvironment are organized, interact, and evolve within tissues. Here, we synthesize advances in spatial technologies that map tumor ecosystems with unprecedented fidelity. We highlighted analytical breakthroughs-including multimodal integration and emerging spatial foundation models-that resolve functional niches and spatial communities, converting spatial patterns into mechanistic insights. We summarize how spatially organized features, from immune hubs to microbiota and neural interfaces, shape tumor evolution and clinical outcomes. We then outline how spatial approaches illuminate precancer biology, metastatic adaptation, and therapy response. Bridging discovery and translation, we provide a …

Adipose Stromal Cell-Derived Cancer-Associated Fibroblasts Promote Pancreatic Adenocarcinoma Progression Through Sfrp4 Signaling, Joseph Rupert, Lingyi Cai, Alexes C Daquinag, Dimitris Anastassiou, Mikhail G Kolonin

Faculty, Staff and Student Publications

Background/objectives: Progression of pancreatic ductal adenocarcinoma (PDAC) and other carcinomas relies on cancer-associated fibroblasts (CAFs). A subset of CAFs is derived from adipose stromal cells (ASCs) recruited by tumors and the ASC-CAF conversion has been associated with invasiveness and poor prognosis.

Methods: To explore the underlying molecular mechanisms, we used a model based on primary ASCs derived from human visceral adipose tissue co-cultured with human PDAC cell line Capan-1. To investigate cancer progression in vivo, we also used mice orthotopically grafted with mouse KPC cells.

Results: Genomic analysis revealed that Capan-1 co-culture induces Wnt and TGFβ signaling and extracellular matrix …

Large-Scale Blood Pressure Gwas Accounting For Gene-Depression Interactions In 564,680 Individuals From Diverse Populations, Songmi Lee, Clint L Miller, Amy R Bentley, Michael R Brown, Pavithra Nagarajan, Raymond Noordam, John L Morrison, Karen Schwander, Kenneth Westerman, Minjung Kho, Aldi T Kraja, Paul S De Vries, Farah Ammous, Hughes Aschard, Traci M Bartz, Anh Do, Charles T Dupont, Mary F Feitosa, Valborg Gudmundsdottir, Xiuqing Guo, Sarah E Harris, Keiko Hikino, Zhijie Huang, Christophe Lefevre, Leo-Pekka Lyytikäinen, Yuri Milaneschi, Giuseppe Giovanni Nardone, Aurora Santin, Helena Schmidt, Botong Shen, Tamar Sofer, Quan Sun, Ye An Tan, Jingxian Tang, Sébastien Thériault, Peter J Van Der Most, Erin B Ware, Stefan Weiss, Wang Ya Xing, Chenglong Yu, Wei Zhao, Md Abu Yusuf Ansari, Pramod Anugu, John R Attia, Lydia A Bazzano, Joshua C Bis, Max Breyer, Brian Cade, Guanjie Chen, Stacey Collins, Janie Corley, Gail Davies, Marcus Dörr, Jiawen Du, Todd L Edwards, Tariq Faquih, Jessica D Faul, Alison E Fohner, Amanda M Fretts, Srushti Gangireddy, Adam Gepner, Mariaelisa Graff, Edith Hofer, Georg Homuth, Michelle M Hood, Xu Jie, Mika Kähönen, Sharon L R Kardia, Carrie A Karvonen-Gutierrez, Lenore J Launer, Daniel Levy, Maitreiyi Maheshwari, Lisa W Martin, Koichi Matsuda, John J Mcneil, Ilja M Nolte, Tomo Okochi, Laura M Raffield, Olli T Raitakari, Lorenz Risch, Martin Risch, Ana Diez Roux, Edward A Ruiz-Narvaez, Tom C Russ, Takeo Saito, Pamela J Schreiner, Rodney J Scott, James Shikany, Jennifer A Smith, Harold Snieder, Beatrice Spedicati, E Shyong Tai, Adele M Taylor, Kent D Taylor, Paola Tesolin, Rob M Van Dam, Rujia Wang, Wei Wenbin, Tian Xie, Jie Yao, Kristin L Young, Ruiyuan Zhang, Alan B Zonderman, Biobank Japan Project, Lifelines Cohort Study, Maria Pina Concas, David Conen, Simon R Cox, Michele K Evans, Ervin R Fox, Lisa De Las Fuentes, Ayush Giri, Giorgia Girotto, Hans J Grabe, Charles Gu, Vilmundur Gudnason, Sioban D Harlow, Elizabeth Holliday, Jonas B Jost, Paul Lacaze, Seunggeun Lee, Terho Lehtimäki, Changwei Li, Ching-Ti Liu, Alanna C Morrison, Kari E North, Brenda W J H Penninx, Patricia A Peyser, Michael M Province, Bruce M Psaty, Susan Redline, Frits R Rosendaal, Charles N Rotimi, Jerome I Rotter, Reinhold Schmidt, Xueling Sim, Chikashi Terao, David R Weir, Xiaofeng Zhu, Nora Franceschini, Jeffrey R O'Connell, Cashell E Jaquish, Heming Wang, Alisa Manning, Patricia B Munroe, Dabeeru C Rao, Han Chen, W James Gauderman, Laura J Bierut, Thomas W Winkler, Myriam Fornage

