Digital Commons Network^™

Timing Whistleblowing, Andrew K. Jennings

Faculty Articles

Whistleblower programs (WBPs) expose hidden corporate wrongdoing. They do so by offering retaliation protection and financial bounties to those who bring original information to law enforcement about unseen, and often complex, misconduct. Under a standard account, whistleblowing serves the public interest by increasing the ex post detection of illegal activity and the ex ante risk of its exposure. That standard view—which centers whistleblowing on detecting wrongdoing—is incomplete, however. To present a fuller view, this Article introduces a complementary model that refocuses whistleblowing as preventing wrongdoing. Working together, these models show that a WBP can do more than enable detection at …

Analyzing An Ai Summary Of An Executive Order, Natalie D. Ebolum

Open Educational Resources

This assignment asks students to critically analyze the Executive Order on Incarceration in Private Prisons by producing an independent summary of its intent, purpose, and implementation, along with best-practice recommendations for improving its effectiveness. Students then use the Grammarly AI Summary Tool to generate an alternative summary and compare it with their own analysis. Through structured self-assessment and revision, students evaluate differences in interpretation, identify gaps or insights, and reflect on the strengths and limitations of AI-assisted analysis. The assignment emphasizes critical policy analysis, ethical use of AI tools, and student-centered judgment.

Language, Gender, And Identity In Immigration Contexts: Pragmatic And Sociocultural Markers In Arabic-Speaking Diaspora Communities, Muhammad Alasmari, Abdu Al-Kadi, Rashad Ahmed, Obied Alaqlobi

Research, Publications & Creative Work

The pragmatics of native language use among immigrants is a central linguistic concern under the pressures of transnational migration. On this backdrop, this study investigates the multifunctionality of the Arabic expression Aiy Khadamat (AK), a discourse marker widely used by Yemenis in both homeland and diaspora contexts. Focusing on politeness, conflict management, and sociocultural signaling, the study examines how AK functions as a discourse marker within immigrant interactions. A descriptive-analytical design grounded in qualitative methods was employed, using nine discourse completion scenarios presented to 30 male and 30 female Yemeni Arabic speakers residing permanently in the United States. Findings reveal …

At The Crossroads Of Law And Society: Understanding The World Of Immigration Attorneys., Elvis Ariri

Senior Independent Study Theses

This independent study examines the professional experiences of immigration attorneys working with immigrant clients in the United States. Through qualitative, semi-structured interviews, the research explores how immigration law operates in practice, emphasizing systemic complexity, administrative delay, and discretionary decision-making. Findings reveal that attorneys navigate a fragmented legal framework shaped by shifting policies, inconsistent adjudication, and high emotional stakes. Beyond technical expertise, immigration practice requires emotional resilience, ethical judgment, and strategic adaptability. By centering attorneys’ perspectives, this study highlights immigration law as a lived social system that structures belonging, exclusion, and stability, illuminating the gap between statutory intent and human consequence.

A User-Friendly Graphical User Interface For Paw Touch Classification In Rodent Cylinder Testing, Tyler R Johnson, Katherine D Zerefos, Dawn M Taylor

Faculty, Staff and Student Publications

In unilateral rodent models of disease or injury, deficits are induced in only one side of the body, allowing the difference in right versus left limb usage to serve as a metric of disease/injury severity and recovery with various treatments. Unilateral rat models are commonly used for conditions such as Parkinson’s disease (via the neurotoxin 6-hydroxydopamine, 6-OHDA), stroke, and traumatic brain injury, as well as cervical spinal cord injury and peripheral nerve damage. The ‘cylinder test’ has been used for over two decades as a reliable metric of asymmetry in forelimb usage. In this test, videos are taken of the …

