Biomedical Informatics Commons^™

A Non-Parametric Approach To Predict The Recruitment For Randomized Clinical Trials: An Example In Elderly Inpatient Settings, Alejandro Villasante-Tezanos, Yong-Fang Kuo, Christopher Kurinec, Yisheng Li, Xiaoying Yu

Faculty, Staff and Student Publications

BACKGROUND: Accurate prediction of subject recruitment, which is critical to the success of a study, remains an ongoing challenge. Previous prediction models often rely on parametric assumptions which are not always met or may be difficult to implement. We aim to develop a novel method that is less sensitive to model assumptions and relatively easy to implement.

METHODS: We create a weighted resampling-based approach to predict enrollment in year two based on recruitment data from year one of the completed GRIPS and PACE clinical trials. Different weight functions accounted for a range of potential enrollment trajectory patterns. Prediction accuracy was …

Mechanisms And Metabolic Consequences Of Adipocyte Progenitor Replicative Senescence, Tonghui Lin, Aftab Mohammad, Mikhail G Kolonin, Kristin L Eckel-Mahan

Faculty, Staff and Student Publications

In recent decades, obesity has become a worldwide epidemic. As a result, the importance of adipose tissue (AT) as a metabolically active storage depot for lipids and a key mediator of body-wide metabolism and energy balance has been increasingly recognized. Emerging from the studies of AT in metabolic disease is a recognition of the importance of the adipocyte progenitor cell (APC) population of AT being the gatekeeper of adipocyte function. APCs have the capability to self-renew and undergo adipogenesis to propagate new adipocytes capable of lipid storage, which is important for maintaining a healthy fat pad, devoid of dysfunctional lipid …

Whole Genome And Reverse Protein Phase Array Landscapes Of Patient Derived Osteosarcoma Xenograft Models, Chia-Chin Wu, Licai Huang, Zhongting Zhang, Zhenlin Ju, Xingzhi Song, E Anders Kolb, Wendong Zhang, Jonathan Gill, Min Ha, Malcolm A Smith, Peter Houghton, Christopher L Morton, Raushan Kurmasheva, John Maris, Yael Mosse, Yiling Lu, Richard Gorlick, P Andrew Futreal, Hannah C Beird

Faculty, Staff and Student Publications

Osteosarcoma is the most common primary bone malignancy in children and young adults, and it has few treatment options. As a result, there has been little improvement in survival outcomes in the past few decades. The need for models to test novel therapies is especially great in this disease since it is both rare and does not respond to most therapies. To address this, an NCI-funded consortium has characterized and utilized a panel of patient-derived xenograft models of osteosarcoma for drug testing. The exomes, transcriptomes, and copy number landscapes of these models have been presented previously. This study now adds …

Neutralization Escape, Infectivity, And Membrane Fusion Of Jn1-Derived Sars-Cov-2 Slip, Flirt, And Kp2 Variants, Pei Li, Julia N Faraone, Cheng Chih Hsu, Michelle Chamblee, Yi-Min Zheng, Claire Carlin, Joseph S Bednash, Jeffrey C Horowitz, Rama K Mallampalli, Linda J Saif, Eugene M Oltz, Daniel Jones, Jianrong Li, Richard J Gumina, Kai Xu, Shan-Lu Liu

Faculty, Staff and Student Publications

We investigate JN.1-derived subvariants SLip, FLiRT, and KP.2 for neutralization by antibodies in vaccinated individuals, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients, or class III monoclonal antibody S309. Compared to JN.1, SLip, KP.2, and especially FLiRT exhibit increased resistance to bivalent-vaccinated and BA.2.86/JN.1-wave convalescent human sera. XBB.1.5 monovalent-vaccinated hamster sera robustly neutralize FLiRT and KP.2 but have reduced efficiency for SLip. All subvariants are resistant to S309 and show decreased infectivity, cell-cell fusion, and spike processing relative to JN.1. Modeling reveals that L455S and F456L in SLip reduce spike binding for ACE2, while R346T in FLiRT and KP.2 strengthens …