Faculty, Staff and Student Publications

Gene-environment interactions may enhance our understanding of blood pressure (BP) biology. We conducted a meta-analysis of multi-population genome-wide association studies (GWASs) of BP traits accounting for gene-depressive symptomatology (DEPR) interactions. Our study included 564,680 adults from 67 cohorts and four population backgrounds: African (5%), Asian (7%), European (85%), and Hispanic (3%). We discovered seven previously unreported BP loci showing gene-DEPR interaction. These loci mapped to genes implicated in neurogenesis (TGFA and CASP3), lipid metabolism (ACSL1), neuronal apoptosis (CASP3), and synaptic activity (CNTN6 and DBI). We also showed evidence for gene-DEPR interaction at nine known BP loci, further suggesting links between …

Proton Versus Photon Radiotherapy For Patients With Oropharyngeal Cancer In The Usa: A Multicentre, Randomised, Open-Label, Non-Inferiority Phase 3 Trial, Steven J Frank, Paul M Busse, J Jack Lee, David I Rosenthal, Mike Hernandez, David M Swanson, Adam S Garden, G Brandon Gunn, Samir H Patel, James W Snider, Daniel J Ma, Jason K Molitoris, Nancy Y Lee, Upendra Parvathaneni, Mark W Mcdonald, Noah S Kalman, Alexander Lin, Nasiruddin Mohammed, Christina Henson, Christian Hyde, Gopal K Bajaj, Sanford R Katz, Roi Dagan, William H Morrison, Jay P Reddy, C David Fuller, Shalin J Shah, Jack Phan, Gregory M Chronowski, Lauren Mayo, Erich M Sturgis, Renata Ferrarotto, Xiaorong R Zhu, Xiaodong Zhang, Li Wang, Katherine A Hutcheson, Adel K El-Naggar, Amy C Moreno, Anna Lee, Michael T Spiotto, Neil D Gross, Stephen Y Lai, Jay J Liao, Jonathan Paly, Zhongxing Liao, Robert L Foote

Faculty, Staff and Student Publications

Background: Radiotherapy is an integral component of treatment for oropharyngeal cancer. Toxicity from the current state-of-the-art photon radiotherapy, intensity-modulated radiation therapy (IMRT), has prompted the search for alternative, less toxic therapies. One such alternative that might de-intensify treatment is proton therapy. In this trial, we aimed to directly compare IMRT with intensity-modulated proton therapy (IMPT), both concurrent with systemic therapy, hypothesising comparable disease control and survival and lower toxicity.