Intra-Coronary Imaging And Transcriptomics Of Calcified Nodules Before And After Intensive Lipid-Lowering Therapy: A Yellow Iii Substudy, Pruthvi C Revaiah, Yuliya Vengrenyuk, Jiajia Liu, Keisuke Yasumura, Vemuri Krishna Santosh, Monika Karki, Ishani Bansal, Amit Hooda, Joseph K Sweeny, Sahil Khera, Vishal Kapur, Prakash Krishnan, Pedro R Moreno, Roxana Mehran, Xiaobo Zhou, Jagat Narula, Samin K Sharma, Annapoorna S Kini

Faculty, Staff and Student Publications

Aims: Calcified nodules (CNs) contribute to 3-5% of acute coronary syndromes (ACS). Identifying peri-calcific lipid-rich areas is challenging with conventional imaging but feasible using near-infrared spectroscopy (NIRS). This YELLOW III substudy investigated the impact of maximal lipid-lowering on CN morphology and lipid content over 26 weeks.

Methods and results: Patients with stable CAD and lipid-rich, non-obstructive plaques (lipid arc >90°, FCT < 120 µm on OCT) received Evolocumab (140 mg biweekly) plus maximally tolerated statins. Lesions were evaluated at baseline and 26 weeks using combined NIRS-IVUS and OCT. Exploratory endpoints were the maximum 4 mm lipid core burden index (LCBI) in segments containing CNs (maxLCBI4mm-CN) and morphological changes in CN. Linear mixed-effects models were used to evaluate temporal changes and group interactions. Peripheral blood mononuclear cell (PBMC) transcriptomics were analysed. Among 110 patients, 43 (39.1%) had CNs. A total of 73 paired CNs were analysed for morphology, of which 65 CNs were ≥4 mm. CNs with lipid signal (CNLS) demonstrated a significant reduction in maxLCBI4mm-CN from 176.8 to 113.3 (β = -63.51 ± 17.63; P < 0.001), whereas no change was observed in dense CNs (P = 0.317). Morphological parameters remained largely unchanged in both groups. A modest increase in the surrounding calcium arc was observed in CNLS (P = 0.018), while depth showed a differential change …

Enhancing Inter-Institutional Ai Research Collaboration Across Multidisciplinary Teams To Increase The National Ai Workforce In Healthcare, Toufeeq Ahmed Syed, Sarah Popal, D'Laney Kernan, Deevakar Rogith, Zulfiia Ditto, Paul Warhurst, Jay Johnson, Jamboor K Vishwanatha

Faculty, Staff and Student Publications

Inter-institutional team collaboration is critical for impactful multidisciplinary AI research in healthcare. The goal of our project (AIM-AHEAD Connect) is to increase multidisciplinary collaborations by connecting AI/ML experts and healthcare researchers, trainees and professionals to enhance research and improve health for all Americans. As of February 2026, AIM-AHEAD Connect has over 10,100 AI/ML and healthcare experts from across 2,400 institutions, has made more than 7,800 connections and facilitated 194 collaborative online groups. We conducted a unique study to understand collaboration, and analyzed profile, connection, and platform engagement metrics to determine if AI experts and healthcare researchers with more inter-institutional connections …

Factors Associated With Opioid And Antibiotic Prescribing At Us Academic Dental Institutions: 2011 To 2020, S Tungare, A-I Yansane, S Gantela, K K Kookal, S Mccurdy, T M Krause, S Sharma, M Walji

Faculty, Staff and Student Publications

Introduction: In the United States, dentists are one of the leading prescribers of opioids and antibiotics. Because dental schools are the training grounds for future dentists, it is crucial to understand how prescribing has changed and why these medications are being prescribed in academic settings.

Objectives: The objective of this research was to describe the prescribing trends and factors associated with opioid and antibiotic medication prescribing at US academic dental institutions between 2011 and 2020.

