Biomedical Informatics Commons^™

Time-Frequency Fingerprint Analysis In Seeg Source-Space To Identify The Epileptogenic Zone, Yash Shashank Vakilna, Deniz Atilgan, Johnson Hampson, Chinmay Chinara, Takfarinas Medani, Richard M Leahy, Nuria Lacuey, Samden D Lhatoo, Sandipan Pati, John C Mosher, Jay R Gavvala

Faculty, Staff and Student Publications

This case study highlights the application of seizure fingerprint analysis in the source-space of stereo-EEG (SEEG) data to accurately localize the epileptogenic zone (EZ) in patients with complex cortical malformations. A 25-year-old female with extensive bilateral perisylvian polymicrogyria (PMG) presented with intractable focal seizures. The source-level analysis performed in Brainstorm using the sLORETA imaging algorithm subsequently showed EZ fingerprint analysis. The patient underwent MR-guided laser interstitial thermal therapy (LITT), targeting the identified EZ, resulting in postoperative seizure freedom with minimal complications. Extending the analysis from the sensor-space to the source-space could further enhance surgical planning and improve outcomes in complex …

Heightened Risk: Childhood Trauma And Anticipatory Grief Exacerbate The Impact Of Loneliness On Depressive Symptoms And Lps-Stimulated Cytokines In Dementia Caregivers, Kelly N Brice, Jensine Paoletti-Hatcher, E Lydia Wu-Chung, Vincent D Lai, Daniel L Argueta, Michelle A Chen, Itee Mahant, Bryan T Denny, Charles Green, Luis D Medina, Paul Schulz, Jennifer Stinson, Samantha K Henry, Cobi Heijnen, Christopher P Fagundes

Faculty, Staff and Student Publications

Dementia spousal caregivers are at a disproportionate risk for adverse mental and physical health outcomes. Loneliness is associated with depressive symptoms and proinflammatory cytokine production among caregivers. Additionally, childhood trauma, anticipatory grief, and poor sleep quality are all associated with enhanced stress reactivity. This study used a cross-sectional design to investigate whether loneliness is associated with proinflammatory cytokine production and depressive symptoms in caregivers, and whether these relationships are strongest among caregivers who report high levels of childhood trauma, high amounts of anticipatory grief, or poor sleep quality. A sample of 111 dementia spousal caregivers provided blood samples and completed …

From Imaging To Impact: A Multi-Disciplinary T32 Program Framework And Initial Insights For Training In Image-Guided Cancer Therapy, Kari J Brewer Savannah, Stephen Y Lai, Clifton D Fuller, Kristy K Brock

Faculty, Staff and Student Publications

As multi-disciplinary image-guided assessment and therapies become increasingly important for precision oncology, the need for comprehensive training opportunities that effectively prepare the next generation of clinician-scientists and scientists is evident. We present an innovative, evidence-based research training framework that integrates the following critical features: 1) intentional and personalized mentoring and career development, 2) immersive research in image-guided cancer therapy, 3) strategic mentored clinical exposure, 4) structured didactic learning and professional development opportunities, and 5) mentored grant writing. Designed to foster scientific rigor, translational thinking, and multi-disciplinary collaboration, the Image-Guided Cancer Therapy T32 Training Program (IGCT-T32) aims to prepare postdoctoral fellows …

Author Correction: Clonal Evolution Of Hematopoietic Stem Cells After Autologous Stem Cell Transplantation, Hidetaka Uryu, Koichi Saeki, Hiroshi Haeno, Chiraag Deepak Kapadia, Ken Furudate, Jyoti Nangalia, Michael Spencer Chapman, Linda Zhang, Jennifer Padilla, Li Zhao, Joanne I Hsu, Chong Zhao, Shujuan Chen, Tomoyuki Tanaka, Zongrui Li, Satoko Ogata, Sarah Hanache, Hui Yang, Courtney Dinardo, Naval Daver, Naveen Pemmaraju, Nitin Jain, Farhad Ravandi, Jianhua Zhang, Xingzhi Song, Erika Thompson, Hongli Tang, Latasha Little, Curtis Gumbs, Robert Z Orlowski, Muzaffar Qazilbash, Kapil Bhalla, Simona Colla, Hagop Kantarjian, Rashmi Kanagal-Shamanna, Carlos Bueso-Ramos, Daisuke Nakada, Gheath Al-Atrash, Jeffery Molldrem, P Andrew Futreal, Elizabeth Shpall, Margaret Goodell, Guillermo Garcia-Manero, Koichi Takahashi