Methods: This randomised, multicentre, open-label, non-inferiority, phase 3 trial was conducted in 21 sites (cancer centres or universities) in the USA. Patients (aged ≥18 years) with stage III or stage IV …

Identification Of Cadm1 As An Immunotherapeutic Target And Evaluation Of A Novel Cadm1-Targeting Antibody-Drug Conjugate In Preclinical Osteosarcoma Models, Yifei Wang, Zhongting Zhang, Caterina Longo, Wendong Zhang, Qi Wang, Amer Najjar, Xiangjun Tian, Rossana N Lazcano Segura, Michael E Roth, Jonathan Gill, Douglas J Harrison, Zhaohui Xu, Yanhua Yi, Xin Zhou, Sylvester Jusu, Timothy M Stearns, Steven B Neuhauser, Carol J Bult, Jing Wang, Alexander J Lazar, Richard Gorlick

Faculty, Staff and Student Publications

Due to the paucity of validated cell surface osteosarcoma-specific targets, patients with this condition have long been excluded from the benefits of antibody-drug conjugate (ADC) therapy observed in patients with several solid and hematologic malignancies. Our comprehensive surfaceome profiling approach previously identified osteosarcoma-specific cell-surface antigens that are highly expressed in osteosarcomas but minimally expressed in normal tissues. As a result, one such antigen, CADM1, was selected for the generation of an ADC. We tested a CADM1-targeting ADC with a tesirine payload (SG3249) in vitro in osteosarcoma, rhabdomyosarcoma, and neuroblastoma patient-derived xenograft cell lines. In vivo, we tested six CADM1-expressing osteosarcoma …

Flipi24: A Modern Prognostic Model And Clinical Trial Enrichment Tool For Newly Diagnosed Follicular Lymphoma, Matthew J Maurer, Vit K Prochazka, Tarec Christoffer El-Galaly, Christopher R Flowers, Diego Villa, Emmanuel Bachy, Elliot J Cahn, Marguerite Fournier, Melissa C Larson, Caroline E Dietrich, Lasse Hjort Jakobsen, Hervé Ghesquières, Robert Kridel, Maher K Gandhi, Chan Y Cheah, Eliza A Hawkes, John F Seymour, Ciara L Freeman, Michael R Clausen, Björn E Wahlin, Jonathan W Friedberg, Carla Casulo, Thomas M Habermann, Yucai Wang, Loretta J Nastoupil, Peter De Nully Brown, David Belada, Andrea Janíková, Heidi Mocikova, Tomáš Fürst, Pierre Feugier, Hervé Tilly, Corinne Haioun, Andrew J Davies, Guillaume Cartron, Richard Burack, Dai Chihara, Peter Martin, Jonathon B Cohen, Izidore S Lossos, Brad S Kahl, Laurie H Sehn, Karin E Smedby, Gilles Salles, Marek Trneny, Brian K Link, Franck Morschhauser, James R Cerhan

Faculty, Staff and Student Publications

Purpose: Although most patients with follicular lymphoma (FL) can expect an indolent course, progressive lymphoma remains the primary cause of death during the first decade after diagnosis. Progression of disease within 24 months (POD24) of starting first-line (1L) immunochemotherapy defines a high-risk population with poor survival, but better risk stratification at diagnosis is needed.

Methods: The FLIPI24 model was developed and internally validated to predict 24-month event rates using individual data from 4,485 patients treated with 1L immunochemotherapy from 10 observational cohorts of FL. Overall and cause-specific survival was further evaluated in FLIPI24 risk groups. External validation in the 1L …