Trim44, A Novel Prognostic Marker, Supports The Survival Of Proteasome-Resistant Multiple Myeloma Cells, Trung Vu, Yuqin Wang, Annaliese Fowler, Anton Simieou, Nami Mccarty

Faculty, Staff and Student Publications

TRIM44, a tripartite motif (TRIM) family member, is pivotal in linking the ubiquitin-proteasome system (UPS) to autophagy in multiple myeloma (MM). However, its prognostic impact and therapeutic potential remain underexplored. Here, we report that TRIM44 overexpression is associated with poor prognosis in a Multiple Myeloma Research Foundation (MMRF) cohort of 858 patients, persisting across primary and recurrent MM cases. TRIM44 expression notably increases in advanced MM stages, indicating its potential role in disease progression. Single-cell RNA sequencing across MM stages showed significant TRIM44 upregulation in smoldering MM (SMM) and MM compared to normal bone marrow, especially in patients with t(4;14) …

Meti: Deep Profiling Of Tumor Ecosystems By Integrating Cell Morphology And Spatial Transcriptomics, Jiahui Jiang, Yunhe Liu, Jiangjiang Qin, Jianfeng Chen, Jingjing Wu, Melissa P Pizzi, Rossana Lazcano, Kohei Yamashita, Zhiyuan Xu, Guangsheng Pei, Kyung Serk Cho, Yanshuo Chu, Ansam Sinjab, Fuduan Peng, Xinmiao Yan, Guangchun Han, Ruiping Wang, Enyu Dai, Yibo Dai, Bogdan A Czerniak, Andrew Futreal, Anirban Maitra, Alexander Lazar, Humam Kadara, Amir A Jazaeri, Xiangdong Cheng, Jaffer Ajani, Jianjun Gao, Jian Hu, Linghua Wang

Faculty, Staff and Student Publications

Recent advances in spatial transcriptomics (ST) techniques provide valuable insights into cellular interactions within the tumor microenvironment (TME). However, most analytical tools lack consideration of histological features and rely on matched single-cell RNA sequencing data, limiting their effectiveness in TME studies. To address this, we introduce the Morphology-Enhanced Spatial Transcriptome Analysis Integrator (METI), an end-to-end framework that maps cancer cells and TME components, stratifies cell types and states, and analyzes cell co-localization. By integrating spatial transcriptomics, cell morphology, and curated gene signatures, METI enhances our understanding of the molecular landscape and cellular interactions within the tissue. We evaluate the performance …

The Icf Syndrome Protein Cdca7 Harbors A Unique Dna Binding Domain That Recognizes A Cpg Dyad In The Context Of A Non-B Dna, Swanand Hardikar, Ren Ren, Zhengzhou Ying, Jujun Zhou, John R Horton, Matthew D Bramble, Bin Liu, Yue Lu, Bigang Liu, Luis Della Coletta, Jianjun Shen, Jiameng Dan, Xing Zhang, Xiaodong Cheng, Taiping Chen

Faculty, Staff and Student Publications

CDCA7, encoding a protein with a carboxyl-terminal cysteine-rich domain (CRD), is mutated in immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a disease related to hypomethylation of juxtacentromeric satellite DNA. How CDCA7 directs DNA methylation to juxtacentromeric regions is unknown. Here, we show that the CDCA7 CRD adopts a unique zinc-binding structure that recognizes a CpG dyad in a non-B DNA formed by two sequence motifs. CDCA7, but not ICF mutants, preferentially binds the non-B DNA with strand-specific CpG hemi-methylation. The unmethylated sequence motif is highly enriched at centromeres of human chromosomes, whereas the methylated motif is distributed throughout …

Active Learning Pipeline To Identify Candidate Terms For A Cdss Ontology, Xia Jing, Rohan Goli, Keerthana Komatineni, Shailesh Alluri, Nina Hubig, Hua Min, Yang Gong, Dean F Sittig, Paul Biondich, David Robinson, Christian Nøhr, Arild Faxvaag, Adam Wright, Timothy Law, Lior Rennert, Ronald Gimbel

Faculty, Staff and Student Publications

Ontology is essential for achieving health information and information technology application interoperability in the biomedical fields and beyond. Traditionally, ontology construction is carried out manually by human domain experts (HDE). Here, we explore an active learning approach to automatically identify candidate terms from publications, with manual verification later as a part of a deep learning model training and learning process. We introduce the overall architecture of the active learning pipeline and present some preliminary results. This work is a critical and complementary component in addition to manually building the ontology, especially during the long-term maintenance stage.

