Digital Commons Network^™

Community And Academic Synergy For Cancer Survivorship Care Delivery Enhancement (Project Cascade): A Study Protocol For A Pragmatic, Stepped-Wedge, Cluster-Randomized Trial In Texas Primary Care Community Health Centers, Mary-Louise E Millett, Lauren Q Malthaner, Katharine Mccallister, Derek W Craig, Rebecca Eary, Melissa A Valerio-Shewmaker, L Aubree Shay, Suja S Rajan, Hilary Y Ma, Samiran Ghosh, Benjamin F Crabtree, Simon J Craddock Lee, Bijal A Balasubramanian

Faculty, Staff and Student Publications

Background: In the United States, over 18 million individuals are living with cancer. The majority of these cancer survivors also manage other chronic conditions and receive care from multiple specialists, including oncology, cardiology, and primary care clinicians. However, it remains unclear who holds primarily responsibility for coordinating their care across specialties. Because of its generalist nature, primary care is uniquely suited to deliver whole-person and coordinated care for all conditions for cancer survivors. However, primary care teams experience many challenges delivering high-quality survivorship care. While integrating care for all conditions including cancer is a core principle of high-quality primary care, …

Detection Of The Linac Jaw Face Angle Misalignment Using High Energy Electron Beam Symmetry, Song Gao, Andres Cibrian, Jared Ohrt, Peter Balter

Faculty, Staff and Student Publications

Purpose: To demonstrate the usage of a high energy electron beam symmetry measured at different collimator angles to detect jaws face angle misalignments on Varian TrueBeam linear accelerators (linac) during acceptance and commissioning processes.

Methods: During the linac acceptance, all beams were steered to a symmetric shape with the gantry and collimator at 0°. We noted that the symmetries of higher energies electrons (e.g., 16 MeV, 20 MeV) changed over 2% when measured with the collimator at 90° and/or 270° for two linacs commissioned within 5-months of each other. Misaligned applicators were ruled out as the cause of this issue. …

Anti-Saccade Error Rates Are Associated With Somatic Depressive Symptoms In Cocaine Use Disorder, Constanza De Dios, Heather E Webber, Margaret C Wardle, Jin H Yoon, Michelle A Patriquin, Jessica N Vincent, Joy M Schmitz, Scott D Lane

Faculty, Staff and Student Publications

Background: Inhibitory control deficits are associated with cocaine use disorder (CUD) development and maintenance. Additionally, drug use and inhibitory control can be negatively affected by depressive symptoms, including somatic factors like sleep disturbance and fatigue.

Aim: The current study assessed the relationship between inhibitory control and depressive symptoms among individuals initiating CUD treatment. We examined associations among anti-saccade response inhibition performance, total scores on the Beck Depression Inventory-II (BDI-II), and individual BDI-II items.

Methods: N = 101 patients enrolled in a clinical trial for CUD completed drug-specific anti-saccade and depression (BDI-II) measures prior to treatment. Generalized linear models tested the …

Cd177+ Neutrophils: New Drivers Of Liver Regeneration, Yankai Wen, Cynthia Ju

Faculty, Staff and Student Publications

No abstract provided.

Perspectives On The Future Of The Profession Of Microbiology, Todd L Kelson, Heidi B Kaplan, Michelle Dziejman, Shilpa Gadwal, Irene Hulede, Jennifer Bennett, Roger Greenwell, Shelley Payne, Kyle Maclea, Eric Miller, Diana L Vullo, Rebecca Sparks-Thissen, Astral Bertolio, Jorge Cervantes

Faculty, Staff and Student Publications

The Profession of Microbiology (POM) embodies the bulk of the American Society for Microbiology (ASM) members and represents the career preparation arm of the ASM for academia, industry, and clinical lab professions. The ASM Council on Microbial Sciences hosted a virtual retreat in 2025 to identify the future of the POM. The retreat presentations centered on workforce development, professional development, innovations in technology, and interdisciplinary collaborations. Various aspects were identified, such as the need to prepare for careers in industry, as an important goal of future training. It was also clear that scientists, in all walks of life, need professional …