An Integrated Single-Cell And Spatial Transcriptomic Atlas Of Thyroid Cancer Progression Identifies Prognostic Fibroblast Subpopulations, Matthew A Loberg, George J Xu, Sheau-Chiann Chen, Hua-Chang Chen, Claudia C Wahoski, Kailey P Caroland, Megan L Tigue, Heather A Hartmann, Jean-Nicolas Gallant, Courtney J Phifer, Andres A Ocampo, Dayle K Wang, Reilly G Fankhauser, Kirti A Karunakaran, Chia-Chin Wu, Maxime Tarabichi, Sophia M Shaddy, James L Netterville, Sarah L Rohde, Carmen C Solórzano, Lindsay A Bischoff, Naira Baregamian, Barbara A Murphy, Jennifer H Choe, Jennifer R Wang, Eric C Huang, Quanhu Sheng, Luciane T Kagohara, Elizabeth M Jaffee, Ryan H Belcher, Ken S Lau, Fei Ye, Ethan Lee, Vivian L Weiss

Faculty, Staff and Student Publications

Although well-differentiated thyroid carcinoma (WDTC) is characterized by a robust treatment response, aggressive subtypes, such as anaplastic thyroid carcinoma (ATC), remain highly lethal. To understand thyroid cancer evolution in both children and adults, we analyzed single-cell transcriptomes of 423,733 cells from 81 samples and spatially resolved key tumor and microenvironment populations across 28 tumors with spatial transcriptomics, including rare and unique composite WDTC/ATC tumors and pediatric diffuse sclerosing thyroid carcinomas. Additionally, we identified gene signatures of stromal cell populations in 5 large thyroid cancer bulk RNA-sequencing cohorts. Through this multi-institutional effort, we defined a population of POSTN+ myofibroblast cancer-associated fibroblasts …

Fibrinogen-Associated Plasma Metabolites And Implications For Coagulation, Inflammation, And Vascular Diseases, Jayna C Nicholas, Taryn Alkis, Joshua C Bis, Eric Boerwinkle, Jennifer A Brody, Clary B Clish, Paul S De Vries, Yan Gao, Robert E Gerzsten, Xiuqing Guo, Andrew D Johnson, Martin G Larson, Rozenn N Lemaitre, Bruce M Psaty, Vasan Ramachandran, Alexander P Reiner, Stephen S Rich, Benjamin Rodriguez, Jian Rong, Jerome I Rotter, Jeanette Simino, Nicholas L Smith, James Wilson, Jie Yao, Alanna C Morrison, Bing Yu, Laura M Raffield

Faculty, Staff and Student Publications

Background: Fibrinogen is a critical coagulation factor that plays an essential role in thrombosis and is elevated in individuals with chronic inflammation. Here, we used fibrinogen as a representative quantitative measure of pro-coagulant risk and evaluated metabolites associated with fibrinogen levels through non-targeted plasma metabolomic profiling (Broad and Metabolon platforms).

Methods: Our analysis included 10,533 individuals across six U.S. based cohorts representing diverse population groups. The cross-sectional relationship between each of 789 tested metabolites and plasma fibrinogen concentration was assessed with adjustment for relevant covariates such as age, sex, body mass index, and circulating lipoprotein levels.

Results: Meta-analysis of per-cohort …

Multi-Institutional Normal Tissue Complication Probability (Ntcp) Prediction Model For Mandibular Osteoradionecrosis: Results From The Predmorn Study, Laia Humbert-Vidan, Christian R Hansen, Steven Petit, Carles Muñoz-Montplet, Katrina Hueniken, Abdallah S R Mohamed, Deborah P Saunders, Vinod Patel, Gerda M Verduijn, Wilma D Heemsbergen, Arjen Van Der Schaaf, Max Witjes, Suzanne P M De Vette, Mohammad Moharrami, Abdul A Khan, Jordi Marruecos Querol, Irene Oliveras Cancio, Mike Oliver, Peter Reich, Stacey A Santi, Andrew G Pearce, Stephen Y Lai, Andrew P King, Ali Hosni, Andrew J Hope, Erin E Watson, Johannes A Langendijk, Jørgen Johansen, Amy C Moreno, Clifton D Fuller, Lisanne V Van Dijk, Teresa Guerrero Urbano