Methods: Data from electronic dental records collected through the BigMouth data repository from 9 anonymized dental institutions between 2011 and 2020 were used. Prescribing rates …

Rewiring The Immune Response In Lung Cancer: Current Progress In Bispecific Antibodies, Car-T Therapy, And The Rise Of In Vivo Car-T Platforms, Lei He, Yi Sun, Bowen Ma, Guojun Lang, Jianguo Wen, George R Blumenschein, Hong Ma

Faculty, Staff and Student Publications

Lung cancer remains the leading cause of cancer mortality worldwide and continues to impose a major clinical burden, particularly in advanced non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Although targeted therapies, antiangiogenic agents, immune checkpoint inhibitors, and antibody-drug conjugates have improved outcomes in selected patients, durable responses remain limited by primary and acquired resistance. Here, we comprehensively review recent progress in immunologically oriented therapeutic strategies for lung cancer, focusing on bispecific antibodies, chimeric antigen receptor (CAR) T-cell therapy, and emerging in vivo CAR-engineering modalities. We further elaborate on the clinical rationale, latest translational and early clinical evidence, …

Deep Learning To Predict Future Cognitive Decline: A Multimodal Approach Using Brain Mri And Clinical Data, Tamoghna Chattopadhyay, Pavithra Senthilkumar, Rahul H Ankarath, Christopher Patterson, Emma J Gleave, Sophia I Thomopoulos, Heng Huang, Li Shen, Lei You, Degui Zhi, Paul M Thompson

Faculty, Staff and Student Publications

Predicting the trajectory of clinical decline in aging individuals is a pressing challenge, especially for people with mild cognitive impairment, Alzheimer's disease, Parkinson's disease, or vascular dementia. Accurate predictions can guide treatment decisions, identify risk factors, and optimize clinical trials. In this study, we compared two deep learning approaches for forecasting changes, over a 2-year interval, in the Clinical Dementia Rating scale 'sum of boxes' score (sobCDR), as a continuous outcome (regression). This is a key metric in dementia research and clinical trials, and scores range from 0 (no impairment) to 18 (severe impairment). To predict decline, we trained a …

A Hybrid Vit-L/32-Maxvit-L Architecture With Adaptive Gated Fusion For Multiclass Gastrointestinal Disease Detection And Multi-Method Post-Hoc Explainability, Shahid Mohammad Ganie, Pijush Kanti Dutta Pramanik, Zhongming Zhao

Faculty, Staff and Student Publications

Introduction: Accurate detection of gastrointestinal diseases from endoscopic images remains challenging due to substantial inter-class similarity, intra-class variability, and heterogeneous lesion presentation. While convolutional neural networks (CNNs) effectively capture fine mucosal textures, their limited receptive field restricts global contextual reasoning. Conversely, transformer architectures model long-range dependencies but may underrepresent localized structural detail.

Methods: This study proposes a dual-branch hybrid transformer framework that integrates global token-level reasoning from ViT-L/32 with hierarchical spatial modeling from MaxViT-L. An adaptive gated fusion mechanism is introduced to dynamically regulate the relative contribution of local and global representations on a per-sample basis, enabling content-aware cross-scale integration. …

Global-Local Feature Fusion: A Robust Hybrid Deep Learning Model For Multiclass Brain Tumor Classification With Grad-Cam++ Interpretation, Kirti Pant, Pijush Kanti Dutta Pramanik, Shahid Mohammad Ganie, Anindita Saha, Zhongming Zhao

Faculty, Staff and Student Publications

Background: Accurate classification of brain tumors in MRI scans is critical for effective clinical decision making, yet manual assessment is labor-intensive and subject to variability. Although deep learning models, particularly CNNs and Transformers, have shown potential, each architecture alone has limitations: CNNs excel at local feature extraction but lack global context awareness, while Transformers capture global relationships but may overlook fine-grained details.

Objectives: To develop a hybrid Transfer Learning-Transformer model that integrates CNN-driven local feature modeling with Transformer-based global reasoning to enhance multi-class brain tumor classification.