Investigating Chronic Toxicity, Diet, Patient-Reported Outcomes And The Microbiome In Immunotherapy-Treated Metastatic Melanoma Survivors: A New Frontier, Margaux Robert, Satabdi Saha, Nazli Dizman, Michelle Rohlfs, Elizabeth Sirmans, Julie Simon, Rodabe N Amaria, Isabella C Glitza Oliva, Hussein A Tawbi, Michael A Davies, Alexandra Ikeguchi, Karen Basen-Engquist, Keri Schadler, Michael E Roth, Wenye Song, Xiaotao Zhang, Nadim J Ajami, Lorenzo Cohen, Jennifer A Wargo, Christine B Peterson, Jennifer L Mcquade, Carrie R Daniel

Faculty, Staff and Student Publications

Background/Objectives: Immune checkpoint blockade (ICB) therapies have significantly improved outcomes in metastatic melanoma. However, immune-related adverse events (irAEs) and persistent chronic toxicities (CTs) among this emerging survivor population likely influence different facets of quality of life. This study characterized CT, patient-reported outcomes (PROs), diet, physical activity and gut microbiome features in a cohort of long-term survivors with a history of ICB-treated metastatic melanoma.

Methods: Forty-eight patients with a history of metastatic melanoma who initiated ICB treatment at least 3 years earlier and were not currently on treatment were prospectively enrolled from a melanoma survivorship clinic. Participants completed screening …

Society For Immunotherapy Of Cancer: Standards For Reporting Of Multiplex Immunohistochemistry/Immunofluorescence Assays (Stormi), Sam Sater, Carlo B Bifulco, Jaime Rodriguez-Canales, Joe Yeong, Guray Akturk, Michael Angelo, Carmen Ballesteros-Merino, Peter Bankhead, Subham Basu, Jorge M Blando, Saska Brajkovic, Marco Cassano, Benjamin J Chen, Ahmet F Coskun, Tricia R Cottrell, Carlos E De Andrea, Robin H Edwards, Colt Egelston, Logan L Engle, Marc S Ernstoff, Rong Fan, Michael Feldman, Bernard A Fox, Jerome Galon, Robyn Gartrell, Sacha Gnjatic, Benjamin F Green, James L Gulley, Anne Hellebust, Stephen Hewitt, Travis J Hollmann, Lucas A Horn, William J Howat, Clifford C Hoyt, Shawn M Jensen, Arutha Kulasinghe, Wiem Lassoued, Steven Lott, James Mansfield, Sebastian Marwitz, George Netto, David B Page, Edwin Parra, David L Rimm, Scott J Rodig, Roberto Salgado, Denis Schapiro, Kurt A Schalper, Joel C Sunshine, Michael J Surace, Alexander S Szalay, Magdalena Thurin, Jose C Villasboas, Keith Wharton, Ignacio I Wistuba, Jennifer H Yearley, Yinyin Yuan, Geroge Zaki, James Ziai, Janis M Taube

Faculty, Staff and Student Publications

Multiplex immunofluorescence and immunohistochemistry (mIF/IHC) are increasingly employed antibody-based technologies that use tissue sparingly and facilitate the detection of co-localized or neighboring biomarkers. Specifically, these platforms enable spatial analyses of the tumor microenvironment as well as extended applications, for example, describing normal tissue anatomy, autoimmunity, infectious diseases, etc. mIF/IHC has greatly enhanced biomarker discovery efforts, and a growing number of studies suggest superiority to traditional IHC. Standardization of staining approaches, reporting of image analysis strategies and resultant data is critical for facilitating cross-study comparisons, validation, deployment, and generalization of findings. To address this challenge, The Society for Immunotherapy of Cancer …

Development Of A Procedure For Prion Surveillance In The Laboratory Setting, Damian Gorski, Isaac Schauer, Kane Spicker, Ananya Tupaki-Sreepurna, Fei Wang, Claudio Soto, Sandra Pritzkow

Faculty, Staff and Student Publications

Infectious prions readily adhere to common surfaces, retain infectivity, and are highly resistant to conventional decontamination, posing significant biosafety challenges in the medical and research environments. Recent occupational exposures underscore the urgency of improving safety measures. Here, we describe an approach combining foam-swab surface sampling and protein misfolding cyclic amplification to enhance prion surveillance. Our results demonstrate the ability to detect prions most relevant to human health directly from contaminated surfaces, even at 100 million-fold dilutions of the brain. We applied our method to assess the completeness of prion decontamination and show that high prion quantities can resist even approved …

Evaluating The Accuracy Of Point Of Care Testing Compared To Standard Laboratory Testing Among Inborn Infants In The Neonatal Intensive Care Unit, Isha Parikh, Sepideh Saroukhani, Matthew Rysavy, Brian Chang, Mar Romero-Lopez, Lindsay F Holzapfel

Faculty, Staff and Student Publications

Objective: Point-of-care (POC) testing offers expedited results with lower blood volume requirements than central laboratory (CL) tests, particularly for low-birth-weight infants.