Faculty, Staff and Student Publications

Purpose: Mandibular osteoradionecrosis (ORN) is a severe late complication affecting patients with head and neck cancer (HNC) treated with radiation therapy (RT) that significantly impacts patients' quality of life and can require costly interventions. Although radiation dose is a key factor, other clinical and demographic risk factors also influence ORN development. Previous predictive models have primarily been single-institutional, limiting their generalizability. In this first analysis from the PREDMORN Consortium, we have aimed to reproduce existing statistical association and modeling analyses on the largest and most diverse mandibular ORN cohort worldwide to allow comparison with previous studies.

Methods and materials: This …

Characterization Of Inflammatory Pseudotumors In A Large Animal Model Of Liver Cancer, Erik N K Cressman, Samantha Hicks, Natalie W Fowlkes, Danielle L Stolley, Maria Sophia Stenkamp

Faculty, Staff and Student Publications

Background: The development of relevant and robust large animal models of hepatocellular carcinoma is needed to test new therapeutic strategies for this disease. Transgenic approaches hold promise in addressing this complex problem. One such model, the Oncopig, has been reported to develop tumors of up to 4 cm in diameter within 7-14 days at sites of in situ vector inoculation. However, the resulting lesions reportedly contained an extensive inflammatory component that has not been evaluated in detail.

Methods: Herein, we describe our results from multiparametric characterization of the lesions generated using liver biopsy cores incubated in vector solution and replaced …

Defective Dna Damage Response Is A Targetable Therapeutic Vulnerability In Esr1 Mutant Breast Cancer, Sarah K Herzog, Jessica H Stevens, Guowei Gu, Sandra L Grimm, Kloma Cardoza, Autumn G M Hawkins, Hangqing Lin, Daniela Ramos, Amanda R Beyer, David G Edwards, Derek Dustin, Harry J Yang, Nicole Liang, Ashfia F Khan, Tasneem Bawa-Khalfe, Daniel J Mcgrail, Shiaw-Yih Lin, Cristian Coarfa, Suzanne A W Fuqua

Faculty, Staff and Student Publications

ESR1 mutations are the leading cause of endocrine therapy resistance and progression in ER-positive metastatic breast cancer. ESR1 mutations are detected in ~50% of metastatic breast cancer patients, and identification of effective targeted therapeutics are critically needed. Here, we identified enrichment of dysregulated replication stress and DNA damage responses in multiple ESR1 mutant models. Targeting the replication stress response utilizing checkpoint inhibition in combination with PARP inhibition synergistically suppressed growth, induced cell cycle arrest, and attenuated DNA replication. PARP inhibition blocked metastatic dissemination in vivo and reduced both PARP1 and ER-regulated protein expression. PARP trapping by olaparib treatment with or …

3d Reconstruction Of Spatial Transcriptomics With Spatial Pattern Enhanced Graph Convolutional Neural Network, Chen Tang, Yuansheng Zhou, Xue Xiao, Lei Dong, Lei Yu, Qiwei Li, Guanghua Xiao, Lin Xu

Faculty, Staff and Student Publications

Spatially resolved transcriptomics (SRT) is a promising new technology that enables simultaneous analysis of gene expression and spatial information for biomedical research. However, the existing statistical and deep learning algorithms used for analyzing SRT data rely solely on two-dimensional (2D) spatial coordinates, which limits their ability to accurately identify spatial domains, spatially variable genes (SVGs), cell-to-cell communications, and developmental trajectories in a three-dimensional (3D) spatial manner. To address these limitations, we introduced Spa3D, which utilized the anti-leakage Fourier transform and graph convolutional neural network model to reconstruct 3D-based spatial structures from multiple 2D SRT slices. We demonstrate that Spa3D is …