Methods: The proposed workflow comprises three stages: (1) benchmarking standalone CNN (ResNet50, VGG19, ConvNeXtBase, …

Genetic Variants Associated With Sjögren’S Disease Subtypes Stratified By Clinical Feature, Nitesh Enduru, Chihiro Iwaya, Akiko Suzuki, Zhongming Zhao, Junichi Iwata

Faculty, Staff and Student Publications

Introduction: Sjögren's disease (SjD) is a chronic autoimmune disorder characterized by dry mouth (xerostomia) and dry eyes (xerophthalmia) due to inflammation in exocrine glands, particularly the salivary and lacrimal glands. The condition presents a wide variety of clinical features, suggesting that it may involve heterogeneous conditions without a clear boundary. Although genome-wide association studies (GWAS) have identified several genetic variants associated with SjD, their roles in SjD pathogenesis remain unclear.

Methods: In this study, we aimed to identify single-nucleotide polymorphisms (SNPs) associated with SjD by categorizing patients based on four diagnostic markers: anti-Ro/SSA and anti-La/SSB antibodies, IgG levels, and lymphocyte …

The Effects Of Measurement Errors On Minimum Ablative Margins After Thermal Ablation Of Liver Tumors: A Simulation Study, Iwan Paolucci, Jessica Albuquerque, Noreen S Siddiqi, A Kyle Jones, Kristy K Brock, Bruno C Odisio

Faculty, Staff and Student Publications

Purpose: To develop a mathematical framework to estimate the in silico A0 threshold based on the technical specifications of a specific ablation confirmation software package for thermal ablation of liver tumors that can then be used to identify the impact of different sources of error.

Methods: To estimate in silico A0 thresholds, we developed a simulation framework incorporating technical parameters and biological effects. Technical parameters were segmentation error, registration error, and slice thickness, and biological effects were tissue shrinkage and microscopic satellite lesions; these parameters and effects were all modeled using statistical distributions. For each permutation of parameters, a logistic …

Dosimetric Effect Of Abdominal Compression In Online Adaptive Planning For Abdominal Cancers Treated With A 15 Tesla Magnetic Resonance-Guided Linear Accelerator, Moghadaseh Khaleghibizaki, Angela Sobremonte, Luis Perles, Surendra Prajapati, Ergys Subashi, Yao Ding, Kristy Brock, Roya Barati, Eugene Koay, Chad Tang, Jinzhong Yang

Faculty, Staff and Student Publications

Compression belts (CBs) are sometimes used to reduce respiratory motion during stereotactic body radiotherapy of abdominal cancers with magnetic resonance (MR)-guided online adaptive planning. This study evaluated the dosimetric effects of overriding the relative electron density (ED) value of CBs in creating synthetic computed tomography (CT) scans for MR-guided adaptive planning. We evaluated plans for 12 patients with abdominal cancer and identified that ED values between 0.2 and 0.3 achieved the best approximation of CB ED in dose calculation. Our study presented an approach to estimate appropriate ED overrides for CBs in MR-guided online adaptive planning.

Association Between Three-Dimensional Margin Assessment And Local Tumor Control In Percutaneous Lung Cryoablation Of Colorectal Metastases, Frank Mohn, Koustav Pal, Caleb O'Connor, Iwan Paolucci, Austin Castelo, Kamran Ahrar, Steven Yevich, Joshua D Kuban, Bruno C Odisio, Alda Lui Tam, Rahul A Sheth, Kristy K Brock

Faculty, Staff and Student Publications

Purpose

To evaluate the association of two minimum ablation margin (MAM) estimation methods: manual three-dimensional segmentation and biomechanical deformable image registration (DIR) with local tumor progression-free survival (LTPFS) after percutaneous lung cryoablation of colorectal pulmonary metastases.