Faculty, Staff and Student Publications

No abstract provided.

Biomarkers For The Diagnosis Of Indeterminate Pulmonary Nodules: Are We There Yet?, Kevin C Mcgann, Timothy A Khalil, Michael N Kammer, Edwin J Ostrin, Harvey I Pass, Jun-Chieh James Tsay, Leopoldo N Segal, Melissa Potter, Stephen A Deppen, Fabien Maldonado, Eric L Grogan

Faculty, Staff and Student Publications

Indeterminate pulmonary nodules (IPNs), which are nodules that cannot be classified as definitively benign or malignant at the time of detection, are now diagnosed on the order of millions per year. Management of IPNs remains heavily debated, and routine practice ultimately involves some balance of overall clinical risk assessment and additional diagnostic tests or procedures which may generate significant risk, cost, and worry. Biomarkers are biologically based tests or indicators capable of accurately characterizing the physiologic properties of homeostasis and disease that are not otherwise easily evaluated by the clinician. Accurate biomarkers thereby serve as reliable surrogates for biological aberrancy, …

Expression Graph Network Framework For Biomarker Discovery, Yang Liu, Jason Huse, Kasthuri Kannan

Faculty, Staff and Student Publications

Biomarker discovery for complex diseases, such as cancer, hinges on uncovering molecular signatures that capture intricate, interconnected relationships within biological data-a challenge that traditional statistical and machine learning methods often fail to meet due to the complexity of high-dimensional gene expression profiles. To overcome this, we introduce the expression graph network framework (EGNF). This cutting-edge graph-based approach integrates graph neural networks with network-based feature engineering to enhance the predictive identification of biomarkers. EGNF constructs biologically informed networks by combining gene expression data and clinical attributes within a graph database, utilizing hierarchical clustering to generate dynamic, patient-specific representations of molecular interactions. …

Auprc: A Metric For Evaluating The Performance Of In-Silico Perturbation Methods In Identifying Differentially Expressed Genes, Hongxu Zhu, Amir Asiaee, Leila Azinfar, Jun Li, Han Liang, Ehsan Irajizad, Kim-Anh Do, James P Long

Faculty, Staff and Student Publications

In silico perturbation models, computational methods that can predict cellular responses to perturbations, present an opportunity to reduce the need for costly and time-intensive in vitro experiments. Many recently proposed models predict high-dimensional cellular responses, such as gene or protein expression to perturbations such as gene knockout or drugs. However, evaluating in silico performance has largely relied on metrics such as $R^{2}$, which assess overall prediction accuracy but fail to capture biologically significant outcomes like the identification of differentially expressed (DE) genes. In this study, we present a novel evaluation framework that introduces the AUPRC metric to assess the precision …

Braingenebot: A Framework For Variant Prioritization And Generative Pretrained Transformer-Informed Interpretation Across Polygenic Risk Score Studies, Gang Qu, Nitesh Enduru, Xinyi Liu, Xiaoqian Jiang, Zhongming Zhao

Faculty, Staff and Student Publications

Polygenic risk scores (PRS) are widely used to assess genetic susceptibility in Alzheimer's disease (AD) research. However, the rapid expansion of PRS studies has led to dataset-specific biases-stemming from factors like population makeup, genotyping methods, and analysis pipelines-that result in inconsistent variant prioritization and limit generalizability and reproducibility. To address these challenges, we propose a transductive learning framework that integrates multiple PRS datasets for more robust risk variant prioritization, incorporating genome-wide association study (GWAS) priority scores as biologically informed priors. Additionally, we introduce BrainGeneBot, an AI-driven tool leveraging generative pretrained transformers with retrieval-augmented generation technology to streamline genomic analyses in …

Cross-Platform Transcriptomic Data Integration Identifies An Overactive Neuro-Immune Signature In Human Osteoarthritis Synovium, Michael D Newton, Hannah Swahn, Dana E Orange, Joseph B Lesnak, Theodore J Price, Anne-Marie Malfait, Rachel E Miller, Martin K Lotz, Tristan Maerz

Faculty, Staff and Student Publications

Objective: Chronic synovitis is associated with osteoarthritis (OA) pain, but the molecular underpinnings remain unclear. Our objective was to characterize the transcriptional phenotype of OA synovium with a focus on signaling relevant to pain.

Design: Eight publicly-available microarray and RNA-sequencing GEO datasets from human non-OA and OA subjects underwent quality control and re-analysis for differentially-expressed genes (DEGs). Cross-platform statistical integration was performed via a weighted Z-test to combine detection power across datasets. Gene set enrichment, cell type enrichment, and regulon analyses were performed. Human single-cell RNA sequencing data was used to map gene expression to cell types. Ligand-receptor interactions were …

Deciphering Transcriptomic Changes In Chemobrain: A Comprehensive Review, Tusar Kanta Acharya, Yuan Pan, Peter M Grace, Cobi J Heijnen, Rajasekaran Mahalingam

Faculty, Staff and Student Publications

Chemotherapy-induced cognitive impairments (CICI), colloquially known as "chemobrain," represents a profound and debilitating side effect experienced by a significant number of cancer survivors, impacting their memory, multitasking, and quality of life. This review critically evaluates the molecular mechanisms underlying CICI, with a particular focus on the insights gained from transcriptomic analyses. As cancer incidence rises globally, understanding the complex interplay between chemotherapy agents and their cognitive repercussions becomes increasingly vital. Key mechanisms implicated in CICI include blood-brain barrier disruption, neuroinflammation, and oxidative stress as a result of various chemotherapy treatments, such as doxorubicin, cisplatin, and paclitaxel. We delve into advanced …

Risk Of Major Depression In Partners Of People With Alzheimer's Disease: A National Cohort Study, Casey Crump, Jingkai Wei, Barbara G Vickrey, Alexis C Edwards, Paul E Schulz, Weiva Sieh, Jan Sundquist, Kristina Sundquist

Faculty, Staff and Student Publications

Background: Alzheimer's disease (AD) may cause significant psychosocial distress not only in the patient but also their partner. However, long-term risks of major depression in partners of AD patients are largely unknown.

Methods: A national cohort study was conducted of all 145 289 partners of people diagnosed with all-cause dementia, including 57 113 partners of people diagnosed with AD, in Sweden during 1998-2017, and 1 300 561 population-based controls. Cox regression was used to compute hazard ratios (HRs) for subsequent risk of major depression identified from nationwide outpatient and inpatient diagnoses through 2018, adjusting for sociodemographic factors and prior mental …

Ras-Membrane Interaction And Oligomerization: There Is More Than Meets The Eye, Abraham C Sianoya, Vijay K Bhardwaj, Alemayehu A Gorfe

Faculty, Staff and Student Publications

Membrane association is fundamental to Rat sarcoma (RAS) function, driving both its physiologic signaling and oncogenic transformation. This review consolidates recent advances in the study of RAS-membrane interactions, emphasizing the molecular mechanisms underlying its membrane engagement and oligomerization. We first discuss the roles of RAS lipid modification and conformational diversity of its intrinsically disordered C-terminus in these processes, and we then examine the debate surrounding RAS dimerization and its potential role in the formation of higher-order oligomers. By integrating emerging insights into these issues, we offer our own perspectives on the driving forces of RAS oligomerization and propose potential new …

Epigenetic Modulation Of Bard1 To Enhance Anti-Vegf Therapy, Emine Bayraktar, Cristian Rodriguez-Aguayo, Elaine Stur, Sudhir Kumar, Lingegowda S Mangala, Nicholas B Jennings, Nazende Nur Bayram, Sara Corvigno, Amma Asare, Cristina Ivan, Mark S Kim, Thanh Chung Vu, Pahul Hanjra, Sangbae Kim, Adrian Lankenau Ahumada, Weichem Wu, Sanghoon Lee, Anna Szymanowska, Hulya Oztatlici, Marcos R Estecio, Ju-Seog Lee, Abhinav K Jain, Nidhi Sahni, John P Hagan, Stephen Baylin, Jinsong Liu, Gabriel Lopez-Berestein, Sunila Pradeep, Anil K Sood

Faculty, Staff and Student Publications

Despite the clinical use of anti-vascular endothelial growth factor (VEGF) antibodies (AVAs) in cancer therapy, resistance frequently develops, leading to disease progression. To address this, we identify a previously unknown role for breast cancer type 1 susceptibility protein (BRCA1)-associated RING domain 1 (BARD1) in modulating AVA sensitivity. Epigenetic modulation-via global and targeted DNA methylation-reveals BARD1 as a key regulator of angiogenesis. Sequential treatment with azacytidine overcomes AVA resistance in vivo. To enable precise epigenetic reactivation, we develop a liposomal CRISPR-deactivated Cas9 (dCas9)-TET1 system guided by BARD1-targeting single-guide RNAs (sgRNAs). This platform achieves CpG-specific demethylation of the BARD1 promoter, restores expression, …

Dna Double-Stranded Breaks, A Hallmark Of Aging, Defined At The Nucleotide Resolution, Are Increased And Associated With Transcription In The Cardiac Myocytes In Lmna-Cardiomyopathy, Benjamin Cathcart, Sirisha M Cheedipudi, Leila Rouhi, Zhongming Zhao, Priyatansh Gurha, Ali J Marian

Faculty, Staff and Student Publications

Aims: An intrinsic feature of gene transcription is the formation of DNA superhelices near the transcription bubble, which are resolved upon induction of transient double-stranded breaks (DSBs) by topoisomerases. Unrepaired DSBs are pathogenic as they lead to cell cycle arrest, senescence, inflammation, and organ dysfunction. We posit that DSBs would be more prevalent at the genomic sites that are associated with gene expression. The objectives were to identify and characterize genome-wide DSBs at the nucleotide resolution and determine the association of DSBs with transcription in cardiac myocytes.

Methods and results: We identified the genome-wide DSBs in ∼1 million cardiac myocytes …

The Immunophenotypic And Genetic Characterization Of Pediatric T -L Ymphoblastic Leukemia With A Mature Immunophenotype, Mahsa Khanlari, Wei Wang, Parastou Tizro, Mohammad K Eldomery

Faculty, Staff and Student Publications

Not available.

Adams Contribute To Triple Negative Breast Cancer Via Mtorc1 Pathway: Targeting Adam-Mtor Axis Improves Efficacy, Shuying Liu, Huiqin Chen, Mihai Gagea, Lorenzo Federico, Fan Zhang, Javier Gomez, Kim-Anh Do, William F Symmans, Gabriel N Hortobagyi, Gordon B Mills, Ana M Gonzalez-Angulo, Debasish Tripathy

Faculty, Staff and Student Publications

Breast cancer is the most frequently diagnosed cancer globally and the second leading cause of cancer-related deaths in American women. Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Thus, fewer targeting therapies are available for this most aggressive subtype. The A Disintegrin and Metalloproteinase (ADAM) family plays a vital role in cancer pathophysiology. Previous studies focused on single ADAM members. However, none of these have entered into the clinical arena as diagnostics or therapeutics for breast cancer. In this study, we demonstrate the upregulation of a panel of ADAM members in TNBC, …

Modulating Treatment Outcomes Of Patients With Solid Tumors In Immunotherapy Trials: A Drug Interaction Analysis From A Phase 1 Unit, Camila Braganca Xavier, Clark R Andersen, Joann Lim, Julian H Slade, Stacie A Bean, Lei Kang, Hung Le, Apostolia M Tsimberidou, Aung Naing, David S Hong, Ecaterina E Dumbrava, Jordi Rodon Ahnert, Paula R Pohlmann, Sarina A Piha-Paul, Stephane Champiat, Timothy A Yap, Tin-Yun Tang, Funda Meric-Bernstam, Siqing Fu

Faculty, Staff and Student Publications

Concurrent use of medications can modulate the effectiveness of immunotherapy. Although this interaction is well documented for immune checkpoint inhibitors, whether this occurs with new experimental compounds has not been evaluated. A computerized data extraction tool was used to collect clinical data and identify the prescription of a predefined set of medications within 30 days of immunotherapy infusion in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center. The primary endpoints were median overall survival (OS) and progression-free survival. Tumor responses were addressed using RECIST. We identified 897 patients. The most prevalent tumor types …

Suppression Of Cardiac Allograft Vasculopathy By A Macrophage Efferocytosis Receptor, Sahil Shah, Aparnaa Ananthakrishnan, Matthew Deberge, Kristofor Glinton, Rebecca T L Jones, Mallory Filipp, Ivana Shen, Joey Lockhart, Connor W Lantz, Edward B Thorp

Faculty, Staff and Student Publications

Cardiac allograft vasculopathy remains a major cause of late morbidity following heart transplantation. While accumulating evidence implicates innate macrophages in the inflammatory progression of CAV, the underlying mechanisms remain incompletely understood. In murine models of CAV, we identified proteolytic cleavage of MERTK, a key anti-inflammatory receptor on macrophages, as a contributing factor to CAV progression. In a model of CAV, MERTK deficiency accelerated allograft rejection and increased intimal leukocyte infiltration. In contrast, mice expressing a genetically cleavage-resistant form of MERTK (MertkCR/CR) exhibited prolonged graft survival, reduced intimal thickening, diminished immune cell infiltration, and decreased circulating effector T cells. …

The Role Of Recruited Adipose Stromal Cells And Their Fibroblastic Differentiation In Cancer, Lingyi Cai, Mikhail G Kolonin, Dimitris Anastassiou

Faculty, Staff and Student Publications

Adipose stromal cells (ASCs) are perivascular mesenchymal progenitors of adipose tissue. In cancer patients, ASCs can mobilize and migrate to the tumor, where they subsequently play an important role in cancer progression. This biological process involves the conversion of recruited ASCs into cancer-associated fibroblasts (CAFs). ASC-derived CAFs influence the tumor microenvironment through extracellular matrix remodeling, vascularization, and immunomodulation. These and other processes mediated by secreted paracrine factors also affect gene expression in carcinoma cells to promote the epithelial-mesenchymal transition (EMT), metabolic adaptation, survival, and invasiveness of cancer cells. ASC-derived CAFs can enhance tumor aggressiveness, accounting in part for the link …

Reproducibility Of Statistically Significant Phase Iii Oncology Trials: An In Silico Meta-Epidemiological Analysis, Alexander D Sherry, Pavlos Msaouel, Avital M Miller, Timothy A Lin, Joseph Abi Jaoude, Ramez Kouzy, Adina H Passy, Tomer Meirson, Nikolaos Ignatiadis, Zachary R Mccaw, Erik Van Zwet, Ethan B Ludmir

Faculty, Staff and Student Publications

Purpose: The conventional assumption that P values ≤ 0.05 imply reproducible effects has come under recent criticism. This concern is particularly relevant in oncology, as phase III oncology trials, which directly inform practice, are usually not repeated. Using advanced modeling techniques, we investigated the relationship between P values and reproducibility in oncology.

Methods: We obtained the signal-to-noise ratio distribution in phase III oncology using outcomes from 632 two-arm superiority trials enrolling 496,219 patients. With this distribution, we estimated successful replication probability as the probability that a replicate trial, having the same design, effect size, and standard error, would have a …

Blood And Neuronal Extracellular Vesicle Mitochondrial Disruptions In Schizophrenia, A Ankeeta, Ashutosh Tripathi, Bindu Pillai, Yizhou Ma, Joshua J Chiappelli, Jessica N Jernberg, Keiko Kunitoki, Xiaoming Du, Si Gao, Bhim M Adhikari, Consuelo Walss-Bass, Giselli Scaini, Peter Kochunov, Anilkumar Pillai, L Elliot Hong

Faculty, Staff and Student Publications

The high energy demand of the human brain obligates robust mitochondrial energy metabolism, while mitochondrial dysfunctions have been linked to neuropsychiatric disorders, including schizophrenia spectrum disorders (SSD). However, in vivo assessments that can directly inform brain mitochondrial functioning and its etiopathophysiological path to SSD remain difficult to obtain. We hypothesized that system and brain mitochondrial dysfunctions in SSD may be indexed by elevated cell-free mitochondrial DNA (cf-mtDNA) levels in the blood and in neuronal extracellular vesicles (nEVs). We also explored if these mtDNA marker elevations were associated with brain metabolites as measured by magnetic resonance spectroscopy (MRS). We examined blood …

Predicting Regional Cerebral Blood Flow Using Voxel-Wise Resting-State Functional Mri, Hongjie Ke, Bhim M Adhikari, Yezhi Pan, David B Keator, Daniel Amen, Si Gao, Yizhou Ma, Paul M Thompson, Neda Jahanshad, Jessica A Turner, Theo G M Van Erp, Mohammed R Milad, Jair C Soares, Vince D Calhoun, Juergen Dukart, L Elliot Hong, Tianzhou Ma, Peter Kochunov

Faculty, Staff and Student Publications

Background: Regional cerebral blood flow (rCBF) is a putative biomarker for neuropsychiatric disorders, including major depressive disorder (MDD).

Methods: Here, we show that rCBF can be predicted from resting-state functional MRI (rsfMRI) at the voxel level while correcting for partial volume averaging (PVA) artifacts. Cortical patterns of MDD-related CBF differences decoded from rsfMRI using a PVA-corrected approach showed excellent agreement with CBF measured using single-photon emission computed tomography (SPECT) and arterial spin labeling (ASL). A support vector machine algorithm was trained to decode cortical voxel-wise CBF from temporal and power-spectral features of voxel-level rsfMRI time series while accounting for PVA. …

Caf-Macrophage Crosstalk Fuels Immunotherapy Resistance, Yang Liu, Linghua Wang

Faculty, Staff and Student Publications

No abstract provided.

Safety Of Contemporary Radiation Therapy In Patients With Cardiac Implantable Electronic Devices: Implications For Clinical Practice, Kaveh Karimzad, Shalin Shah, Stephen F Kry, Christopher Peeler, Julianne Pollard-Larkin, Amit Koduri, Martin Chacon Portillo, Siddharth Chauhan, Atia Amatullah, Chase Miller, Amanda Strang, Juhee Song, Khatera Mir Zaman Shah, Donelo Lopez, Darla Wagner, January Tsai, Shital Vachhani, Dilip Thakar, Cezar Iliescu, Jean-Bernard Durand, Anne H Dougherty, Bharat Kantharia, Anita Deswal

Faculty, Staff and Student Publications

Background: Radiation therapy (RT) can cause cardiac implantable electronic device (CIED) malfunction, primarily reset. Given changes in RT and CIED technologies, large observational studies examining malfunction of contemporary CIEDs during modern-day RT are needed to guide clinical practice.

Methods: Electronic medical records of all consecutive patients with CIEDs who underwent RT at a large tertiary cancer center between January 2015 and January 2022 were reviewed. All patients had CIED interrogation before and after completion of RT. Device-related data and RT-specific variables were collected. Statistical analyses were performed at the RT course level.

Results: Over a period of 7 years, 677 …

A Multimodal Approach To Assess A Liposomal Carrier’S Biodistribution, Stability, And Clearance, Cayla A Wood, Claire E Jones, Ananthakrishnan Soundaram Jeevarathinam, Riley Watson, Sangheon Han, Jennifer Meyer, Konstantin V Sokolov, Richard R Bouchard

Faculty, Staff and Student Publications

Liposomal carriers, used for site-specific drug delivery, are being investigated for diagnostic approaches by replacing the therapeutic with an imaging contrast agent, exploring potential for selective treatment planning. There remains a critical need to improve in vivo assessment of biodistribution, stability, and clearance kinetics of liposomal carriers. This pilot study presents a multimodal approach in which liposome-encapsulated J-aggregated indocyanine green (ICG) dye (Lipo-JICG) is imaged with high spatial resolution using both in vivo photoacoustic (PA) imaging, to assess the absorbance characteristics of JICG and monomeric ICG, and ex vivo cryofluorescence tomography (CFT), to measure ICG fluorescence. An in vitro assay …

Prefrontal Cortex Astrocytes Modulate Distinct Neuronal Populations To Control Anxiety-Like Behavior, Eunyoung Kim, Hairuo Du, Yanqi Tan, Brandon L Brown, Yaowen Chang, Blanca Díaz-Castro, Jonathan V Sweedler, Xinzhu Yu

Faculty, Staff and Student Publications

Accumulating evidence has supported diverse regulatory functions of astrocytes in different neural circuits as well as various aspects of complex behaviors. However, little is known about how astrocytes regulate different neuronal subpopulations that are linked to specific behavioral aspects within a single brain region. Here, we show that astrocytes in the medial prefrontal cortex (mPFC) encode anxiogenic environmental cues in freely behaving mice. Silencing mPFC astrocyte Ca

Phase 1/2 Trial Of Encorafenib, Cetuximab, And Nivolumab In Microsatellite Stable Brafv600e Metastatic Colorectal Cancer, Van K Morris, Christine M Parseghian, Vahid Bahrambeigi, Nourhan Abdelfattah, Lianchun Xiao, Anjali Agrawal, Kangyu Lin, Kanwal P S Raghav, Robert A Wolff, Arvind Dasari, Ryan W Huey, Bryan K Kee, Michael J Overman, Jason A Willis, Phat H Le, Michelle Escano, Yunyu C Baig, Kelsey Pan, David Menter, Alda L Tam, Wai C Foo, Li Shen, Hey Min Lee, Thomas D Gallup, Cori Margain, Dave Gallup, Kimal I Rajapakshe, Paola A Guerrero, Jing Wang, Ryan B Corcoran, Anirban Maitra, Kyuson Yun, Scott Kopetz

Faculty, Staff and Student Publications

The BRAF inhibitor encorafenib and anti-epidermal growth factor receptor (EGFR) antibody cetuximab modestly improve survival for patients with microsatellite stable (MSS) BRAFV600E metastatic colorectal cancer (mCRC), characterized by higher immune activation than MSS BRAFwild-type colorectal cancer (CRC). In this phase 1/2 study (NCT04017650) of 26 participants with MSS BRAFV600E mCRC who received encorafenib, cetuximab, and anti-PD-1 antibody nivolumab, we report an overall response rate of 50% (95% confidence interval [CI] 29–71) and median progression-free survival of 7.4 months (95% CI, 5.6–9.6). Transcriptomic profiling of pretreatment biopsies and extracellular vesicle RNA (evRNA) isolated from plasma show …

Circzfr/Ythdf3 Axis Drives Lymph Node Metastasis In Cervical Cancer Via Fasn Translation, Mingyi Zhou, Yan Gao, Yong Zhang, Lian He, Bo Gao, Yue Zhang, Francois X Claret, George A Calin, Danbo Wang

Faculty, Staff and Student Publications

Background: Lymph node metastasis is a key driver of poor outcomes in cervical cancer. However, the molecular mechanisms of circular RNAs (circRNAs) driving cervical cancer lymph node metastasis remain unclear.

Methods: We identified circZFR, fatty acid synthase (FASN) and YTH N6-methyladenosine RNA binding protein F3 (YTHDF3) protein expression in the cervical cancer patients with long and short disease-free survival (DFS). Functional experiments were performed to investigate the function of circZFR, FASN and YTHDF3 on cell migration and invasion. MeRIP-qPCR, RNA pulldown, RNA Immunoprecipitation (RIP), and Co-Immunoprecipitation (Co-IP) assays were executed to investigate the mechanism of circZFR regulating FASN protein expression. …

Human Interpretable Grammar Encodes Multicellular Systems Biology Models To Democratize Virtual Cell Laboratories, Jeanette A I Johnson, Daniel R Bergman, Heber L Rocha, David L Zhou, Eric Cramer, Ian C Mclean, Yoseph W Dance, Max Booth, Zachary Nicholas, Tamara Lopez-Vidal, Atul Deshpande, Randy Heiland, Elmar Bucher, Fatemeh Shojaeian, Matthew Dunworth, André Forjaz, Michael Getz, Inês Godet, Furkan Kurtoglu, Melissa Lyman, John Metzcar, Jacob T Mitchell, Andrew Raddatz, Jacobo Solorzano, Aneequa Sundus, Yafei Wang, David G Denardo, Andrew J Ewald, Daniele M Gilkes, Luciane T Kagohara, Ashley L Kiemen, Elizabeth D Thompson, Denis Wirtz, Laura D Wood, Pei-Hsun Wu, Neeha Zaidi, Lei Zheng, Jacquelyn W Zimmerman, Jude M Phillip, Elizabeth M Jaffee, Joe W Gray, Lisa M Coussens, Young Hwan Chang, Laura M Heiser, Genevieve L Stein-O'Brien, Elana J Fertig, Paul Macklin

Faculty, Staff and Student Publications

Cells interact as dynamically evolving ecosystems. While recent single-cell and spatial multi-omics technologies quantify individual cell characteristics, predicting their evolution requires mathematical modeling. We propose a conceptual framework-a cell behavior hypothesis grammar-that uses natural language statements (cell rules) to create mathematical models. This enables systematic integration of biological knowledge and multi-omics data to generate in silico models, enabling virtual "thought experiments" that test and expand our understanding of multicellular systems and generate new testable hypotheses. This paper motivates and describes the grammar, offers a reference implementation, and demonstrates its use in developing both de novo mechanistic models and those informed …

Deep Phenotyping Of Obesity: Electronic Health Record-Based Temporal Modeling Study, Xiaoyang Ruan, Shuyu Lu, Liwei Wang, Andrew Wen, Sameer Murali, Hongfang Liu

Faculty, Staff and Student Publications

Background: Obesity affects approximately 40% of adults and 15%-20% of children and adolescents in the United States, and poses significant economic and psychosocial burdens. Currently, patient responses to any single antiobesity medication (AOM) vary significantly, making obesity deep phenotyping and associated precision medicine important targets of investigation.

Objective: This study aimed to evaluate the potential of electronic health records (EHR) as a primary data source for obesity deep phenotyping. We conducted an in-depth analysis of the data elements and quality available from obesity patients prior to pharmacotherapy and applied a multimodal longitudinal deep autoencoder to investigate the feasibility, data requirements, …