Thermodynamic Stability Modulates Chaperone-Mediated Disaggregation Of Α-Synuclein Fibrils, Celia Fricke, Antonin Kunka, Rasmus K Norrild, Shuangyan Wang, Thi Lieu Dang, Jonas Folke, Mohammad Shahnawaz, Claudio Soto, Susana Aznar, Anne S Wentink, Bernd Bukau, Alexander K Buell

Faculty, Staff and Student Publications

Aggregation of the intrinsically disordered protein alpha-synuclein into amyloid fibrils and their subsequent intracellular accumulation are hallmark features of several neurodegenerative disorders, including Parkinson's disease, for which no curative treatments currently exist. In this study, we investigate the relationship between fibril morphology, thermodynamic stability, and susceptibility to disaggregation by the human chaperone system comprising HSP70, DNAJB1, and Apg2. By varying assembly conditions and incubation times, we generated alpha-synuclein fibrils with diverse morphological and biochemical properties, including a broad range of thermodynamic stabilities, which we quantified using a chemical depolymerization assay. The chaperone system effectively disaggregated three of the four fibril …

Loss Of Twist1 Leads To Disruption Of Ciliary Length, Endocytic Vesicle Dynamics, And Cell-Cell Junctions During Neural Tube Formation, Derrick Thomas, Brittany M Hufft-Martinez, Zarna Lalwani, Vi Pham, Mary Elmeniawi, An J Tran, Jianming Xu, Irfan Saadi, Walid D Fakhouri

Faculty, Staff and Student Publications

Background: Endocytosis constitutes a fundamental cellular process governing development through coordinated regulation of plasma membrane remodeling and ciliogenesis, processes essential for cell shape changes and tissue development. Although Twist1 null embryos display complete cranial neural tube (NT) closure defects and conditional knockout in neuroectoderm disrupts cranial neural crest cell fate determination and delamination, the function of TWIST1 in NT morphogenesis remains unknown. We investigated the basis underlying neuroectodermal morphological abnormalities in TWIST1 mutant embryos, specifically the formation of ectopic lateral bending points and cellular disorganization, by examining Twist1's role in cilia formation, adherens junction integrity, and endocytic vesicle dynamics.

Results: …

Knockrbp: An Integrated Multi-Omics Database Of Functional Perturbation Profiles For Rna-Binding Proteins, Mengyuan Yang, Jiawei Li, Jiajia Liu, Xingzheng Lu, Xiaobo Zhou, Yungang Xu

Faculty, Staff and Student Publications

RNA-binding proteins (RBPs) regulate diverse post-transcriptional processes, yet their functional impacts across multiple molecular layers remain incompletely characterized. KnockRBP (https://knockrbp.xu-bioinfo.com) is presented as a comprehensive, multi-omics database systematically cataloging regulatory changes resulting from genetic perturbation of RBPs. The resource integrates 1453 datasets from GEO, ENA, and ENCORE, encompassing RNA-seq, Ribo-seq, microRNA (miRNA)-seq, and 3'RACE-seq across 639 RBPs, 182 cell lines, and 61 diseases. Regulatory outcomes covered include alternative splicing, alternative polyadenylation, RNA editing, transcript abundance, translation efficiency, and miRNA expression, with all events processed through standardized analytical pipelines and annotated with open reading frame consequences, predicted loss-of-function impacts, and established …

Peripheral Nerve Injury Reduces Macrophage Efferocytosis To Facilitate Neuropathic Pain, Vipul K Pandey, Tusar K Acharya, Kendal F Willcox, Sandeep Dembla, Ajeena Ramanujan, Anamaria R Grieco, Younus A Zuberi, Rajasekaran Mahalingam, Andrew J Shepherd, Cobi J Heijnen, Peter M Grace