Materials and Methods

This retrospective single-institution study included patients who underwent percutaneous lung cryoablation between May 2012 and March 2023 (median follow-up, 3.6 years; range, 0.8–9.6 years). Manual three-dimensional MAM was calculated for all tumors, and DIR-based MAM was estimated in a subset with intraprocedural full-thorax imaging. Cox proportional hazards regression assessed associations between MAM and LTPFS. The primary outcome was 2-year LTPFS, with …

Outcomes Of Patients With Melanoma Brain Metastases Treated With Ipilimumab And Nivolumab With Or Without Upfront Comprehensive Stereotactic Radiosurgery, Troy J Kleber, Denái R Milton, Subhiksha Srinivasan, Bikash Panthi, Warren Floyd, Eric A Goethe, Michael A Davies, Hussein A Tawbi, Isabella C Glitza Oliva, Diana Kaya, Jing Li, Todd A Swanson, Subha Perni, Martin C Tom, Chenyang Wang, Sujit Prabhu, Jeffrey S Weinberg, Ian E Mccutcheon, Caroline Chung, Sherise D Ferguson, Thomas H Beckham

Faculty, Staff and Student Publications

Background: The efficacy of ipilimumab and nivolumab (ipi/nivo) for melanoma brain metastases (MBMs) has been previously reported, leading to uncertainty regarding the optimal role of comprehensive stereotactic radiosurgery (cSRS). We therefore conducted a single-institution retrospective study to compare outcomes of upfront versus deferred cSRS for MBM treated with ipi/nivo.

Methods: We identified patients who started ipi/nivo for newly diagnosed MBMs between 2018 and 2023, with or without upfront cSRS. Patients with >15 MBMs, leptomeningeal disease, or whole-brain radiotherapy at baseline were excluded. Outcomes were compared using multivariable regression and reported as adjusted hazard ratios (aHRs) with 95% CIs.

Results: Of …

Reply To: Late Nonrelapse Mortality: A Hidden Risk In Triplet Therapy For Idh-Mutated Aml?, Jennifer Marvin-Peek, Courtney D Dinardo

Faculty, Staff and Student Publications

No abstract provided.

Perspective: Radiotherapy And Body Composition: Unmet Needs In Low- And Middle-Income Countries, Alexia J Murphy-Alford, Aaron J Grossberg, Vickie E Baracos, Maha Barbar, Judy Bauer, Jonathan P Bennett, Elena Fidarova, Clifton D Fuller, Anastassia Löser, Amy C Moreno, Anurima Patra, Deepa Puttaswamy, David I Rosenthal, Judy Schoeman, Yavuz Anacak

Faculty, Staff and Student Publications

Radiotherapy plays a vital role in cancer treatment, yet its effects on patients' nutritional status can precipitate muscle loss, with significant implications for treatment tolerance and outcomes. Evidence from high-income countries increasingly links radiation-induced muscle loss to adverse clinical outcomes. In contrast, low- and middle-income countries face a stark evidence gap, despite the heightened vulnerability of cancer patients in these settings due to delayed diagnosis, limited access to care, and high rates of co-morbidities. This paper highlights the critical gaps in nutritional care for radiotherapy patients in low- and middle-income countries.

Metastasis-Directed Radiotherapy For Oligometastatic Urothelial Carcinoma Of The Bladder And Upper Tract, Patrick Carriere, Omar Alhalabi, Jianjun Gao, Amishi Shah, Sangeeta Goswami, Matthew Campbell, Ruitao Lin, Lauren Mayo, Osama Mohamad, Karen Hoffman, Henry Mok, Charmaigne Lozano, Ashish Kamat, Neema Navai, Kelly Bree, Byron Lee, Charles Guo, Michael Rooney, Chad Tang, Seungtaek Choi, Comron Hassanzadeh

Faculty, Staff and Student Publications

Background: Metastasis-directed therapy (MDT) for oligometastatic cancer is utilized for genitourinary malignancies including prostate and kidney cancers. Clinical research on MDT for urothelial carcinoma (UC) remains sparse, especially as systemic therapy advances have improved outcomes.

