Biomedical Informatics Commons^™

Fak Drives Resistance To Therapy In Hpv-Negative Head And Neck Cancer In A P53-Dependent Manner, Phillip M Pifer, Liangpeng Yang, Manish Kumar, Tongxin Xie, Mitchell Frederick, Andrew Hefner, Beth Beadle, David Molkentine, Jessica Molkentine, Annika Dhawan, Mohamed Abdelhakiem, Abdullah A Osman, Brian J Leibowitz, Jeffrey N Myers, Curtis R Pickering, Vlad C Sandulache, John Heymach, Heath D Skinner

Faculty, Staff and Student Publications

PURPOSE: Radiation and platinum-based chemotherapy form the backbone of therapy in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). We have correlated focal adhesion kinase (FAK/PTK2) expression with radioresistance and worse outcomes in these patients. However, the importance of FAK in driving radioresistance and its effects on chemoresistance in these patients remains unclear.

EXPERIMENTAL DESIGN: We performed an in vivo shRNA screen using targetable libraries to identify novel therapeutic sensitizers for radiation and chemotherapy.

RESULTS: We identified FAK as an excellent target for both radio- and chemosensitization. Because TP53 is mutated in over 80% of HPV-negative HNSCC, we …

Clinicalomicsdb: Exploring Molecular Associations Of Oncology Drug Responses In Clinical Trials, Chang In Moon, John Michael Elizarraras, Jonathan Thomas Lei, Byron Jia, Bing Zhang

Faculty, Staff and Students Publications

Matching patients to optimal treatment is challenging, in part due to the limited availability of real-world clinical datasets for predictive biomarker identification. The growing integration of omics profiling into clinical trials presents a new opportunity to tackle this challenge. Here, we introduce ClinicalOmicsDB, a web application for exploring molecular associations of oncology drug responses in clinical trials. This database includes transcriptomic data from 40 clinical trial studies, with 5913 patients spanning 11 cancer types. These studies include 67 treatment arms with a variety of chemotherapy, targeted therapy and immunotherapy drugs, and their combinations, which we organize based on an established …

Experiences Of Family Communication And Cascade Genetic Testing For Hereditary Cancer In Medically Underserved Populations-A Qualitative Study, Erica M Bednar, J Alejandro Rauh-Hain, Jose J Garcia, Norma De Aguinaga, Mary Anne Powell, Sylvia L Peral, Roni Nitecki, Kirsten Jorgensen, Natasha L Rudy, Karen H Lu, Charles A Leath, Isabel C Scarinci

Faculty, Staff and Student Publications

UNLABELLED: We sought to explore the intrafamilial communication and cascade genetic testing (CGT) experiences of patients with hereditary cancer from diverse, medically underserved populations and their relatives. Participants included patients receiving oncology care at an urban, safety net hospital in Texas or comprehensive cancer center in Alabama and their first-degree relatives. In-depth semi-structured qualitative interviews were completed wherein patients shared their experiences with genetic counseling (GC), genetic testing (GT), and communicating their results to relatives. Relatives shared their experiences receiving information from the patient and considering CGT. Interviews were transcribed, coded, and themes were identified. Of 25 participating patients, most …

Contributions Of The Microbiome-Derived Metabolome For Risk Assessment And Prognostication Of Pancreatic Cancer, Ricardo A León-Letelier, Rongzhang Dou, Jody Vykoukal, Michele T Yip-Schneider, Anirban Maitra, Ehsan Irajizad, Ranran Wu, Jennifer B Dennison, Kim-An Do, Jianjun Zhang, C Max Schmidt, Samir Hanash, Johannes F Fahrmann

Faculty, Staff and Student Publications

Background: Increasing evidence implicates microbiome involvement in the development and progression of pancreatic ductal adenocarcinoma (PDAC). Studies suggest that reflux of gut or oral microbiota can lead to colonization in the pancreas, resulting in dysbiosis that culminates in release of microbial toxins and metabolites that potentiate an inflammatory response and increase susceptibility to PDAC. Moreover, microbe-derived metabolites can exert direct effector functions on precursors and cancer cells, as well as other cell types, to either promote or attenuate tumor development and modulate treatment response.