Perceptions Of Hiv-Related Comorbidities And Usability Of A Virtual Environment For Cardiovascular Disease Prevention Education In Sexual Minority Men With Hiv: Formative Phases Of A Pilot Randomized Controlled Trial, S Raquel Ramos, Harmony Reynolds, Constance Johnson, Gail Melkus, Trace Kershaw, Julian F Thayer, Allison Vorderstrasse

Faculty, Staff and Student Publications

Background: Sexual minority men with HIV are at an increased risk of cardiovascular disease (CVD) and have been underrepresented in behavioral research and clinical trials.

Objective: This study aims to explore perceptions of HIV-related comorbidities and assess the interest in and usability of a virtual environment for CVD prevention education in Black and Latinx sexual minority men with HIV.

Methods: This is a 3-phase pilot behavioral randomized controlled trial. We report on formative phases 1 and 2 that informed virtual environment content and features using qualitative interviews, usability testing, and beta testing with a total of 25 individuals. In phase …

Sexannodb, A Knowledgebase Of Sex-Specific Regulations From Multi-Omics Data Of Human Cancers, Mengyuan Yang, Yuzhou Feng, Jiajia Liu, Hong Wang, Sijia Wu, Weiling Zhao, Pora Kim, Xiaobo Zhou

Faculty, Staff and Student Publications

Background

Sexual differences across molecular levels profoundly impact cancer biology and outcomes. Patient gender significantly influences drug responses, with divergent reactions between men and women to the same drugs. Despite databases on sex differences in human tissues, understanding regulations of sex disparities in cancer is limited. These resources lack detailed mechanistic studies on sex-biased molecules.

Methods

In this study, we conducted a comprehensive examination of molecular distinctions and regulatory networks across 27 cancer types, delving into sex-biased effects. Our analyses encompassed sex-biased competitive endogenous RNA networks, regulatory networks involving sex-biased RNA binding protein-exon skipping events, sex-biased transcription factor-gene regulatory networks, …

A Data Pipeline For Enhancing Quality Of Maude-Based Studies, Yuheng Shi, Yue Yu, Yubo Feng, Yang Gong

Faculty, Staff and Student Publications

The increasing use of MAUDE reports in patient safety research highlights the importance of understanding the processing and dissemination of open-access MAUDE data. However, the absence of a structured data pipeline undermines the reproducibility and transparency of studies relying on MAUDE data. In response, we conducted a comprehensive analysis of a recent study on endoscopic clips, assessing methodologies and results. We advocate for implementing an extract, transform, and load (ETL) pipeline, utilizing openFDA and integrating keyword search strategies and data visualization techniques. This approach aims to enhance the quality of MAUDE-based studies, ensuring their reproducibility and transparency. Moreover, ETL serves …

Challenges And Opportunities Of Artificial Intelligence In Cdss And Patient Safety, Yang Gong, Hua Min, Xia Jing, Ping Yu

Faculty, Staff and Student Publications

Ensuring patient safety in healthcare involves training professionals and implementing clinical decision support systems (CDSS) and health IT solutions to reduce errors and adverse events. The integration of artificial intelligence (AI) into health IT has revolutionized clinical settings by enabling real-time insights and personalized recommendations. However, the use of health IT can lead to unintended consequences that are not adequately addressed during training and implementation. These consequences can hinder the maximization of benefits and limit equitable access to healthcare. In this paper, we explore the impact of AI on CDSS and health IT, discuss the challenges in educating clinical informaticians, …