Methods: A retrospective cohort included 118 patients with paired POC and CL tests within one hour in the first 14 postnatal days. Differences and agreement were assessed using linear mixed-effect models that account for within and between-subject variations.

Results: Compared to CL, POC testing underestimated sodium (6.0 mEq/L), potassium (0.1 mEq/L), chloride (5.1 mEq/L), and glucose (2.3 mg/dL), and overestimated hemoglobin (0.08 g/dL) and hematocrit (0.8%). Differences (CL- POC) varied by postnatal age and sample type, with larger differences …

Single-Nucleus Multiomics Reveals The Disrupted Regulatory Programs In Three Brain Regions Of Sporadic Early-Onset Alzheimer’S Disease, Andi Liu, Citu Citu, Nitesh Enduru, Xian Chen, Chia-Hao Tung, Tirthankar Sinha, Sofia E Sepulveda, Astrid M Manuel, Damian Gorski, Brisa S Fernandes, Meifang Yu, Paul E Schulz, Lukas M Simon, Claudio Soto, Zhongming Zhao

Faculty, Staff and Student Publications

Sporadic early-onset Alzheimer’s disease (sEOAD) represents a substantial but less-studied subtype of Alzheimer’s disease (AD). Here, we generated a single-nucleus multiome atlas derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of nine individuals with or without sEOAD. Comprehensive analyses were conducted to delineate cell type–specific transcriptomic changes and linked candidate cis-regulatory elements (cCREs) across brain regions. We prioritized eight conservative transcription factors in glial cells in multiple brain regions, including RFX4 in astrocytes and IKZF1 in microglia, which are implicated in regulating sEOAD-associated genes. Moreover, we identified the top 25 altered intercellular signaling between glial cells …

Omics Approaches To Understand Cardiovascular Disease, Zeeshan Ahmed, Goo Jun

Faculty, Staff and Student Publications

Omics approaches have emerged as indispensable tools in unravelling the intricate molecular landscape of cardiovascular disease (CVD) by providing comprehensive insights into the underlying mechanisms driving CVD pathogenesis, progression, and response to therapy. Integrative omics approaches further enhance our understanding by integrating multi-omics data to explain complex molecular networks and identify novel disease pathways. In this collection of BMC Cardiovascular Disorders, we invited submissions on omics approaches to investigate and understand CVD. Successfully achieving the goals of this collection, we were able to publish some interesting and impactful research articles after a rigorous peer review process.

Transposable Element-Derived Mir-28-5p And Mir-708-5p: Exploring Potential Roles In Lung Cancer, Sergiu Chira, Cornelia Braicu, Stefan Strilciuc, George A Calin, Ioana Berindan-Neagoe

Faculty, Staff and Student Publications

Background: Transposable elements are normally silenced by epigenetic mechanisms; however, during malignant transformation, epigenetic alterations enable transposons to produce functional molecules like miRNAs. Among these, LINE-2 (L2) elements can generate miRNAs capable of regulating key genes, including tumor suppressors. Two L2-derived miRNAs, miR-28 and miR-708, have been linked to lung cancer, yet the mechanisms underlying their dysregulation remain poorly understood. Our study reveals how genomic context contributes to aberrant gene expression through comprehensive bioinformatic analyses.

Methods: Using bioinformatics analysis, we evaluated the expression of miR-28 and miR-708 in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) datasets from TCGA. …

Trametinib Decreased Intracerebral Hemorrhages And Endothelial-To-Mesenchymal Transition In Kras, Ohnmar Myint, Bridger Freeman, Jae Yeong Jeong, Hyejin Park, Samantha M Wilfur, Shuning Huang, Jung-Eun Park, Jakob Körbelin, Jaroslaw Aronowski, Eun S Park, Peng R Chen, Eunhee Kim

Faculty, Staff and Student Publications

Background: Brain arteriovenous malformations (bAVMs) are a major risk factor for intracerebral hemorrhages in young patients. Recent clinical studies have reported that the majority of human bAVMs harbor somatic KRAS mutations. In our previous study, we confirmed the causal role of endothelial KRASG12V mutation in bAVM development in mice through hyperactivation of the MEK/ERK (extracellular signal-regulated kinase) pathway. However, the treatment efficacy of targeting MEK/ERK signaling in bAVMs, regarding clinical and biological outcomes, remains unclear.