Content: The occurrence of microbial metabolites in biofluids thereby enables risk assessment and prognostication of PDAC, …

Proteogenomic Characterization Of Small Cell Lung Cancer Identifies Biological Insights And Subtype-Specific Therapeutic Strategies, Qian Liu, Jing Zhang, Chenchen Guo, Mengcheng Wang, Chenfei Wang, Yilv Yan, Liangdong Sun, Di Wang, Lele Zhang, Huansha Yu, Likun Hou, Chunyan Wu, Yuming Zhu, Gening Jiang, Hongwen Zhu, Yanting Zhou, Shanhua Fang, Tengfei Zhang, Liang Hu, Junqiang Li, Yansheng Liu, Hui Zhang, Bing Zhang, Li Ding, Ana I Robles, Henry Rodriguez, Daming Gao, Hongbin Ji, Hu Zhou, Peng Zhang

Faculty, Staff and Students Publications

We performed comprehensive proteogenomic characterization of small cell lung cancer (SCLC) using paired tumors and adjacent lung tissues from 112 treatment-naive patients who underwent surgical resection. Integrated multi-omics analysis illustrated cancer biology downstream of genetic aberrations and highlighted oncogenic roles of FAT1 mutation, RB1 deletion, and chromosome 5q loss. Two prognostic biomarkers, HMGB3 and CASP10, were identified. Overexpression of HMGB3 promoted SCLC cell migration via transcriptional regulation of cell junction-related genes. Immune landscape characterization revealed an association between ZFHX3 mutation and high immune infiltration and underscored a potential immunosuppressive role of elevated DNA damage response activity via inhibition of the …

A Phase 2 Trial Of Cd24fc For Prevention Of Graft-Versus-Host Disease, John Magenau, Samantha Jaglowski, Joseph Uberti, Sherif S Farag, Mary Mansour Riwes, Attaphol Pawarode, Sarah Anand, Monalisa Ghosh, John Maciejewski, Thomas Braun, Martin Devenport, Susan Lu, Bhramori Banerjee, Carolyn Dasilva, Steven Devine, Mei-Jie Zhang, Linda J Burns, Yang Liu, Pan Zheng, Pavan Reddy

Faculty, Staff and Students Publications

Patients who undergo human leukocyte antigen–matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor–based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, …

A Syndromic Neurodevelopmental Disorder Caused By Rare Variants In Ppfia3, Maimuna S Paul, Sydney L Michener, Hongling Pan, Hiuling Chan, Jessica M Pfliger, Jill A Rosenfeld, Vanesa C Lerma, Alyssa Tran, Megan A Longley, Richard A Lewis, Monika Weisz-Hubshman, Mir Reza Bekheirnia, Nasim Bekheirnia, Lauren Massingham, Michael Zech, Matias Wagner, Hartmut Engels, Kirsten Cremer, Elisabeth Mangold, Sophia Peters, Jessica Trautmann, Jessica L Mester, Maria J Guillen Sacoto, Richard Person, Pamela P Mcdonnell, Stacey R Cohen, Laina Lusk, Ana S A Cohen, Jean-Baptiste Le Pichon, Tomi Pastinen, Dihong Zhou, Kendra Engleman, Caroline Racine, Laurence Faivre, Sébastien Moutton, Anne-Sophie Denommé-Pichon, Hyun Yong Koh, Annapurna Poduri, Jeffrey Bolton, Cordula Knopp, Dong Sun Julia Suh, Andrea Maier, Mehran Beiraghi Toosi, Ehsan Ghayoor Karimiani, Reza Maroofian, Gerald Bradley Schaefer, Vijayalakshmi Ramakumaran, Pradeep Vasudevan, Chitra Prasad, Matthew Osmond, Sarah Schuhmann, Georgia Vasileiou, Sophie Russ-Hall, Ingrid E Scheffer, Gemma L Carvill, Heather Mefford, Undiagnosed Diseases Network, Carlos A Bacino, Brendan H Lee, Hsiao-Tuan Chao

Faculty, Staff and Students Publications

PPFIA3 encodes the protein-tyrosine phosphatase, receptor-type, F-polypeptide-interacting-protein-alpha-3 (PPFIA3), which is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. The protein structure and function are evolutionarily well conserved, but human diseases related to PPFIA3 dysfunction are not yet reported in OMIM. Here, we report 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy with reduced penetrance. Seventeen unique PPFIA3 variants were detected in 18 families. To determine the pathogenicity …