Loss Of Symmetric Cell Division Of Apical Neural Progenitors Drives Dennd5a-Related Developmental And Epileptic Encephalopathy, Emily Banks, Vincent Francis, Sheng-Jia Lin, Fares Kharfallah, Vladimir Fonov, Maxime Lévesque, Chanshuai Han, Gopinath Kulasekaran, Marius Tuznik, Armin Bayati, Reem Al-Khater, Fowzan S Alkuraya, Loukas Argyriou, Meisam Babaei, Melanie Bahlo, Behnoosh Bakhshoodeh, Eileen Barr, Lauren Bartik, Mahmoud Bassiony, Miriam Bertrand, Dominique Braun, Rebecca Buchert, Mauro Budetta, Maxime Cadieux-Dion, Daniel G Calame, Heidi Cope, Donna Cushing, Stephanie Efthymiou, Marwa Abd Elmaksoud, Huda G El Said, Tawfiq Froukh, Harinder K Gill, Joseph G Gleeson, Laura Gogoll, Elaine S-Y Goh, Vykuntaraju K Gowda, Tobias B Haack, Mais O Hashem, Stefan Hauser, Trevor L Hoffman, Jacob S Hogue, Akimoto Hosokawa, Henry Houlden, Kevin Huang, Stephanie Huynh, Ehsan G Karimiani, Silke Kaulfuß, G Christoph Korenke, Amy Kritzer, Hane Lee, James R Lupski, Elysa J Marco, Kirsty Mcwalter, Arakel Minassian, Berge A Minassian, David Murphy, Juanita Neira-Fresneda, Hope Northrup, Denis M Nyaga, Barbara Oehl-Jaschkowitz, Matthew Osmond, Richard Person, Davut Pehlivan, Cassidy Petree, Lynette G Sadleir, Carol Saunders, Ludger Schoels, Vandana Shashi, Rebecca C Spillmann, Varunvenkat M Srinivasan, Paria N Torbati, Tulay Tos, Maha S Zaki, Dihong Zhou, Christiane Zweier, Jean-François Trempe, Thomas M Durcan, Ziv Gan-Or, Massimo Avoli, Cesar Alves, Gaurav K Varshney, Reza Maroofian, David A Rudko, Peter S Mcpherson

Faculty, Staff and Student Publications

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells …

The Dna Repair Pathway As A Therapeutic Target To Synergize With Trastuzumab Deruxtecan In Her2-Targeted Antibody-Drug Conjugate-Resistant Her2-Overexpressing Breast Cancer, Jangsoon Lee, Kumiko Kida, Jiwon Koh, Huey Liu, Ganiraju C Manyam, Young Jin Gi, Dileep R Rampa, Asha S Multani, Jing Wang, Gitanjali Jayachandran, Dae-Won Lee, James M Reuben, Aysegul Sahin, Lei Huo, Debu Tripathy, Seock-Ah Im, Naoto T Ueno

Faculty, Staff and Student Publications

Background: Anti-HER2 therapies, including the HER2 antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have led to improved survival outcomes in patients with HER2-overexpressing (HER2+) metastatic breast cancer. However, intrinsic or acquired resistance to anti-HER2-based therapies remains a clinical challenge in these patients, as there is no standard of care following disease progression. The purpose of this study was to elucidate the mechanisms of resistance to T-DM1 and T-DXd in HER2+ BC patients and preclinical models and identify targets whose inhibition enhances the antitumor activity of T-DXd in HER2-directed ADC-resistant HER2+ breast cancer in vitro and in vivo. …

Transcriptome Profiling Of Pediatric Extracranial Solid Tumors And Lymphomas Enables Rapid Low-Cost Diagnostic Classification, Kofi B Opoku, Teresa Santiago, Priya Kumar, Sophia M Roush, Yuri Fedoriw, Tamiwe Tomoka, Vasiliki Leventaki, Larissa V Furtado, Nickhill Bhakta, Thomas B Alexander, Jeremy R Wang

Faculty, Staff and Student Publications

Approximately 80% of pediatric tumors occur in low- and middle-income countries (LMIC), where diagnostic tools essential for treatment decisions are often unavailable or incomplete. Development of cost-effective molecular diagnostics will help bridge the cancer diagnostic gap and ultimately improve pediatric cancer outcomes in LMIC settings. We investigated the feasibility of using nanopore whole transcriptome sequencing on formalin-fixed paraffin embedded (FFPE)-derived RNA and a composite machine learning model for pediatric solid tumor diagnosis. Transcriptome cDNA sequencing was performed on a heterogenous set of 221 FFPE and 32 fresh frozen pediatric solid tumor and lymphoma specimens on Oxford Nanopore Technologies' sequencing platforms. …