Methods: In this study, we used the Food and Drug Administration-approved MEK inhibitor, trametinib, to treat mice with bAVMs induced by brain endothelial cell (EC)-specific …

Clinical Outcomes Of Patients With Unsuccessful Mechanical Thrombectomy Versus Best Medical Management Of Medium Vessel Occlusion Stroke In The Middle Cerebral Artery Territory, Tobias D Faizy, Vivek Yedavalli, Hamza Adel Salim, Dhairya A Lakhani, Basel Musmar, Nimer Adeeb, Muhammed Amir Essibayi, Motaz Daraghma, Kareem El Naamani, Nils Henninger, Sri Hari Sundararajan, Anna Luisa Kuhn, Jane Khalife, Sherief Ghozy, Luca Scarcia, Leonard Ll Yeo, Benjamin Yq Tan, Robert W Regenhardt, Jeremy Josef Heit, Nicole M Cancelliere, Aymeric Rouchaud, Jens Fiehler, Sunil A Sheth, Ajit S Puri, Christian Dyzmann, Marco Colasurdo, Leonardo Renieri, João Pedro Filipe, Pablo Harker, Răzvan Alexandru Radu, Mohamad Abdalkader, Piers Klein, Thomas R Marotta, Julian Spears, Takahiro Ota, Ashkan Mowla, Pascal Jabbour, Arundhati Biswas, Frédéric Clarençon, James E Siegler, Thanh N Nguyen, Ricardo Varela, Amanda Baker, David Altschul, Nestor Gonzalez, Markus A Möhlenbruch, Vincent Costalat, Benjamin Gory, Christian Paul Stracke, Constantin Hecker, Gaultier Marnat, Hamza Shaikh, Christoph J Griessenauer, David S Liebeskind, Alessandro Pedicelli, Andrea Maria Alexandre, Illario Tancredi, Erwah Kalsoum, Max Wintermark, Boris Lubicz, Aman B Patel, Vitor Mendes Pereira, Adam A Dmytriw, Adrien Guenego, Mad-Mt Investigators

Faculty, Staff and Student Publications

Background: Current randomized controlled trials are investigating the efficacy and safety of mechanical thrombectomy (MT) in patients with medium vessel occlusion (MeVO) stroke. Whether best medical management (MM) is more efficient than unsuccessful vessel recanalization during MT remains unknown.

Methods: This was a retrospective cohort study using data from 37 academic centers across North America, Asia, and Europe between September 2017 and July 2021. Only patients with occlusion of the distal branches (M2 and M3) of the middle cerebral artery territory were included. Unsuccessful MT was defined as a modified Thrombolysis in Cerebral Infarction score of 0-2a. Propensity score matching …

Successful Treatment Of Comorbid Sapho Syndrome And Hidradenitis Suppurativa With Upadacitinib, Deepika Narayanan, Tiffaney Tran, Valeria Duque-Clavijo, Hung Q Doan, Stephen K Tyring

Faculty, Staff and Student Publications

No abstract provided.

Targeting Kinesin Family Member 20a Sensitizes Stem-Like Triple-Negative Breast Cancer Cells To Standard Chemotherapy, Yayoi Adachi, Weilong Chen, Cheng Zhang, Tao Wang, Nina Gildor, Rachel Shi, Haoyong Fu, Masashi Takeda, Qian Liang, Fangzhou Zhao, Hongyi Liu, Jun Fang, Jin Zhou, Hongwei Yao, Lianxin Hu, Shina Li, Lei Guo, Lin Xu, Ling Xie, Xian Chen, Chengheng Liao, Qing Zhang

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC), being both aggressive and highly lethal, poses a major clinical challenge in terms of treatment. Its heterogeneity and lack of hormone receptors or HER2 expression further restrict the availability of targeted therapy. Breast cancer stem cells (BCSCs), known to fuel TNBC malignancy, are now being exploited as a vulnerability for TNBC treatment. Here, we dissected the transcriptome of BCSCs and identified kinesin family member 20A (KIF20A) as a key regulator of BCSC survival and TNBC tumorigenesis. Genetic depletion or pharmacological inhibition of KIF20A impairs BCSC viability and tumor initiation and development in vitro and in vivo. …