Faculty, Staff and Student Publications

For reasons not fully understood, proresolving immune processes sometimes fail to engage after peripheral nerve injury (PNI), leading to enhanced neuropathic pain and inflammation. Here, we implicate reduced efferocytosis due to proteolytic cleavage of surface MER tyrosine kinase (MERTK) from macrophages at the site of PNI. After PNI, the proportion of macrophages expressing MERTK progressively decreased, while soluble (cleaved) MER increased. Using male and female knock-in mice encoding cleavage-resistant Mertk, we demonstrated that cleavage of MERTK from macrophages at the PNI site led to exaggerated pain-related behaviors. PNI-induced hyperactivity of TRPV1+ sensory neurons and damage to myelin and myelinated …

Spatial2gwas: A Database For Linking Spatial Transcriptomic Regions With Gwas Traits, Xi Hu, Aoqi Wang, Huan Yu, Pora Kim, Xiaobo Zhou

Faculty, Staff and Student Publications

Spatial heterogeneity of gene expression within tissue regions has a critical influence on biological functions, thereby affecting disease pathogenesis. However, systematic associations between spatially resolved transcriptomes and phenotypes, especially in complex diseases, remain underexplored. Here, we developed spatial2GWAS (http://www.spatial2gwas.cn), a comprehensive resource linking spatial transcriptomic (ST) regions with GWAS traits. In the database, we collected 1196 ST slices (human and mouse) from five technologies and 812 GWAS traits spanning 18 phenotype categories and identified 29 701 ST slice-GWAS trait pairs containing 47 492 significant regions. Functional analyses reveal distinct patterns of cell type composition, gene expression, GO/KEGG pathway activation, and …

Modality-Agnostic, Patient-Specific Digital Twins Modeling Temporally Varying Digestive Motion, Jorge Tapias Gomez, Nishant Nadkarni, Lando S Bosma, Jue Jiang, Ergys D Subashi, William P Segars, James M Balter, Mert R Sabuncu, Neelam Tyagi, Harini Veeraraghavan

Faculty, Staff and Student Publications

No abstract provided.

A Prognostic Matrix Gene Expression Signature Defines Functional Glioblastoma Phenotypes And Niches, Monika Vishnoi, Zeynep Dereli, Zheng Yin, Elisabeth K Kong, Meric Kinali, Kisan Thapa, Ozgun Babur, Kyuson Yun, Nourhan Abdelfattah, Xubin Li, Behnaz Bozorgui, Mary C Farach-Carson, Robert C Rostomily, Anil Korkut

Faculty, Staff and Student Publications

Interactions among tumor, immune, and vascular niches play major roles in glioblastoma (GBM) malignancy and treatment responses. The composition and heterogeneity of extracellular core matrix proteins (CMPs) that mediate such interactions are not well understood. Here, we present an analysis of the clinical relevance of CMP expression in GBM at bulk, single-cell, and spatial anatomical resolution. We show that CMP enrichment is associated with worse patient survival, specific driver oncogenic alterations, mesenchymal state, pro-tumor immune infiltration, and immune checkpoint expression. Matrisome expression is enriched in vascular and leading edge/infiltrative niches that are known to harbor glioma stem cells. Finally, we …

Precision Targeting Of Sting: Challenges, Innovations, And Clinical Outlook For Cancer Therapy, Jiaqi Shi, Yingying Zhang, Na Zhao, Ekihiro Seki, Li Ma, Gordana Kocic, Xiaobo Li, Janoš Terzić, Tongsen Zheng

Faculty, Staff and Student Publications

The stimulator of interferon genes (STING) pathway plays a crucial role in immune responses and has emerged as a compelling target in cancer therapy. Despite promising preclinical studies, clinical trials of STING agonists have largely failed to deliver durable efficacy, with no agents progressing to phase III trials. This review examines the biological, pharmacological, and clinical barriers limiting STING pathway activation in cancer treatment. We discuss the inherent limitations of STING agonists as well as host-related resistance driven by tumor heterogeneity, immune suppression, and chronic STING activation. Mechanisms of acquired resistance, such as immune checkpoint upregulation and suppression of effector …

Celltra: Aligning Cell Names With Gene Expression Via A Pathway-Informed Transformer, Zhao Li, Zaiyi Zheng, Rongbin Li, Wenbo Chen, Yuntao Yang, Meer A Ali, Jundong Li, W Jim Zheng

Faculty, Staff and Student Publications

Motivation: Single-cell RNA sequencing (scRNA-Seq) technology enables detailed exploration of gene expression at the individual cell level, crucial for annotating cell types and understanding cellular diversity. Traditional methods for cell type annotation often rely on marker genes and manual labeling, posing challenges due to low data quality and incomplete reference datasets.