Objective: We investigated the role of MDT, specifically radiotherapy, for patients with oligometastatic bladder or upper-tract UC.

Methods: Data were collated on patients with metastatic UC with 5 or fewer metastatic sites undergoing MDT with ablative radiotherapy with or without preceding systemic therapy during January 2016 to July 2024. Endpoints were progression-free survival (PFS), and overall survival (OS). Cox proportional hazards analysis was conducted to …

Functional, Pharmacogenomic, And Immune Landscapes Of Long Non-Coding Rnas In Cancer, Runhao Wang, Mei Luo, Yuan Liu, Jingwen Yang, Yamei Chen, Chengxuan Chen, Lifei Ma, Stephanie Ding, James Wengler, Yong Zang, Bora Lim, Wenbo Li, Liuqing Yang, Chunru Lin, Lixia Diao, Leng Han

Faculty, Staff and Student Publications

Long non-coding RNAs (lncRNAs) are emerging as key regulators in cancer, with significant potential as diagnostic, prognostic, and therapeutic targets. Here, this work systematically analyzes lncRNA associations with targeted therapies and immunotherapies across 33 cancer types using The Cancer Genome Atlas (TCGA) and real-world datasets. This work identifies 53,173 lncRNA-pathway associations, millions of lncRNA-drug response associations (via CancerRxTissue and VAEN), and extensive correlations with immune checkpoints and infiltration. This work further identifies 69 lncRNAs associated with immunotherapy response and 2,611 differentially expressed lncRNAs between low and high objective response rate (ORR) groups. Additionally, two lncRNAs are correlated with immune-related adverse …

Bop2-Comb: Bayesian Optimal Phase Ii Design For Optimizing Doses And Assessing Contribution Of Components In Drug Combinations, Xiaohan Chi, Ying Yuan, Ruitao Lin

Faculty, Staff and Student Publications

Background: Personalized cancer treatment using combination therapies offers substantial therapeutic benefits over single-agent treatments in most cancers. However, unmet clinical needs and increasing market competition pressure drug developers to quickly optimize combination doses and clearly demonstrate the contribution of each component when developing and evaluating new combination treatments.

Methods: We propose a Bayesian optimal phase II drug-combination (BOP2-Comb) design that optimizes the combination dose and evaluates the proof-of-concept as well as the contribution of each component in two seamless stages. Our optimal calibration scheme minimizes the total trial sample size while controlling incorrect decision rates at nominal levels. This calibration …

Peripheral Cd200r Signaling: A Critical Regulator Of Post-Stroke Inflammation In Aged Mice, Conelius Ngwa, Afzal Misrani, Yan Xu, Jingjing Wang, Rodney Ritzel, Fudong Liu

Faculty, Staff and Student Publications

The immune responses to ischemic stroke are subjected to endogenous inhibitory pathways that delimitate the post-stroke inflammation. Among them, the interaction between CD200 and its receptor (CD200R) is increasingly recognized for its role in regulating neuroinflammation across various central nervous system (CNS) disorders. In the present study, we have examined the role of central (brain) vs. peripheral CD200R signaling in acute ischemic stroke using aged bone marrow chimeric (BMC) mice (16-19 months old). These chimeras were generated by transplanting bone marrow from CD200R knockout (KO), green fluorescent protein (GFP), or wild-type (WT) donor mice into irradiated recipient mice, and then …

The Legacy Of A Gentleman Scientist: Pierre Hainaut, Christophe Arnoult, Laura D Attardi, Kerem Batsheva, Giovanni Blandino, Kathleen H Burns, Giannino Del Sal, David G Kirsch, David P Lane, Arnold J Levine, Guillermina Lozano, David Malkin, Gerry Melino, Moshe Oren, Carol Prives, Daniel Schramek

Faculty, Staff and Student Publications

No abstract provided.

Contemporary Opportunities And Potential Of Auger Electron-Emitting Theranostics, Seok-Yong Lee, H Charles Manning

Faculty, Staff and Student Publications

Recent breakthroughs in radiopharmaceutical (RP) therapy have emerged interest in employing Auger electron (AE)-emitting radionuclides as potential agents for precise theranostics. AE provides energy with exceptional localization due to their short tissue penetration range (TPR, < 10 nm), rendering them particularly effective for targeting nuclear DNA in tumor cells. In this context, AE-emitting radionuclide therapy (AE-emitting RLT) enables the targeted destruction of tumor cells while reducing harm to adjacent healthy tissue, a significant challenge in this field. Preclinical and early clinical investigations reveal the efficacy of AE-emitting RLTs in the theranostics of diverse malignancies, such as glioblastoma, prostate cancer, and neuroendocrine tumors. Notwithstanding these developments, challenges and limitations persist regarding dosimetry, delivery efficiency, and the treatment of radiotoxicity. A new paradigm is being developed to tackle the obstacles encountered by integrating molecular target markers (e.g., PARP) that function near the nucleus to improve the intranuclear delivery efficiency of AE-emitting radionuclides. Novel radiochemical methods such as these have facilitated the more stable and efficient labeling of biomolecules with AE-emitting radionuclides. Also, recent advances in DNA-molecular targeting, nanoparticles, nucleic acid/protein engineering, click- or bioorthogonal conjugation chemistry, and artificial intelligence (AI)-based structure modeling present concrete opportunities to overcome these limitations. Moreover, the integration of diagnostic imaging companion platforms employing theranostic radioisotope pairings facilitates real-time assessment of therapeutic efficacy and biodistribution, resulting in the formulation of enhanced treatment regimens. This review summarizes the prior development, recent advancements, barriers in clinical implementation, and future perspective of AE-emitting RLTs.

Nsd2 Inhibitors Rewire Chromatin To Treat Lung And Pancreatic Cancers, Jinho Jeong, Simone Hausmann, Hanyang Dong, Kacper Szczepski, Natasha M Flores, Andy Garcia Gonzalez, Liyang Shi, Xiaoyin Lu, Joanna Lempiäinen, Moritz Jakab, Liyong Zeng, Tourkian Chasan, Eric Bareke, Rui Dong, Emma Carlson, Reinnier Padilla, Dylan Husmann, Julia Thompson, Gerry A Shipman, Emily Zahn, Courtney A Barnes, Laiba F Khan, Liz Marie Albertorio-Sáez, Eva Brill, Vishnu Udayakumar Sunita Kumary, Matthew R Marunde, Danielle N Maryanski, Cheryl C Szany, Bryan J Venters, Carolina Lin Windham, Michal Eligiusz Nowakowski, Iwona Czaban, Mariusz Jaremko, Michael-Christopher Keogh, Kang Le, Michael J Soth, Benjamin A Garcia, Łukasz Jaremko, Jacek Majewski, Pawel K Mazur, Or Gozani

Faculty, Staff and Student Publications

NSD2 catalyses the epigenetic modification H3K36me2 (refs. 1,2) and is a candidate convergent downstream effector of oncogenic signalling in diverse malignancies3–5. However, it remains unclear whether the enzymatic activity of NSD2 is therapeutically targetable. Here we characterize a series of clinical-grade small-molecule catalytic NSD2 inhibitors (NSD2i) and show that the pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven preclinical cancer models. NSD2i inhibits NSD2 with single-digit nanomolar half-maximal inhibitory concentration potency and high selectivity over related methyltransferases. Structural analyses reveal that the specificity of NSD2i for NSD2 …

Respiratory Motion Effects And Plan Robustness For Lattice Radiation Therapy, Rachael M Martin-Paulpeter, Peter A Balter, Luis A Perles, Ethan B Ludmir, Joshua S Niedzielski

Faculty, Staff and Student Publications

Introduction: Lattice radiation therapy (LRT), a form of spatially fractionated radiation therapy (SFRT), has shown promise in treating bulky tumors. It consists of hot and cold spots within the tumor, and the ratio between these doses is thought to be important in clinical outcomes. Respiratory motion is expected to degrade these peak-to-valley dose ratios (PVDRs) but has largely been ignored in LRT literature and clinical practice. This work aims to quantify the response of LRT dose distributions to motion to better inform motion management decisions and improve clinical outcomes.

Methods: Respiratory motion of peak-to-peak amplitudes from 0.3 to 2 cm …

Freeze-Dried, Not Frozen: Lyophilized Mesenchymal Stromal Cell-Derived Extracellular Vesicles And Therapeutic Function In Neuroinflammatory Models, Janet R Ashley, Aidan M Collier, Scott D Olson, Charles S Cox

Faculty, Staff and Student Publications

Background: Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) offer a promising acellular therapy for immune modulation, but clinical translation is hindered by variability and storage constraints. Lyophilization (freeze-drying) could enable shelf-stable EV therapeutics, although its effects on biological activity remain incompletely defined.

Study design: We compared the immunomodulatory effects of frozen and lyophilized EVs from bone marrow (BM), adipose tissue (AD), and umbilical cord (UC) MSCs using lipopolysaccharide-stimulated rodent splenocytes and microglial models and human peripheral blood mononuclear cells (PBMCs). Variables included batch scale (small vs large), cytokine priming, and MSC source. Tumor necrosis factor alpha (TNF-α) secretion was measured …

Single-Cell Lineage Trajectory Defines Cyclin-Dependent Kinase Inhibitor-Sensitive Cells-Of-Origin In Esophageal Squamous Cell Carcinoma, Kyung-Pil Ko, Jie Zhang, Sohee Jun, Jae-Il Park

Faculty, Staff and Student Publications

Background and aims: Understanding the cells of origin is essential for overcoming therapy resistance and improving early intervention strategies in esophageal squamous cell carcinoma (ESCC). Despite recent advances in genomic profiling, the precise cellular hierarchies and molecular programs driving ESCC initiation remain poorly defined.

Methods: We utilized machine learning-based single-cell trajectory analysis on 4-nitroquinoline 1-oxide-induced murine models and genetically engineered organoids to identify cellular lineages during tumorigenesis. Combined with gene regulatory network analysis, we identified transcriptional drivers of tumor initiation and employed transcriptome-based drug repurposing to predict compounds targeting these initiating populations.

Results: Our analyses revealed multiple distinct epithelial clusters …

Key Regulatory Roles Of Prdm1 In Human Nk-Cell Differentiation And Activation, Xuxiang Liu, Yunfei Shi, Jibin Zhang, Kunal Shetty, Krystie Chew, Can Küçük, Qiang Gong, Esra Esmeray, Haiqing Li, Ru Chen, Sheng Pan, Katarzyna Dąbrowska, Roger E Moore, Krystine Garcia-Mansfield, Patrick Pirrotte, Jinhui Wang, Yuping Li, Gehong Dong, Logan Lee, Timothy W Mckeithan, Javeed Iqbal, Wing C Chan

Faculty, Staff and Student Publications

PRDM1, encoding a transcription factor (TF), regulates plasma cell and CD8+ T-cell terminal differentiation and Th2 lineage specification, while its role in human NK-cell differentiation and homeostasis is largely unknown. Here, we employed a multi-omics approach to dissect the transcriptional control of PRDM1 on human NK-cells. PRDM1 is important in NK-cell terminal differentiation based on gene expression profiling and its targeting of key regulators in the process. PRDM1-deleted NK-cells displayed a less mature phenotype simulating the CD56bright NK-cell population accompanied by upregulation of stem-like gene signatures. PRDM1-bound genes were enriched in T/NK-cell receptor signaling, activation, and NK-cell effector …