Concurrent Tb And Hiv Therapies Control Tb Reactivation During Co-Infection But Not Chronic Immune Activation, Riti Sharan, Yi Zou, Bindu Singh, Vinay Shivanna, Edward J Dick, Shannan Hall-Ursone, Xi Luo, Guanlin Guo, Shabaana A Khader, Xavier Alvarez, Jyothi Rengarajan, Zhao Lai, Smriti Mehra, Hulin Wu, Deepak Kaushal

Faculty, Staff and Student Publications

Most HIV-negative individuals exposed to Mycobacterium tuberculosis (Mtb) control infection as latent TB infection (LTBI), but HIV co-infection greatly increases progression to tuberculosis (TB), the leading cause of death in people living with HIV (PLHIV). Although combination antiretroviral therapy (cART) reduces LTBI reactivation, immune control of Mtb is not fully restored, as shown by persistent TB incidence in PLHIV on cART. In macaques, skewed pulmonary effector memory CD4⁺ T-cell (TEM) responses and new TB lesions persist despite cART. We hypothesize that concurrent anti-TB therapy with cART would improve bacterial control and immune restoration compared to cART alone. Using …

Anexelekto (Axl)/Mer Inhibitor Tamnorzatinib In Patients With Relapsed/Refractory Acute Myeloid Leukaemia: Results From A Phase I (Monotherapy) And Phase Ii (Combination With Venetoclax) Clinical Study, Margaret T Kasner, Nigel Courtenay-Luck, Courtney Dinardo, Sean M Post, Praneeth Baratam, George N Magrath, Takaaki Nakamura, Akifumi Fujii, Sergio Prados, Naoki Honda, Mary Mcbride, Paula Edwards-Holmes, Robert Stuart

Faculty, Staff and Student Publications

Introduction: Relapsed/refractory (R/R) acute myeloid leukaemia (AML) is a life-threatening haematological malignancy without effective treatments. Anexelekto (Axl) and Mer receptor tyrosine kinases have emerged as important therapeutic targets in AML for their crucial role in survival of AML cells. Tamnorzatinib (ONO-7475) is a potent and highly selective inhibitor of Axl/Mer. We report first-in-human study of tamnorzatinib (NCT03176277) in patients with R/R AML.

Methods: Tamnorzatinib was administered as monotherapy (n = 20) to determine an appropriate biological dose of tamnorzatinib and then in combination (n = 22) with venetoclax to evaluate safety and clinical efficacy.

Results: Tamnorzatinib was safe …

A Review Of Cutaneous Viral Infections And Their Potential Role In Neurologic Diseases, Valeria Duque-Clavijo, Hung Q Doan, Stephen K Tyring

Faculty, Staff and Student Publications

Background: Cutaneous viral infections, defined as viral pathogens that either primarily affect the skin (e.g., herpesviruses, enteroviruses) or frequently produce dermatologic manifestations despite systemic tropism (e.g., HIV, SARS-CoV-2), can trigger systemic inflammatory and neurotropic responses that extend their impact to the nervous system. A growing body of evidence suggests that viruses with dermatologic manifestations may play a significant role in the pathogenesis of neurologic disorders.

Summary: Although individual viruses have been studied in isolation, the skin-brain axis in viral infections remains incompletely characterized. This review synthesizes existing knowledge and highlights gaps in understanding the mechanisms linking cutaneous viral infections to …

First-In-Child Phase I Trial Of P-Stat3 Inhibitor Wp1066 In Pediatric Brain Tumor Patients, Robert C Castellino, Hope L Mumme, Andrea T Franson, Bing Yu, M Hope Robinson, Kavita Dhodapkar, Dolly Aguilera, Matthew J Schniederjan, Rohali Keesari, Zhulin He, Manoj Bhasin, Waldemar Priebe, Amy B Heimberger, Tobey J Macdonald

Faculty, Staff and Student Publications

Background: WP1066 is an orally bioavailable, small molecule inhibitor of activated p-STAT3 that has demonstrated preclinical efficacy in pediatric brain tumor models.

