Medicine and Health Sciences Commons^™

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, …

Targeted Proteomic Analysis Identifies Acvrl1 As A Marker Of Cerebral Edema In Aneurysmal Subarachnoid Hemorrhage, Bosco Seong Kyu Yang, Lena O'Keefe, Sarah Hinds, Hua Chen, Athziry Paz, Jude Savarraj, Han-Gil Jeong, Moon-Ku Han, Aaron Gusdon, Xuefang Sophie Ren, Spiros Blackburn, Huimahn Alex Choi

Faculty, Staff and Student Publications

Cerebral edema (CE) is a major component of early brain injury from aneurysmal subarachnoid hemorrhage (SAH). Despite the utility of blood-based protein markers, biomarkers targeting cerebral edema have yet to be developed. We performed a targeted proteomic search analyzing 141 proteins in plasma samples taken from 80 adult patients within 48 hours after aneurysmal rupture to identify plasma biomarkers of cerebral edema. The protein expression profiles were analyzed for associations with a higher level of the subarachnoid hemorrhage early brain edema score measured in admission computed tomography scans. Five differentially expressed proteins-brorin, ectodysplasin A2 receptor, layilin, scavenger receptor class A …

Clinical Validity Of Foundationone Liquid Cdx For Detection Of Braf V600e In Colorectal Cancer, Rona Yaeger, Jean-François Martini, Lincoln Pasquina, Brian Tunquist, Xiaosong Zhang, Fatima Khaiser, Norberto Panoja Galicia, Shibing Deng, Siliang Gong, Cui Guo, Jimmy Kiely, Ta-Chou Vincent Ng, Graham Ferrier, Josep Tabernero, Scott Kopetz

Faculty, Staff and Student Publications

Background: The BRAF inhibitor encorafenib plus the anti-EGFR antibody cetuximab improved overall survival, objective response rate, and progression-free survival in previously treated BRAF V600E-mutant metastatic colorectal cancer in BEACON, a phase 3 randomized trial, leading to regulatory approval for this indication. To support rapid, plasma-based testing for BRAF V600E identification, clinical validity of a circulating tumor DNA (ctDNA)-based assay, FoundationOne®Liquid CDx (F1LCDx) was assessed, versus the reference tumor-based clinical trial assay (CTA) in liquid biopsy-evaluable samples from BEACON and commercially-obtained tissue-matched plasma samples.

Methods: Pre-treatment tissue samples were collected in BEACON to confirm BRAF mutational status using the central single …

First-Line Pd-1 +/- Ctla-4 Blockade In Patients With Deficient Mismatch Repair And/Or Microsatellite Instability-High Metastatic Colorectal Cancer, Vincenzo Nasca, Gabriele Tinè, Julien Taieb, Sara Lonardi, Ben Boursi, Ofer Margalit, Lisa Salvatore, Romain Cohen, Javier Ros, Margherita Ambrosini, Koen Zwart, Jeanine Roodhart, Priya Jayachandran, Michael J Overman, Maria Elena Elez, Chiara Cremolini, David Tougeron, Miriam Koopman, Thierry André, Rosalba Miceli, Filippo Pietrantonio

Faculty, Staff and Student Publications

Background: Patients with deficient mismatch repair (dMMR) and/or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) show marked sensitivity to immune checkpoint inhibitors (ICIs). Dual PD-1/CTLA-4 blockade with nivolumab and ipilimumab showed superior progression-free survival (PFS) over chemotherapy and anti-PD-1 monotherapy, but data on treatment-naïve patients is not available yet.

Methods: This international multicenter study included patients with dMMR/MSI-H mCRC receiving either chemotherapy with or without biologics, or anti-PD-1 monotherapy, or dual PD-1/CTLA-4 blockade as a first-line treatment. Data were adjusted using inverse probability of treatment weighting (IPTW) to account for baseline imbalances. IPTW-adjusted survival and subgroup analyses were conducted.

Results: …

Genomic Editing Of A Pathogenic Sequence Variant In Acta2 Rescues Multisystemic Smooth Muscle Dysfunction Syndrome In Mice, Qianqian Ding, Peiheng Gan, Zhisheng Xu, Hui Li, Lei Guo, Camryn Macdonald, Wei Tan, Efrain Sanchez-Ortiz, John R Mcanally, Yu Zhang, Dileep Karri, Lin Xu, Ning Liu, Eric N Olson

Faculty, Staff and Student Publications

Background: Vascular smooth muscle cells (SMCs), the predominant cell type in the aortic wall, play a crucial role in maintaining aortic integrity, blood pressure, and cardiovascular function. Vascular SMC contractility and function depend on ACTA2 (smooth muscle α-actin 2). The pathogenic variant ACTA2 c.536G>A (p.R179H) causes multisystemic smooth muscle dysfunction syndrome, a severe disorder marked by widespread smooth muscle abnormalities, resulting in life-threatening aortic disease and high risk of early death from aneurysms or stroke. No effective treatments exist for multisystemic smooth muscle dysfunction syndrome.

Methods: To develop a comprehensive therapy for multisystemic smooth muscle dysfunction syndrome, we used …

Lipid-Laden Microglia: Characterization And Roles In Diseases, Jiani Xing, Takese Mckenzie, Jian Hu

Faculty, Staff and Student Publications

Microglia are resident phagocytes of the central nervous system that play an essential role in brain development and homeostasis. When the intracellular lipid content exceeds the metabolic capacity of microglia, lipid droplets accumulate, giving rise to a distinct population termed lipid-laden microglia (LLMs). LLMs have been implicated in various neuroinflammatory and neurodegenerative diseases, functioning as both regulators/indicators of inflammation and potential therapeutic targets. This review summarizes the current research on LLMs, focusing on disease-specific regulators and functions, protective roles, interactions with neighboring cells, and advances in diagnostic and analytical tools. We also discuss the blurred distinction between LLMs and macrophages, …

Therapeutic Targeting Of Syndecan-1 Axis Overcomes Acquired Resistance To Kras-Targeted Therapy In Gastrointestinal Cancers, Madelaine S Theardy, Mitsunobu Takeda, Alexey Sorokin, Shuaitong Chen, Zecheng Yang, Xiaofei Wang, Preeti Kanikarla, Oluwadara Coker, Phuoc Nguyen, Yongkun Wei, Jun Yao, Liang Yan, Yanqing Jin, Yiming Cai, Masakatsu Paku, Ziheng Chen, Kara Z Li, Francesca Citron, Hideo Tomihara, Sisi Gao, Angela K Deem, Jun Zhao, Huamin Wang, Samir Hanash, Ronald A Depinho, Anirban Maitra, Giulio F Draetta, Haoqiang Ying, Scott Kopetz, Wantong Yao

Faculty, Staff and Student Publications

The therapeutic benefit of recently developed mutant KRAS (KRAS∗) inhibitors remains limited by the rapid onset of resistance. Here, we aim to delineate mechanisms underlying acquired resistance and identify actionable targets for overcoming this clinical challenge. Previously, we identified syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by KRAS∗. By leveraging both pancreatic and colorectal cancer models, we show that surface SDC1 expression initially diminishes upon KRAS∗ inhibition but recovers in tumor cells that bypass KRAS∗ dependency. Mechanistically, we reveal that YAP1 activation drives the recovery of SDC1 surface localization to enhance macropinocytosis-mediated …

Optimizing Motion Management And Baseline Shifts In Magnetic Resonance-Guided Spine Stereotactic Body Radiation Therapy, Yao Ding, Travis C Salzillo, Debra N Yeboa, Martin C Tom, Zhiheng Wang, Parmeswaran Diagaradjane, Ergys Subashi, Jinzhong Yang, Todd Swanson, Thomas Beckham, Chenyang Wang, Amol J Ghia, Tina Briere, Jihong Wang, Fabienne Lathuilière, Sneha Cloake, Eun Young Han

Faculty, Staff and Student Publications

BACKGROUND: Stereotactic body radiation therapy (SBRT) has proven effective in controlling spinal lesions with minimal toxicity, primarily due to its ability to limit spinal cord dose. Recent advances in MR-linac (MRL) technology offer superior spinal cord visualization and real-time gating, which can facilitate dose escalation in spinal tumor treatment while maintaining safety.

PURPOSE: This study aimed to optimize motion management for spine SBRT on an MRL by analyzing patient-specific motion dynamics and evaluating the most effective registration structures. We hypothesized that baseline shifts (BLS) would improve delivery efficiency while maintaining spinal cord dose constraints. The goal was to establish displacement …

A Brief History Of Circadian Time In The Heart, Martin E Young, Vanya Khanna, Mallory Metcalfe, Niruththaan Rameshkumar, Sarah Harington, Leo H Li, Janan Shoja Doost, Heinrich Taegtmeyer, Tami A Martino

Faculty, Staff and Student Publications

This review tracks the discovery of circadian biology in cardiovascular science, starting with early clinical observations of daily changes in heart rate, blood pressure, and cardiovascular events. These patterns suggested that time of day matters, but it was not until the past two decades that the mechanisms and knowledge translation of these rhythms were uncovered. We describe the heart's intrinsic circadian properties and importantly how this leads to regulation of cardiac gene and protein expression, neuroendocrine and vascular rhythms, metabolism, cellular electrophysiology, and cell signaling pathways. Next, we explore emerging themes, including the impact of circadian timing on ischemic injury, …

Causes Of Symptoms And Symptom Persistence In Long Covid And Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Anthony L Komaroff, Robert Dantzer

Faculty, Staff and Student Publications

Debilitating symptoms for many years can follow acute COVID-19 ("long COVID"), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and various post-acute infection syndromes (PAISs). Together, long COVID and ME/CFS affect 60-400 million individuals, globally. Many similar underlying biological abnormalities have been identified in both conditions including autoantibodies against neural targets, endothelial dysfunction, acquired mitochondrial dysfunction, and a pro-inflammatory gut microbiome. Each of these abnormalities may directly cause some of the symptoms. In addition, the symptoms also may be caused by ancient, evolutionarily conserved symptomatic and metabolic responses to vital threats-sickness behavior and torpor-responses mediated by specific, recently discovered neural circuits. These neural …

Trpc4 Regulates Limbic Behavior And Neuronal Development By Stabilizing Dendrite Branches Through Actomyosin-Driven Integrin Activation, Jaepyo Jeon, Travis I Moore, Insuk So, Marc Freichel, Veit Flockerzi, Lutz Birnbaumer, Michael X Zhu

Faculty, Staff and Student Publications

Transient Receptor Potential Canonical 4 (TRPC4) channels have been implicated in multiple neurological functions, including anxiety and sociability. TRPC4 variants were also found in patients with autism. However, the contributions of TRPC4 to neurodevelopment remain undefined. Here, we show that neurobehavioral deficits appear early in young TRPC4 knockout (Trpc4^−/−) mice immediately after weaning, manifesting as alterations in multiple, limbic-related behaviors, such as nesting, marble burying, burrowing, self-grooming, and social interactions. Hippocampal neurons of Trpc4−/− mice exhibit reduced dendritic arborization both in vivo and in vitro. Mechanistically, we found that TRPC4 expression in dendrites surged at the …

Simulated Emergency Room Sign-Outs: What They Tell Us About Diagnostic Accuracy And Opportunities For Improvement, Roni Matin, Brent R King, Amit M Mehta, Susan H Fenton, Nathan R Hoot, David J Robinson, Charles L Maddow, Amy Franklin

Faculty, Staff and Student Publications

Objective: Emergency department (ED) sign-outs provide continuity of care for patients at shift changes. However, these periods have been associated with communication breakdowns and medical errors. We explored information factors (stage-of-the-case and the explicitness of the sign-out narrative) to determine their impact on clinicians' diagnostic accuracy and confidence.

Methods: Clinicians from 2 academic ED sites reviewed patient vignettes sign-out narratives (N=69). Using a within-subjects experiment, the explicitness of the sign-out information (i.e., broad statement about labs versus stating each test) and the patient's stage in the diagnostic process (e.g., labs pending, treatment occurring, etc.) at the time of sign-out varied. …

Newly Diagnosed Acute Myeloid Leukemia In Unfit Patients: 2026 Treatment Algorithms, Naseema Gangat, Courtney D Dinardo

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Management paradigms for newly-diagnosed acute myeloid leukemia (ND-AML) in patients considered unfit to receive intensive chemotherapy have evolved with improved understanding of disease biology. In this setting, management requires clear delineation of goals of therapy that should include preservation of quality-of-life (QoL). Combination of venetoclax (Ven) and a hypomethylating agent (HMA) is the current standard-of-care in most circumstances with flexible options in regard to drug dose and duration of treatment as well as the addition (triplet combinations) or alternative use of targeted therapies, such as inhibitors of FLT3, IDH1, IDH2, or menin for patients with NPM1MUT …