Results: We developed CeLLTra, a novel contrastive learning framework that leverages a Transformer-based model integrating biological pathway information to group genes into super tokens, effectively capturing comprehensive gene expression from scRNA-Seq data. By combining this pathway-informed Transformer with a pretrained domain-specific language model, CeLLTra accurately aligns cell-type annotations with …

Cholesterol Efflux Protein, Abca1, Supports Anticancer Functions Of Myeloid Immune Cells, Shruti V Bendre, Yu Wang, Basel Hajyousif, Rajendra K C, Shounak G Bhogale, Dhanya Pradeep, Natalia Krawczynska, Claire P Schane, Erin Weisser, Avni Singh, Simon Han, Hannah Kim, Lara Kockaya, Anasuya Das Gupta, Adam T Nelczyk, Hashni Epa Vidana Gamage, Yifan Fei, Desirée Rodríguez-Casiano, Xingyu Guo, Haoyun Li, Ryan J Deaton, Fei Mo, Maria Sverdlov, Peter H Gann, Saurabh Sinha, Sahil Sahni, Kun Wang, Kevin Van Bortle, Emad Tajkorshid, Wendy A Woodward, Wonhwa Cho, Erik R Nelson

Faculty, Staff and Student Publications

Breast and other solid tumors respond poorly to immune therapy. Myeloid cells (MCs) such as macrophages contribute to resistance. Established clinical evidence links cholesterol to cancer outcomes, with MC function being regulated by cholesterol metabolism. We screened MC-expressed regulators of cholesterol homeostasis linked to survival and identified the cholesterol efflux protein ABCA1. ABCA1 activity increases anticancer functions of macrophages: enhancing tumor infiltration, decreasing angiogenic potential, reducing efferocytosis, and improving support of CD8+ T cell activity. Mechanistically, different AKT isoforms are involved, through both PI3K-dependent and PI3K-independent mechanisms. Highlighting the clinical relevance of our findings are correlations between ABCA1 in macrophages …

Nf2 Loss Malignantly Transforms Human Pancreatic Acinar Cells And Enhances Cell Fitness Under Environmental Stress, Yi Xu, Michael H Nipper, Angel A Dominguez, Chenhui He, Francis E Sharkey, Sajid Khan, Han Xu, Daohong Zhou, Lei Zheng, Yu Luan, Jun Liu, Pei Wang

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) occurs as a complex, multifaceted event driven by the interplay of tumor-permissive genetic mutations, the nature of the cellular origin, and microenvironmental stress. In this study, using primary human pancreatic acinar 3D organoids, we performed a CRISPR-KO screen targeting 199 potential tumor suppressors curated from clinical PDAC samples. Our data revealed significant enrichment of a list of candidate genes, with neurofibromatosis type 2 associated gene (NF2) emerging as the top target. Functional validation confirmed that loss of NF2 promoted the transition of PDAC to an invasive state, potentially through extracellular matrix modulation. NF2 inactivation …

Public Support For Alcohol-Control Policies And Political Ideology In The Us, Joël Fokom Domgue, Robert Yu, Ernest Hawk, Sanjay Shete

Faculty, Staff and Student Publications

This cross-sectional study examines the role of US adults’ political affiliation, perception about alcohol use and cancer, and sociodemographic and behavioral factors in banning outdoor alcohol advertising and adding cancer warnings on alcohol containers.