Targeting Dna Repair And Survival Signaling In Diffuse Intrinsic Pontine Gliomas To Prevent Tumor Recurrence, Monika Sharma, Ivana Barravecchia, Robert Teis, Jeanette Cruz, Rachel Mumby, Elizabeth K Ziemke, Carlos E Espinoza, Varunkumar Krishnamoorthy, Brian Magnuson, Mats Ljungman, Carl Koschmann, Joya Chandra, Christopher E Whitehead, Judith S Sebolt-Leopold, Stefanie Galban

Faculty, Staff and Student Publications

Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. On the basis of these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary …

Mir126-Targeted-Nanoparticles Combined With Pi3k/Akt Inhibitor As A New Strategy To Overcome Melanoma Resistance, Maria Beatrice Arasi, Gabriele De Luca, Laura Chronopoulou, Francesca Pedini, Eleonora Petrucci, Michela Flego, Annarita Stringaro, Marisa Colone, Luca Pasquini, Massimo Spada, Valentina Lulli, Maria Chiara Perrotta, George Adrian Calin, Cleofe Palocci, Mauro Biffoni, Federica Felicetti, Nadia Felli

Faculty, Staff and Student Publications

Metastatic melanoma poses significant challenges as a highly lethal disease. Despite the success of molecular targeting using BRAFV600E inhibitors (BRAFis) and immunotherapy, the emergence of early recurrence remains an issue and there is the need for novel therapeutic approaches. This study aimed at creating a targeted delivery system for the oncosuppressor microRNA 126 (miR126) and testing its effectiveness in combination with a phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) inhibitor for treating metastatic melanoma resistant to BRAFis. To achieve this, we synthesized chitosan nanoparticles containing a chemically modified miR126 sequence. These nanoparticles were further functionalized with an antibody specific to …

Impact Of Opioid-Free Analgesia On Pain Severity And Patient Satisfaction After Discharge From Surgery: Multispecialty, Prospective Cohort Study In 25 Countries, Tasman Collaborative

Faculty, Staff and Student Publications

BACKGROUND: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.

METHODS: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview …

Class Ii Hla-Drb4 Is A Predictive Biomarker For Survival Following Immunotherapy In Metastatic Non-Small Cell Lung Cancer, Cindy Y Jiang, Lili Zhao, Michael D Green, Shashidhar Ravishankar, Andrea M H Towlerton, Anthony J Scott, Malini Raghavan, Matthew F Cusick, Edus H Warren, Nithya Ramnath

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICI) are important treatment options for metastatic non-small cell lung cancer (mNSCLC). However, not all patients benefit from ICIs and can experience immune-related adverse events (irAEs). Limited understanding exists for germline determinants of ICI efficacy and toxicity, but Human Leukocyte Antigen (HLA) genes have emerged as a potential predictive biomarker. We performed HLA typing on 85 patients with mNSCLC, on ICI therapy and analyzed the impact of HLA Class II genotype on progression free survival (PFS), overall survival (OS), and irAEs. Most patients received pembrolizumab (83.5%). HLA-DRB4 genotype was seen in 34/85 (40%) and its presence correlated …

An Evolutionary Perspective On Complex Neuropsychiatric Disease, Jon M Mcclellan, Anthony W Zoghbi, Joseph D Buxbaum, Carolina Cappi, James J Crowley, Jonathan Flint, Dorothy E Grice, Suleyman Gulsuner, Conrad Iyegbe, Sanjeev Jain, Po-Hsiu Kuo, Maria Claudia Lattig, Maria Rita Passos-Bueno, Meera Purushottam, Dan J Stein, Anna B Sunshine, Ezra S Susser, Christopher A Walsh, Olivia Wootton, Mary-Claire King

Faculty, Staff and Students Publications

The forces of evolution-mutation, selection, migration, and genetic drift-shape the genetic architecture of human traits, including the genetic architecture of complex neuropsychiatric illnesses. Studying these illnesses in populations that are diverse in genetic ancestry, historical demography, and cultural history can reveal how evolutionary forces have guided adaptation over time and place. A fundamental truth of shared human biology is that an allele responsible for a disease in anyone, anywhere, reveals a gene critical to the normal biology underlying that condition in everyone, everywhere. Understanding the genetic causes of neuropsychiatric disease in the widest possible range of human populations thus yields …