Methods: In a first-in-child, single-center, single-arm 3+3 design Phase I clinical trial, ten patients were treated with WP1066 twice daily, Monday-Wednesday-Friday, for 14 days of each 28-day cycle to determine the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066. Compassionate use treatment with WP1066 in three pediatric patients with H3.3 G34R/V-mutant high-grade glioma (HGG) is also described.

Results: There was no significant toxicity and the MFD was determined to be 8 mg/kg. Treatment-related adverse events were Grade …

Genetic Modifiers And Ascertainment Drive Variable Expressivity Of Complex Disorders, Matthew Jensen, Corrine Smolen, Anastasia Tyryshkina, Lucilla Pizzo, Jiawan Sun, Serena Noss, Deepro Banerjee, Matthew Oetjens, Hermela Shimelis, Cora M Taylor, Vijay Kumar Pounraja, Hyebin Song, Laura Rohan, Emily Huber, Laila El Khattabi, Ingrid Van De Laar, Rafik Tadros, Connie R Bezzina, Marjon Van Slegtenhorst, Janneke Kammeraad, Paolo Prontera, Jean-Hubert Caberg, Harry Fraser, Siddharth Banka, Anke Van Dijck, Charles Schwartz, Els Voorhoeve, Patrick Callier, Anne-Laure Mosca-Boidron, Nathalie Marle, Mathilde Lefebvre, Kate Pope, Penny Snell, Amber Boys, Paul J Lockhart, Myla Ashfaq, Elizabeth Mccready, Margaret Nowacyzk, Lucia Castiglia, Ornella Galesi, Emanuela Avola, Teresa Mattina, Marco Fichera, Maria Grazia Bruccheri, Giuseppa Maria Luana Mandarà, Francesca Mari, Flavia Privitera, Ilaria Longo, Aurora Curró, Alessandra Renieri, Boris Keren, Perrine Charles, Silvestre Cuinat, Mathilde Nizon, Olivier Pichon, Claire Bénéteau, Radka Stoeva, Dominique Martin-Coignard, Sophia Blesson, Cedric Le Caignec, Sandra Mercier, Marie Vincent, Christa L Martin, Katrin Mannik, Alexandre Reymond, Laurence Faivre, Erik Sistermans, R Frank Kooy, David J Amor, Corrado Romano, Joris Andrieux, Santhosh Girirajan

Faculty, Staff and Student Publications

Variable expressivity of disease-associated variants implies a role for secondary variants that modify clinical features. We assessed the effects of modifier variants on the clinical outcomes of 2,455 individuals with primary variants. Among 124 families with the 16p12.1 deletion, distinct rare and common variant classes conferred risks for specific developmental features, including short tandem repeats for neurological defects. Network analysis suggested distinct mechanisms involving 16p12.1 genes and secondary variants specific to each proband. Within disease and population cohorts of 976 individuals with the 16p12.1 deletion, we found opposing effects of secondary variants on clinical features across ascertainments. Additional analysis of …

Exploring Mediated Psychosocial Effects On Dating Violence Perpetration And Victimization In The Me & You Building Healthy Relationships Program For Middle School Students, Mike Henson-Garcia, Elizabeth R Baumler, Christine M Markham, Robert C Addy, Ross Shegog, Belinda Hernandez, Paula Cuccaro, Jeffery Temple, Susan Tortolero Emery, Melissa F Peskin

Faculty, Staff and Student Publications

Teen dating violence (TDV) is a prevalent and injurious public health threat affecting adolescent populations across the globe. In response, a plethora of interventions have been developed and implemented with various effects emerging from evaluation studies of these prevention initiatives. The purpose of this study was to investigate whether attitudes toward sexting, gender-based norms toward violence, and constructive conflict resolution skills mediate the main effects of a TDV intervention. Specifically, this study leverages data from the original efficacy trial of the

Imaging Reactive Oxygen Species With L-012 Reveals Neutrophil Extracellular Trap Formation In Pancreatic Ductal Adenocarcinoma, Angisha Basnet, Kaitlyn M Landreth, Michael Sestito, Kristen Ranson, Seth T Gammon, David Piwnica-Worms, Brian A Boone, Tracy W Liu