Clinical And Genomic-Based Decision Support System To Define The Optimal Timing Of Allogeneic Hematopoietic Stem-Cell Transplantation In Patients With Myelodysplastic Syndromes, Cristina Astrid Tentori, Caterina Gregorio, Marie Robin, Nico Gagelmann, Carmelo Gurnari, Somedeb Ball, Juan Carlos Caballero Berrocal, Luca Lanino, Saverio D'Amico, Marta Spreafico, Giulia Maggioni, Erica Travaglino, Elisabetta Sauta, Manja Meggendorfer, Lin-Pierre Zhao, Alessia Campagna, Victor Savevski, Armando Santoro, Najla Al Ali, David Sallman, Francesc Sole, Guillermo Garcia-Manero, Ulrich Germing, Nicolaus Kroger, Shahram Kordasti, Valeria Santini, Guillermo Sanz, Wolfgang Kern, Uwe Platzbecker, Maria Diez-Campelo, Jaroslaw P Maciejewski, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Amer M Zeidan, Gastone Castellani, Rami Komrokji, Francesca Ieva, Matteo Giovanni Della Porta, Genomed4all And Synthema Consortiums

Faculty, Staff and Student Publications

Purpose: Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M).

Patients and methods: We studied a retrospective population of 7,118 patients, stratified into training and validation …

Association Of Social Determinants, Lifestyle, And Metabolic Factors With Mortality In Chinese Adults: A Nationwide 10-Year Prospective Cohort Study, Jieli Lu, Mian Li, Jiang He, Yu Xu, Ruizhi Zheng, Jie Zheng, Guijun Qin, Yingfen Qin, Yuhong Chen, Xulei Tang, Zhen Ye, Min Xu, Tiange Wang, Lixin Shi, Qing Su, Xuefeng Yu, Li Yan, Zhiyun Zhao, Qin Wan, Gang Chen, Zhengnan Gao, Guixia Wang, Feixia Shen, Xuejiang Gu, Zuojie Luo, Li Chen, Xinguo Hou, Yanan Huo, Qiang Li, Hong Qiao, Yinfei Zhang, Tianshu Zeng, Chunyan Hu, Qiuyu Cao, Xiaojing Jia, Chao Liu, Youmin Wang, Shengli Wu, Tao Yang, Huacong Deng, Hongyan Qi, Xueyan Wu, Di Zhang, Meng Dai, Donghui Li, Shenghan Lai, Lulu Chen, Jiajun Zhao, Yiming Mu, Weiguo Hu, Guang Ning, Ruying Hu, Yufang Bi, Weiqing Wang, 4c Study Group

Faculty, Staff and Student Publications

Nationwide estimates of the impact of common modifiable risk factors on mortality remain crucial. We aim to assess the influence of social determinants, lifestyle, and metabolic factors on mortality in 174,004 adults aged ≥40 years from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. We reveal that 17 modifiable factors are independently associated with mortality, accounting for 64.8% of all-cause mortality, 77.4% of cardiovascular mortality, and 44.8% of cancer mortality. Low education emerges as the leading factor for both all-cause and cancer mortality, while hypertension is predominant for cardiovascular mortality. Moreover, low gross domestic product per capita and high …

Epcam-Targeted Betulinic Acid Analogue Nanotherapy Improves Therapeutic Efficacy And Induces Anti-Tumorigenic Immune Response In Colorectal Cancer Tumor Microenvironment, Debasmita Dutta, Ashique Al Hoque, Brahamacharry Paul, Jun Hyoung Park, Chinmay Chowdhury, Mohiuddin Quadir, Soumyabrata Banerjee, Arghadip Choudhury, Soumik Laha, Nayim Sepay, Priyanka Boro, Benny Abraham Kaipparettu, Biswajit Mukherjee