Proteome-Wide Association Study And Functional Validation Identify Novel Protein Markers For Pancreatic Ductal Adenocarcinoma, Jingjing Zhu, Ke Wu, Shuai Liu, Alexandra Masca, Hua Zhong, Tai Yang, Dalia H Ghoneim, Praveen Surendran, Tanxin Liu, Qizhi Yao, Tao Liu, Sarah Fahle, Adam Butterworth, Md Ashad Alam, Jaydutt V Vadgama, Youping Deng, Hong-Wen Deng, Chong Wu, Yong Wu, Lang Wu

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy, largely due to the paucity of reliable biomarkers for early detection and therapeutic targeting. Existing blood protein biomarkers for PDAC often suffer from replicability issues, arising from inherent limitations such as unmeasured confounding factors in conventional epidemiologic study designs. To circumvent these limitations, we use genetic instruments to identify proteins with genetically predicted levels to be associated with PDAC risk. Leveraging genome and plasma proteome data from the INTERVAL study, we established and validated models to predict protein levels using genetic variants. By examining 8,275 PDAC cases and 6,723 controls, we identified …

Effect Of Acupuncture Vs Sham Acupuncture On Patients With Poststroke Motor Aphasia: A Randomized Clinical Trial, Boxuan Li, Shizhe Deng, Bifang Zhuo, Bomo Sang, Junjie Chen, Menglong Zhang, Guang Tian, Lili Zhang, Yuzheng Du, Peng Zheng, Gonglei Yue, Zhihong Meng

Faculty, Staff and Student Publications

IMPORTANCE: Motor aphasia is common among patients with stroke. Acupuncture is recommended as an alternative therapy for poststroke aphasia, but its efficacy remains uncertain.

OBJECTIVE: To investigate the effects of acupuncture on language function, neurological function, and quality of life in patients with poststroke motor aphasia.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter, sham-controlled, randomized clinical trial was conducted in 3 tertiary hospitals in China from October 21, 2019, to November 13, 2021. Adult patients with poststroke motor aphasia were enrolled. Data analysis was performed from February to April 2023.

INTERVENTIONS: Eligible participants were randomly allocated (1:1) to manual acupuncture (MA) …

Inpatient Costs Of Treating Patients With Covid-19, Kandice A Kapinos, Richard M Peters, Robert E Murphy, Samuel F Hohmann, Ankita Podichetty, Raymond S Greenberg

Faculty, Staff and Student Publications

IMPORTANCE: With more than 6.2 million hospitalizations due to COVID-19 in the US, recognition of the average hospital costs to provide inpatient care during the pandemic is necessary to understanding the national medical resource use and improving public health readiness and related policies.

OBJECTIVE: To examine the mean cost to provide inpatient care to treat COVID-19 and how it varied through the pandemic waves and by important sociodemographic patient characteristics.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used inpatient-level data from March 1, 2020, to March 31, 2022, extracted from a repository of clinical, administrative, and financial information covering 97% …

Crispr-Cas9 Base Editing Of Pathogenic Camkiiδ Improves Cardiac Function In A Humanized Mouse Model, Simon Lebek, Xurde M Caravia, Leon G Straub, Damir Alzhanov, Wei Tan, Hui Li, John R Mcanally, Kenian Chen, Lin Xu, Philipp E Scherer, Ning Liu, Rhonda Bassel-Duby, Eric N Olson

Faculty, Staff and Student Publications

Cardiovascular diseases are the most common cause of worldwide morbidity and mortality, highlighting the necessity for advanced therapeutic strategies. Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is a prominent inducer of various cardiac disorders, which is mediated by 2 oxidation-sensitive methionine residues within the regulatory domain. We have previously shown that ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing enables the heart to recover function from otherwise severe damage following ischemia/reperfusion (IR) injury. Here, we extended this therapeutic concept toward potential clinical translation. We generated a humanized CAMK2D knockin mouse model in which the genomic sequence encoding the entire regulatory domain was …

Cell State Of Origin Impacts Development Of Distinct Endometriosis-Related Ovarian Carcinoma Histotypes, Ian Beddows, Huihui Fan, Karolin Heinze, Benjamin K Johnson, Anna Leonova, Janine Senz, Svetlana Djirackor, Kathleen R Cho, Celeste Leigh Pearce, David G Huntsman, Michael S Anglesio, Hui Shen

Faculty, Staff and Student Publications

Clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (ENOC) are ovarian carcinoma histotypes, which are both thought to arise from ectopic endometrial (or endometrial-like) cells through an endometriosis intermediate. How the same cell type of origin gives rise to two morphologically and biologically different histotypes has been perplexing, particularly given that recurrent genetic mutations are common to both and present in nonmalignant precursors. We used RNA transcription analysis to show that the expression profiles of CCOC and ENOC resemble those of normal endometrium at secretory and proliferative phases of the menstrual cycle, respectively. DNA methylation at the promoter of …

Integrated Multi-Omics Analyses Identify Anti-Viral Host Factors And Pathways Controlling Sars-Cov-2 Infection, Jiakai Hou, Yanjun Wei, Jing Zou, Roshni Jaffery, Long Sun, Shaoheng Liang, Ningbo Zheng, Ashley M Guerrero, Nicholas A Egan, Ritu Bohat, Si Chen, Caishang Zheng, Xiaobo Mao, S Stephen Yi, Ken Chen, Daniel J Mcgrail, Nidhi Sahni, Pei-Yong Shi, Yiwen Chen, Xuping Xie, Weiyi Peng

Faculty, Staff and Student Publications

Host anti-viral factors are essential for controlling SARS-CoV-2 infection but remain largely unknown due to the biases of previous large-scale studies toward pro-viral host factors. To fill in this knowledge gap, we perform a genome-wide CRISPR dropout screen and integrate analyses of the multi-omics data of the CRISPR screen, genome-wide association studies, single-cell RNA-Seq, and host-virus proteins or protein/RNA interactome. This study uncovers many host factors that are currently underappreciated, including the components of V-ATPases, ESCRT, and N-glycosylation pathways that modulate viral entry and/or replication. The cohesin complex is also identified as an anti-viral pathway, suggesting an important role of …

Serine Synthesis Via Reversed Shmt2 Activity Drives Glycine Depletion And Acetaminophen Hepatotoxicity In Masld, Alia Ghrayeb, Alexandra C Finney, Bella Agranovich, Daniel Peled, Sumit Kumar Anand, M Peyton Mckinney, Mahasen Sarji, Dongshan Yang, Natan Weissman, Shani Drucker, Sara Isabel Fernandes, Jonatan Fernández-García, Kyle Mahan, Zaid Abassi, Lin Tan, Philip L Lorenzi, James Traylor, Jifeng Zhang, Ifat Abramovich, Y Eugene Chen, Oren Rom, Inbal Mor, Eyal Gottlieb

Faculty, Staff and Student Publications

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative …

Cell Cycle Arrest Induces Lipid Droplet Formation And Confers Ferroptosis Resistance, Hyemin Lee, Amber Horbath, Lavanya Kondiparthi, Jitendra Kumar Meena, Guang Lei, Shayani Dasgupta, Xiaoguang Liu, Li Zhuang, Pranavi Koppula, Mi Li, Iqbal Mahmud, Bo Wei, Philip L Lorenzi, Khandan Keyomarsi, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan

Faculty, Staff and Student Publications

How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)-dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug-resistant cancer cells, such as …

Mutant P53 Gains Oncogenic Functions Through A Chromosomal Instability-Induced Cytosolic Dna Response, Mei Zhao, Tianxiao Wang, Frederico O Gleber-Netto, Zhen Chen, Daniel J Mcgrail, Javier A Gomez, Wutong Ju, Mayur A Gadhikar, Wencai Ma, Li Shen, Qi Wang, Ximing Tang, Sen Pathak, Maria Gabriela Raso, Jared K Burks, Shiaw-Yih Lin, Jing Wang, Asha S Multani, Curtis R Pickering, Junjie Chen, Jeffrey N Myers, Ge Zhou

Faculty, Staff and Student Publications

Inactivating TP53 mutations leads to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promotes tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome and find that by targeting minichromosome maintenance complex components (MCMs), GOF mutp53 predisposes cells to replication stress and chromosomal instability (CIN), leading to a tumor cell-autonomous and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent cytosolic DNA response that activates downstream non-canonical nuclear factor kappa light chain …

Unraveling The Intercellular Communication Disruption And Key Pathways In Alzheimer’S Disease: An Integrative Study Of Single-Nucleus Transcriptomes And Genetic Association, Andi Liu, Brisa S Fernandes, Citu Citu, Zhongming Zhao

Faculty, Staff and Student Publications

BACKGROUND: Recently, single-nucleus RNA-seq (snRNA-seq) analyses have revealed important cellular and functional features of Alzheimer's disease (AD), a prevalent neurodegenerative disease. However, our knowledge regarding intercellular communication mediated by dysregulated ligand-receptor (LR) interactions remains very limited in AD brains.