Faculty, Staff and Student Publications

Neutrophils, key effector cells of the innate immune system, combat pathogens through mechanisms including the production of reactive oxygen species (ROS) and the release of neutrophil extracellular traps (NETs). While these responses are critical for host defense, prolonged elevation of ROS and dysregulated NETosis mediated by neutrophils have been implicated in autoimmune diseases, chronic inflammation, and cancer. In pancreatic ductal adenocarcinoma (PDAC), a highly aggressive and inflammatory malignancy, an increase in neutrophils infiltrating the tumor microenvironment promotes cancer progression and metastasis through increased ROS production and NET release. Using bioluminescence imaging with the reporter L-012 and NET assays, we assessed …

Bayesian Learning To Reduce Cardiac Risk Of Patients With Locally Advanced Non-Small Cell Lung Cancer Based On Personalized Radiation Therapy Prescription, Ruitao Lin, Mei Chen, Xiaodong Zhang, Tianlin Xu, Ting Xu, Rachel C Maguire, Kelsey L Corrigan, Efstratios Koutroumpakis, Joe Y Chang, Steven H Lin, Aileen B Chen, Quynh-Nhu Nguyen, Saumil J Gandhi, Matthew S Ning, Julianna Bronk, Stephen Chun, Ali Ajdari, Joshua S Niedzielski, Jinzhong Yang, Xinru Chen, Tinsu Pan, Qing H Meng, Anne S Tsao, Anita Deswal, Radhe Mohan, Zhongxing Liao

Faculty, Staff and Student Publications

Purpose: Radiation-induced heart damage is a significant concern in the treatment of non-small cell lung cancer (NSCLC) that can have debilitating or life-threatening consequences. Current strategies focus on minimizing heart exposure, but individual susceptibility varies. Existing evidence also suggests that a uniform "one-size-fits-all" dosimetric constraint for the heart may not be optimal for all patients.

Methods and materials: We developed a prospective study using Bayesian continuous learning and adaptation to develop a framework for personalized adaptive radiation treatment (PART) to reduce cardiovascular adverse events among patients with locally advanced NSCLC. The trial includes a Bayesian personalized risk prediction model to …

Health-Related Quality Of Life In The Era Of Immune Checkpoint Blockade: What Do Patient-Reported Outcomes Reveal?, Alexandra M Dunker, Neha Malik, Kathryn J Krause, Emily Z Keung, Jason B Liu, Elise F Nassif Haddad, Neeta Somaiah, Heather G Lyu, Christina L Roland

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by providing durable survival gains, but understanding their effects on patient health-related quality of life (HRQL) is critical.

Methods: We performed a narrative review of cross-sectional surveys, early-phase trials, and large-scale phase II and III randomized controlled clinical trials assessing FDA-approved ICIs, including programmed cell death protein 1 (PD-1) inhibitors, programmed death ligand 1 (PD-L1) inhibitors, and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors, with emphasis on patient-reported HRQL. Validated HRQL instruments were summarized, and for pivotal trials, the positioning of HRQL outcomes as primary, secondary, or exploratory endpoints was taken …

Fgf13 Regulates Vgsc-Independent Cardiomyocyte Impulse Propagation Via Cx43 Trafficking, Lala Tanmoy Das, Mattia Malvezzi, Aravind R Gade, Maiko Matsui, Margaret Mckay, Eric Q Wei, Matea J Zelich, Keon Mazdisnian, Jared Kushner, Bi-Xing Chen, Isabella Distefano, Daniel Roybal, Lin Yang, Lisa Stoll, James C Lo, Marian Kalocsay, Fadi G Akar, Steven O Marx, Geoffrey S Pitt

Faculty, Staff and Student Publications

Background: FHF (fibroblast growth factor homologous factor) variants associate with arrhythmias. Although FHFs are best characterized as regulators of voltage-gated sodium channel (VGSC) gating, recent studies suggest broader, non-VGSC-related functions, including regulation of Cx43 (connexin 43) gap junctions and hemichannels, mechanisms that have generally been understudied or disregarded.

Methods: We assessed cardiac conduction and cardiomyocyte action potentials in mice with constitutive cardiac-specific Fgf13 ablation (cFgf13KO) while targeting Cx43 gap junctions and hemichannels pharmacologically. We characterized FGF13 regulation of Cx43 abundance and subcellular distribution. With proximity labeling proteomics, we investigated novel candidate mechanisms underlying FGF13 regulation of Cx43. …

Historical Review: More Than Two Decades Understanding The Genetic Architecture Of Hemostasis And Thrombosis, Maria Sabater-Lleal, Florian Thibord, Paul S De Vries, Jennifer Huffman, Alisa S Wolberg, Charles J Lowenstein, Alanna C Morrison, Andrew D Johnson, Nicholas L Smith