Faculty, Staff and Students Publications

Background: Betulinic acid (BA) has been well investigated for its antiproliferative and mitochondrial pathway-mediated apoptosis-inducing effects on various cancers. However, its poor solubility and off-target activity have limited its utility in clinical trials. Additionally, the immune modulatory role of betulinic acid analogue in the tumor microenvironment (TME) is largely unknown. Here, we designed a potential nanotherapy for colorectal cancer (CRC) with a lead betulinic acid analogue, named as 2c, carrying a 1,2,3-triazole-moiety attached to BA through a linker, found more effective than BA for inhibiting CRC cell lines, and was chosen here for this investigation. Epithelial cell adhesion molecule (EpCAM) …

The Complex Molecular Epileptogenesis Landscape Of Glioblastoma, Victoria Soeung, Ralph B Puchalski, Jeffrey L Noebels

Faculty, Staff and Students Publications

The cortical microenvironment surrounding malignant glioblastoma is a source of depolarizing crosstalk favoring hyperexcitability, tumor expansion, and immune evasion. Neosynaptogenesis, excess glutamate, and altered intrinsic membrane currents contribute to excitability dyshomeostasis, yet only half of the cases develop seizures, suggesting that tumor and host genomics, along with location, rather than mass effect, play a critical role. We analyzed the spatial contours and expression of 358 clinically validated human epilepsy genes in the human glioblastoma transcriptome compared to non-tumor adult and developing cortex datasets. Nearly half, including dosage-sensitive genes whose expression levels are securely linked to monogenic epilepsy, are strikingly enriched …

Trim44 Enhances Autophagy Via Sqstm1 Oligomerization In Response To Oxidative Stress, Yuqin Wang, Lin Lyu, Trung Vu, Nami Mccarty

Faculty, Staff and Student Publications

The deubiquitinase tripartite motif containing 44 (TRIM44) plays a critical role in linking the proteotoxic stress response with autophagic degradation, which is significant in the context of cancer and neurological diseases. Although TRIM44 is recognized as a prognostic marker in various cancers, the complex molecular mechanisms through which it facilitates autophagic degradation, particularly under oxidative stress conditions, have not been fully explored. In this study, we demonstrate that TRIM44 significantly enhances autophagy in response to oxidative stress, reducing cytotoxicity in cancer cells treated with arsenic trioxide. Our research emphasizes the critical role of the posttranslational modification of sequestosome-1 (SQSTM1) and …

Monitoring Response To Neoadjuvant Chemotherapy In Triple Negative Breast Cancer Using Circulating Tumor Dna, Jennifer H Chen, Sridevi Addanki, Dhruvajyoti Roy, Roland Bassett, Ekaterina Kalashnikova, Erik Spickard, Henry M Kuerer, Salyna Meas, Vanessa N Sarli, Anil Korkut, Jason B White, Gaiane M Rauch, Debu Tripathy, Banu K Arun, Carlos H Barcenas, Clinton Yam, Himanshu Sethi, Angel A Rodriguez, Minetta C Liu, Stacy L Moulder, Anthony Lucci

Faculty, Staff and Student Publications

BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive subtype with poor prognosis. We aimed to determine whether circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) could predict response and long-term outcomes to neoadjuvant chemotherapy (NAC).

METHODS: Patients with TNBC were enrolled between 2017-2021 at The University of Texas MD Anderson Cancer Center (Houston, TX). Serial plasma samples were collected at four timepoints: pre-NAC (baseline), 12-weeks after NAC (mid-NAC), after NAC/prior to surgery (post-NAC), and one-year after surgery. ctDNA was quantified using a tumor-informed ctDNA assay (Signatera

RESULTS: In total, 37 patients were enrolled. The mean age was 50 …

Hematopoietic Growth Factors Regulate The Entry Of Monocytes Into The Adult Brain Via Chemokine Receptor Ccr5, Xuefang Sophie Ren, Junchi He, Songruo Li, Heng Hu, Michele Kyle, Shinichi Kohsaka, Li-Ru Zhao

Faculty, Staff and Student Publications

Monocytes are circulating macrophage precursors generated from bone marrow hematopoietic stem cells. In adults, monocytes continuously replenish cerebral border-associated macrophages under physiological conditions. Monocytes also rapidly infiltrate the brain in pathological settings. The mechanisms of recruiting monocyte-derived macrophages into the brain under pathological conditions have been extensively studied. However, it remains unclear how monocytes enter the brain to renew border-associated macrophages under physiological conditions. Using both in vitro and in vivo approaches, this study reveals that a combination of two hematopoietic growth factors, stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF), complementarily and synergistically enhances the adhesion of monocytes …

Proteomics Meets Dose Response: A New Paradigm For Deciphering Drug Effects, Chenwei Wang, Bing Zhang

Faculty, Staff and Students Publications

In a groundbreaking study, Eckert and colleagues introduce DecryptE, an innovative approach to dose-resolved proteomics that significantly advances our understanding of drug effects at the proteomic level. This method integrates cutting edge sample preparation and mass spectrometry technologies, establishing a robust platform for high-throughput proteome analysis. DecryptE enables the quantification of more than 7,000 proteins per hour and was employed to study 144 clinical drugs and research compounds, generating more than 1 million dose-response curves using Jurkat acute T-cell leukemia cells as a model system. The platform demonstrates outstanding reproducibility, ensuring reliable and consistent results across multiple experiments. By providing …

Hybridizing Mechanistic Modeling And Deep Learning For Personalized Survival Prediction After Immune Checkpoint Inhibitor Immunotherapy, Joseph D Butner, Prashant Dogra, Caroline Chung, Eugene J Koay, James W Welsh, David S Hong, Vittorio Cristini, Zhihui Wang

Faculty, Staff and Student Publications

We present a study where predictive mechanistic modeling is combined with deep learning methods to predict individual patient survival probabilities under immune checkpoint inhibitor (ICI) immunotherapy. This hybrid approach enables prediction based on both measures that are calculable from mechanistic models of key mechanisms underlying ICI therapy that may not be directly measurable in the clinic and easily measurable quantities or patient characteristics that are not always readily incorporated into predictive mechanistic models. A deep learning time-to-event predictive model trained on a hybrid mechanistic + clinical data set from 93 patients achieved higher per-patient predictive accuracy based on event-time concordance, …

Association Of Genetic Ancestry With Molecular Tumor Profiles In Colorectal Cancer, Brooke Rhead, David M Hein, Yannick Pouliot, Justin Guinney, Francisco M De La Vega, Nina N Sanford

Faculty, Staff and Student Publications

Background: There are known disparities in incidence and outcomes of colorectal cancer (CRC) by race and ethnicity. Some of these disparities may be mediated by molecular changes in tumors that occur at different rates across populations. Genetic ancestry is a measure complementary to race and ethnicity that can overcome missing data issues and better capture genetic similarity in admixed populations. We aimed to identify somatic mutations and tumor gene expression differences associated with both genetic ancestry and imputed race and ethnicity.

Methods: Sequencing was performed with the Tempus xT NGS 648-gene panel and whole exome capture RNA-Seq for 8454 primarily …

The Biology And Function Of Extracellular Vesicles In Immune Response And Immunity, Raghu Kalluri

Faculty, Staff and Student Publications

Extracellular vesicles (EVs), such as ectosomes and exosomes, contain DNA, RNA, proteins and are encased in a phospholipid bilayer. EVs provide intralumenal cargo for delivery into the cytoplasm of recipient cells with an impact on the function of immune cells, in part because their biogenesis can also intersect with antigen processing and presentation. Motile EVs from activated immune cells may increase the frequency of immune synapses on recipient cells in a proximity-independent manner for local and long-distance modulation of systemic immunity in inflammation, autoimmunity, organ fibrosis, cancer, and infections. Natural and engineered EVs exhibit the ability to impact innate and …

Prostate Cancer-Induced Endothelial-Cell-To-Osteoblast Transition Drives Immunosuppression In The Bone-Tumor Microenvironment Through Wnt Pathway-Induced M2 Macrophage Polarization, Guoyu Yu, Paul G Corn, Celia Sze Ling Mak, Xin Liang, Miao Zhang, Patricia Troncoso, Jian H Song, Song-Chang Lin, Xingzhi Song, Jingjing Liu, Jianhua Zhang, Christopher J Logothetis, Marites P Melancon, Theocharis Panaretakis, Guocan Wang, Sue-Hwa Lin

Faculty, Staff and Student Publications

Immune checkpoint therapy has limited efficacy for patients with bone-metastatic castration-resistant prostate cancer (bmCRPC). To improve immunotherapy for bmCRPC, we aimed to identify the mechanism of bmCRPC-induced changes in the immune microenvironment. Among bmCRPC patients, higher levels of a 32-gene M2-like macrophage signature in bone metastasis samples correlated with shorter overall survival. Immunohistochemistry showed that CD206-positive (CD206+) macrophages were enriched in bmCRPC bone biopsy specimens compared with primary tumors or lymph node metastases. In preclinical osteogenic prostate cancer (Pca) xenograft models, CD206+ macrophages were recruited to areas with tumor-induced bone. RNA sequencing (RNAseq) analysis showed higher expression of an M2-like …

Final Phase 1 Substudy Results Of Ivosidenib For Patients With Mutant Idh1 Relapsed/Refractory Myelodysplastic Syndrome, Courtney D Dinardo, Gail J Roboz, Justin M Watts, Yazan F Madanat, Gabrielle T Prince, Praneeth Baratam, Stéphane De Botton, Anthony Stein, James M Foran, Martha L Arellano, David A Sallman, Mohammad Hossain, Dylan M Marchione, Xiaofei Bai, Prapti A Patel, Stephanie M Kapsalis, Guillermo Garcia-Manero, Amir T Fathi

Faculty, Staff and Student Publications

Ivosidenib is a first-in-class mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor with efficacy and tolerability in patients with advanced mIDH1 hematologic malignancies, leading to approval in frontline and relapsed/refractory (R/R) mIDH1 acute myeloid leukemia. We report final data from a phase 1 single-arm substudy of once-daily ivosidenib in patients with R/R mIDH1 myelodysplastic syndrome (MDS) after failure of standard-of-care therapies. Primary objectives were to determine safety, tolerability, and clinical activity. The primary efficacy end point was the complete remission (CR) + partial remission (PR) rate. Nineteen patients were enrolled; 18 were included in the efficacy analysis. Treatment-related adverse events occurred in …

Pressing Issues For Oral Care Quality Improvement: Findings From The Eu Deliver Project, Paulo Melo, Leonor Frey-Furtado, Daniela Correia, Stefan Listl, Michael Lorenz, Nagihan Bostanci, Álvaro Azevedo, Maria Lurdes Pereira

Faculty, Staff and Student Publications

BACKGROUND: While oral health often takes a backseat to other health domains, it silently affects nearly half of the Worldwide population. The DELIVER project, funded by the EU's Horizon Europe program, seeks to develop a blueprint model for improving the quality of oral health care for everyone.

METHODS: Applying the Nominal Group Technique (NGT), 17 stakeholders from various backgrounds participated in identifying pressing issues for oral care quality improvement across practice, community, and policy levels.

RESULTS: The results revealed significant differences at the different levels, with accessibility emerging as a prominent issue, encompassing affordability, availability, and acceptability of oral healthcare …

Interleukin-21 Engineering Enhances Nk Cell Activity Against Glioblastoma Via Cebpd, Mayra Shanley, May Daher, Jinzhuang Dou, Sufang Li, Rafet Basar, Hind Rafei, Merve Dede, Joy Gumin, Jezreel Pantaleόn Garcίa, Ana Karen Nunez Cortes, Shan He, Corry M Jones, Sunil Acharya, Natalie W Fowlkes, Donghai Xiong, Sanjay Singh, Hila Shaim, Samantha Claire Hicks, Bin Liu, Abhinav Jain, Mohammad Fayyad Zaman, Qi Miao, Ye Li, Nadima Uprety, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Vakul Mohanty, Patrick Zhang, Scott E Evans, Elizabeth J Shpall, Frederick F Lang, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as …