METHODS: We systematically assessed the intercellular communication networks by using a discovery snRNA-seq dataset comprising 69,499 nuclei from 48 human postmortem prefrontal cortex (PFC) samples. We replicated the findings using an independent snRNA-seq dataset of 56,440 nuclei from 18 PFC samples. By integrating genetic signals from AD genome-wide association studies (GWAS) summary statistics and whole genome sequencing (WGS) data, we prioritized …

Il-12 Reprograms Car-Expressing Natural Killer T Cells To Long-Lived Th1-Polarized Cells With Potent Antitumor Activity, Elisa Landoni, Mark G Woodcock, Gabriel Barragan, Gabriele Casirati, Vincenzo Cinella, Simone Stucchi, Leah M Flick, Tracy A Withers, Hanna Hudson, Giulia Casorati, Paolo Dellabona, Pietro Genovese, Barbara Savoldo, Leonid S Metelitsa, Gianpietro Dotti

Faculty, Staff and Students Publications

Human natural killer T cells (NKTs) are innate-like T lymphocytes increasingly used for cancer immunotherapy. Here we show that human NKTs expressing the pro-inflammatory cytokine interleukin-12 (IL-12) undergo extensive and sustained molecular and functional reprogramming. Specifically, IL-12 instructs and maintains a Th1-polarization program in NKTs in vivo without causing their functional exhaustion. Furthermore, using CD62L as a marker of memory cells in human NKTs, we observe that IL-12 maintains long-term CD62L-expressing memory NKTs in vivo. Notably, IL-12 initiates a de novo programming of memory NKTs in CD62L-negative NKTs indicating that human NKTs circulating in the peripheral blood possess an intrinsic …

Clonal Hematopoiesis Risk Score And All-Cause And Cardiovascular Mortality In Older Adults, Seyedmohammad Saadatagah, Md Mesbah Uddin, Lachelle D Weeks, Abhishek Niroula, Meng Ru, Koichi Takahashi, Lukasz Gondek, Bing Yu, Alexander G Bick, Benjamin L Ebert, Elizabeth A Platz, Pradeep Natarajan, Christie M Ballantyne

Faculty, Staff and Student Publications

IMPORTANCE: Clonal hematopoiesis (CH) with acquired pathogenic variants in myeloid leukemia driver genes is common in older adults but of unknown prognostic value.

OBJECTIVE: To investigate the prevalence of CH and the utility of the CH risk score (CHRS) in estimating all-cause and disease-specific mortality in older adults with CH.

DESIGN, SETTING, AND PARTICIPANTS: This population-based prospective cohort study involved community-dwelling older adults (aged 67-90 years) without hematologic malignant neoplasms (HMs) who were participants in the Atherosclerosis Risk in Communities Visit 5 at 4 US centers: Forsyth County, North Carolina; Jackson, Mississippi; Minneapolis, Minnesota; and Washington County, Maryland. Samples were …

Evidence Based Practice: A Decision-Making Guide For Health Information Professionals, Jonathan Eldredge

Faculty Book Display Case

This Guide introduces Evidence Based Practice to newcomers as well as serves as a resource for experienced practitioners. It focuses on health information professionals (informaticists, health sciences librarians, informationists, information scientists, data managers, archivists, etc.) within the US context, although others outside of the US health context might find elements of it to be valuable.

Enhancing Reproducibility In Single Cell Research With Biocytometry: An Inter-Laboratory Study, Pavel Fikar, Laura Alvarez, Laura Berne, Martin Cienciala, Christopher Kan, Hynek Kasl, Mona Luo, Zuzana Novackova, Sheyla Ordonez, Zuzana Sramkova, Monika Holubova, Daniel Lysak, Lyndsay Avery, Andres A. Caro, Roslyn N. Crowder, Laura A. Diaz-Martinez, David W. Donley, Rebecca R. Giorno, Irene K. Guttilla Reed, Lori Hensley

Research, Publications & Creative Work

Biomedicine today is experiencing a shift towards decentralized data collection, which promises enhanced reproducibility and collaboration across diverse laboratory environments. This inter-laboratory study evaluates the performance of biocytometry, a method utilizing engineered bioparticles for enumerating cells based on their surface antigen patterns. In centralized and aggregated inter-lab studies, biocytometry demonstrated significant statistical power in discriminating numbers of target cells at varying concentrations as low as 1 cell per 100,000 background cells. User skill levels varied from expert to beginner capturing a range of proficiencies. Measurement was performed in a decentralized environment without any instrument cross-calibration or advanced user training outside …

In Vivo Scanning Laser Fundus And High-Resolution Oct Imaging Of Retinal Ganglion Cell Injury In A Non-Human Primate Model With An Activatable Fluorescent-Labeled Tat Peptide Probe, Xudong Qiu, Seth T Gammon, Carol Rasmussen, Federica Pisaneschi, Charlene B Y Kim, James Ver Hoeve, Steven W Millward, Edward M Barnett, T Michael Nork, Paul L Kaufman, David Piwnica-Worms

Faculty, Staff and Student Publications

The optical imaging agent TcapQ488 has enabled imaging of retinal ganglion cell (RGC) injury in vivo in rodents and has potential as an effective diagnostic probe for early detection and intervention monitoring in glaucoma patients. In the present study, we investigated TcapQ488 in non-human primates (NHPs) to identify labeling efficacy and early signals of injured RGC, to determine species-dependent changes in RGC probe uptake and clearance, and to determine dose-limiting toxicities. Doses of 3, 6, and 12 nmol of TcapQ488 were delivered intravitreally to normal healthy NHP eyes and eyes that had undergone hemiretinal endodiathermy axotomy (HEA) in the inferior …

An Automated Approach For Identifying Erroneous Is-A Relations In Snomed Ct, Ran Hu, Jay Shi, Licong Cui, Rashmie Abeysinghe

Faculty, Staff and Student Publications

SNOMED CT is the most comprehensive clinical terminology employed worldwide and enhancing its accuracy is of utmost importance. In this work, we introduce an automated approach to identifying erroneous IS-A relations in SNOMED CT. We first extract linked concept-pairs from which we generate Term Difference Pairs (TDPs) that contain differences between the concepts. Given a TDP, if the reversed TDP also exists and the number of linked-pairs generating this TDP is less than those generating the reversed TDP, then we suggest the former linked-pairs as potentially erroneous IS-A relations. We applied this approach to the Clinical finding and Procedure subhierarchies …

Facilitating Clinical Information Extraction With Synthetic Data And Ontology Using Large Language Models, Yan Hu, Huan He, Qingyu Chen, Xiaoqian Jiang, Kirk Roberts, Hua Xu

Faculty, Staff and Student Publications

The rapid growth of unstructured clinical text in electronic health records necessitates robust information extraction systems, yet their development is hindered by the scarcity of high-quality annotated data. This study explores the potential of large language models to generate synthetic data for clinical named entity recognition and examines its impact on model performance. We propose a novel framework that integrates self-verified synthetic data generation with domain-specific semantic mapping using SNOMED-CT. By leveraging GPT-4o-mini for synthetic data creation and refining its quality through iterative verification and anomaly detection, we systematically evaluate the influence of synthetic data quality and quantity on fine-tuning …

Xuebijing Improves Intestinal Microcirculation Dysfunction In Septic Rats By Regulating The Vegf-A/Pi3k/Akt Signaling Pathway, A-Ling Tang, Yan Li, Li-Chao Sun, Xiao-Yu Liu, Nan Gao, Sheng-Tao Yan, Guo-Qiang Zhang

Faculty, Staff and Student Publications

BACKGROUND: This study aims to explore whether Xuebijing (XBJ) can improve intestinal microcirculation dysfunction in sepsis and its mechanism.

METHODS: A rat model of sepsis was established by cecal ligation and puncture (CLP). A total of 30 male SD rats were divided into four groups: sham group, CLP group, XBJ + axitinib group, and XBJ group. XBJ was intraperitoneally injected 2 h before CLP. Hemodynamic data (blood pressure and heart rate) were recorded. The intestinal microcirculation data of the rats were analyzed via microcirculation imaging. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the serum levels of interleukin-6 (IL-6), …