Faculty, Staff and Student Publications

From the beginning of the millennium and the development of genome-wide analyses, the technical advances and remarkable increase in research sample sizes have led to an escalating number of discoveries revealing genetic determinants of levels of the main factors regulating hemostasis and thrombosis and demonstrating a clear polygenic complex regulation of most coagulation factors. These discoveries have been useful to understand the biology underlying hemostasis regulation and to understand risk of associated thrombotic disease, such as venous thromboembolism, coronary artery disease, and ischemic stroke. In this historical review, we outline the main discoveries in genetic studies of coagulation factors (fibrinogen …

Hsp90 Buffers Deleterious Genetic Variations In Brca1, Brant Gracia, Xing-Han Zhang, Patricia Montes, Tin Chanh Pham, Min Huang, Junjie Chen, Georgios Ioannis Karras

Faculty, Staff and Student Publications

Protein-folding chaperone heat shock protein 90 (HSP90) buffers genetic variation in diverse organisms, but the clinical significance of HSP90 buffering in human disease remains unclear. Here, we show that HSP90 buffers mutations in the BRCT domain of BRCA1. HSP90-buffered BRCA1 mutations result in protein variants that retain interactions with partner proteins and strongly rely on HSP90 for protein stability and function in cell survival. Moreover, HSP90-buffered BRCA1 variants confer poly (ADP-ribose) polymerase (PARP) inhibitor resistance in cancer cells. Low-level HSP90 inhibition overcomes this resistance, revealing a cryptic and mutant-specific HSP90-contingent synthetic lethality. Furthermore, by stabilizing metastable variants across the entirety …

Can Cta-Based Machine Learning Identify Patients For Whom Successful Endovascular Stroke Therapy Is Insufficient?, Jerome A Jeevarajan, Yingjun Dong, Anjan Ballekere, Sergio Salazar Marioni, Arash Niktabe, Rania Abdelkhaleq, Sunil A Sheth, Luca Giancardo

Faculty, Staff and Student Publications

Background and purpose: Despite advances in endovascular stroke therapy (EST) devices and techniques, many patients are left with substantial disability, even if the final infarct volumes (FIVs) remain small. Here, we evaluate the performance of a machine learning (ML) approach by using pretreatment CTA to identify this cohort of patients that may benefit from additional interventions.

Materials and methods: We identified consecutive subjects with large vessel occlusion (LVO) acute ischemic stroke (AIS) who underwent EST with successful reperfusion in a multicenter prospective registry cohort. We included only subjects with FIV < 30 mL and recorded 90-day outcome (mRS). A deep learning model was pretrained and then fine-tuned to predict 90-day mRS 0-2 by using pretreatment CTA images (DeepsymNet-v3 model pretrained on radiology reports and fine-tuned on detection of unexpected clinical outcomes using brain CTA images [DSN-CTA] model). The primary outcome was the predictive performance of the DSN-CTA model compared with a logistic regression model with clinical variables, measured by the area under the receiver operating characteristic curve (AUROC).

Results: The DSN-CTA model was pretrained on 1542 subjects and …

Epigenome-Wide Association Study Of Nuclear Dna Methylation In Relation To Mitochondrial Heteroplasmy, Meng Lai, Kyeezu Kim, Yinan Zheng, Christina A Castellani, Scott M Ratliff, Mengyao Wang, Xue Liu, Jeffrey Haessler, Tianxiao Huan, Kwadwo Bonsu, Charles Newcomb, Kyler Mckessy, Lawrence F Bielak, Wei Zhao, Roby Joehanes, Jiantao Ma, Xiuqing Guo, Joann E Manson, Megan L Grove, Jan Bressler, Kent D Taylor, Tuuli Lappalainen, Silva Kasela, Thomas W Blackwell, Nicole J Lake, Jessica D Faul, Kendra R Ferrier, Stephen C Ekker, Lifang Hou, Charles Kooperberg, Alexander P Reiner, Kai Zhang, Patricia A Peyser, Myriam Fornage, Eric Boerwinkle, Laura M Raffield, April P Carson, Stephen S Rich, Yongmei Liu, Daniel Levy, Jerome I Rotter, Jennifer A Smith, Dan E Arking, Chunyu Liu

Faculty, Staff and Student Publications

We analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA-nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait …