Medical Genetics Commons^™

Ai-Powered Immune Cell Knowledge Graph (Ickg) With Granular Immune Contexts Enables Immune Program Interpretation, Shan He, Yukun Tan, Qing Ye, Matthew M Gubin, Merve Dede, Hind Rafei, Weiyi Peng, Katayoun Rezvani, Vakul Mohanty, Ken Chen

Faculty, Staff and Student Publications

The widespread application of single-cell and spatial omics to models and patient samples has transformed immune cell profiling across physiological conditions. However, knowledge of immune cell states, functions, and gene regulation remains fragmented across publications, limiting our ability to synthesize insights and derive mechanistic understanding from the literature. To address this gap and facilitate literature integration, we constructed Immune Cell Knowledge Graphs (ICKGs)-four cell type-specific graphs derived from over 24,000 cancer immunotherapy-focused PubMed abstracts using large language models (LLMs) with "human verifiable" validation. Unlike conventional databases, which provide context-agnostic pathways, ICKGs capture directed, literature-supported relationships among genes, pathways and immune …

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.

A Gut-Activated Nhr-86-Cyp Pathway Mediates The Neuroprotective Effects Of Enterococcus Faecium Probiotics In A Nematode Model Of Amyotrophic Lateral Sclerosis, Yu Sang, Jie Ren, Alejandro Aballay

Faculty, Staff and Student Publications

Neurodegenerative diseases are often associated with oxidative stress, and while probiotics may influence neuronal health, the underlying mechanisms remain poorly understood. Using the sod-1 A4VM amyotrophic lateral sclerosis (ALS) model in Caenorhabditis elegans, we investigated the protective effects of the probiotic Enterococcus faecium against oxidative stress-induced neurodegeneration. Animals fed E. faecium showed reduced motor neuron degeneration under oxidative stress compared to those maintained on a standard Escherichia coli diet. Transcriptome analysis revealed a significant enrichment of oxidoreductase genes, including cytochrome P450 (cyp) genes. RNAi-mediated knockdown of cyp genes impaired E. faecium-mediated neuroprotection, and this loss correlated with increased reactive oxygen …

Guadecitabine Improved Relapse-Free Survival In High-Risk Acute Myeloid Leukemia And Myelodysplastic Syndrome Patients After Transplant: Phase Ii Results From A Single Center, Betül Oran, Peter Thall, Amin Alousi, Gheath Al-Atrash, Rohtesh Mehta, David Marin, Partow Kebriaei, Uday Popat, Roland Bassett, Qaiser Bashir, Jin Im, Amanda Olson, Jessica Jewell, Portia Smallbone, Elizabeth Shpall, Richard Champlin

Faculty, Staff and Student Publications

This phase II, single-center clinical trial evaluated the efficacy and safety of guadecitabine, with or without donor lymphocyte infusion, following allogeneic stem cell transplantation in adult patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). The study had three treatment cohorts based on post-transplant disease status. Cohort 1 included patients with hematologic relapse after transplant (N=13). Cohort 2 consisted of patients with minimal residual disease (MRD) detected after transplant (N=18). Cohort 3 compromised patients in remission without MRD within 100 days after transplant (N=24). The primary objectives were achievement of morphological complete remission in cohort 1 and MRD eradication …

Endogenous Processes Underlying Clock-Like Mutational Signatures, Teresa Druck, Rami I Aqeilan, C Marcelo Aldaz, Nicola Zanesi, Kay Huebner

Faculty, Staff and Student Publications

Wellcome Trust scientists have shown that “mutational signatures” in specific nucleotide contexts accumulate in genomes of mammalian tissues, providing clues to underlying causes of specific signatures. Analysis of cancer genomes has identified more than 50 single‐base substitution (SBS) signatures, with SBS1, SBS5, and SBS40 linked to aging and present in normal tissues. SBS1 results from cytosine demethylation, whereas SBS5 and SBS40 arise from unknown endogenous mechanisms. We hypothesized that loss of fragile‐site genes drives these two signatures. FHIT, located at FRA3B, is frequently deleted in cancers, and Fhit‐deficient mouse tissues exhibit a mutation profile resembling human SBS5. Data mining of …

Preclinical Ischemic Stroke Multicenter Trials (Prism) Collective Statement: Opportunities, Challenges, And Recommendations For A New Era, Cenk Ayata, Philip M Bath, Anna M Planas, Stuart M Allan, Johannes Boltze, Ryan P Cabeen, Claire L Gibson, Marilyn J Cipolla, Marcio A Diniz, Stefano Fumagalli, Fahmeed Hyder, Raymond C Koehler, Arthur Liesz, Sarah K Mccann, Tim Magnus, Louise D Mccullough, Emily S Sena, Simone Beretta, Jaroslaw Aronowski, Francesca Bosetti, Clinton B Wright, Patrick D Lyden, Lauren H Sansing

Faculty, Staff and Student Publications

Preclinical stroke research faces a critical translational gap, with animal studies failing to reliably predict clinical efficacy. To address this, the field is moving toward rigorous, multicenter preclinical randomized controlled trials (mpRCTs) that mimic phase 3 clinical trials in several key components. This collective statement, derived from experts involved in mpRCTs, outlines considerations for designing and executing such trials. mpRCTs offer advantages such as increased sample sizes, robust statistical design, incorporation of heterogeneity, and standardized protocols, but they face challenges in finding the right balance between standardization and heterogeneity, appropriate stroke model selection, and outcome measures, as well as the …

Poly(A) Probe Hcr Rna-Fish Specifically Marks Pyriform Nurse Cells In The Brown Anole Lizard Ovary, Zoe B Griffin, Bonnie K Kircher, Richard R Behringer

Faculty, Staff and Student Publications

Hybridization chain reaction RNA-fluorescent in situ hybridization (HCR RNA-FISH) is a powerful and increasingly used method for visualizing gene expression in cells and tissues. A probe set against polyadenylated RNA (poly(A)) is often used as a positive control for RNA integrity and staining quality. While optimizing this technique in the ovary of the brown anole lizard (Anolis sagrei), we found that the poly(A) probe produced a strikingly specific and intense signal in pyriform cells, a specialized lizard-specific nurse cell type. This staining pattern was found in both whole-mount samples and paraffin sections, suggesting that poly(A) signal intensity can serve as …

Refining Aicardi Syndrome Diagnostic Criteria: An Expert-Based Consensus Using A Modified Delphi Approach, Silvia Masnada, Valentina De Giorgis, Umberto Carugo, Nadia Bahi-Buisson, Mara Cavallin, Mark Corbett, Manuela Formica, Jozef Gecz, Natalia Petros, Emilio Perucca, Anna Pichiecchio, Paolo Fusar Poli, Elliott H Sherr, Ignatia B Van Den Veyver, Federico Zara, Martin Geroldinger, Pierangelo Veggiotti, Alexis Arzimanoglou

Duncan NRI Faculty and Staff Publications

Background and objectives: Aicardi syndrome (AIC) is a rare neurodevelopmental disorder historically characterised by the presence of chorioretinal lacunae, corpus callosum agenesis, infantile spasms and several supporting features that aid in diagnosis. However, the unclear aetiology and evolving diagnostic tools have led to ongoing reconsideration of the criteria, based on individual approaches. Our study aimed to establish, for the first time, an expert-based consensus on diagnostic criteria for AIC by integrating both existing and novel ones.

Methods: A geographically diverse and multidisciplinary group of expert physicians was invited to participate in a modified Delphi study, to achieve consensus on major, …

Photobiomodulation Mitigates The Inhibitory Effects Of Pirfenidone On Cancer-Associated Fibroblasts And Their Pro-Tumorigenic Properties: A Cause For Concern, Nima Rastegar-Pouyani, Alireza Nasirpour, Fatemeh Javani Jouni, Hossein Vazini, Ahmad Moshaii

Electrical & Computer Engineering Faculty Publications

Cancer-associated fibroblasts (CAFs) within the tumor microenvironment highly contribute to cancer progression and poor prognosis. Recent findings introduce pirfenidone, a medication for pulmonary fibrosis, as a promising repurposed candidate for inhibiting CAFs. Moreover, photobiomodulation (PBM), or low-level laser therapy, has surfaced as a potential modality against cancer; however, its impact on CAFs is not thoroughly comprehended. The present study scrutinized the effects of PBM, pirfenidone, and PBM+pirfenidone on CAFs, and their consequent impact on cancer cells using the CAF-conditioned media. After treating CAFs with PBM at wavelengths 660 and 980 nm with/without PFD and then culturing cancer cells in the …

Deep Reinforcement Learning–Driven Multi-Omics Integration For Constructing Gtage: A Novel Aging Clock From Igg N-Glycome And Blood Transcriptome, Yao Xia, Syed Mohammed Shamsul Islam, Xingang Li, Abdul Baten, Xuerui Tan, Wei Wang

Research outputs 2022 to 2026

Previous studies have demonstrated that the immunoglobulin G (IgG) N-glycome and transcriptome are potential biochemical signatures of chronological and biological ages, and several aging clocks have been developed. By integrating the IgG N-glycome and transcriptome, we propose a novel aging clock, gtAge. We developed a deep reinforcement learning-based multiomics integration method called AlphaSnake. The results showed that AlphaSnake achieved a predicted coefficient of determination (R²) value of 0.853, outperforming the concatenation-based integration method (R² = 0.820). The gtAge estimated by AlphaSnake explained up to 85.3% of the variance in chronological age, which was higher than that in …

Access To Digital Health Technologies: Personalized Framework And Global Perspectives, Sanjiv M Narayan, Mina K Chung, Demilade Adedinsewo, Luisa C C Brant, Leslie L Davis, David Duncker, Jennifer L Hall, Janet K Han, Carolyn S P Lam, Eldrin Lewis, Joseph Loscalzo, Manlio F Márquez, Vasiliki Rahimzadeh, Fatima Rodriguez, Prashanthan Sanders, Emma Svennberg, Kenneth Stein, Mintu Turakhia, Clyde Yancy, Antonis A Armoundas

Center for Medical Ethics and Health Policy Staff Publications

The emergence and rapid adoption of digital health technologies (DHT) present unprecedented opportunities to democratize and reduce disparities in health care by monitoring health and disease at the point of care in all patients. However, limited access to DHT is becoming a major obstacle to realizing these goals. Access to DHT is influenced not only by well-recognized social determinants of health, but also by digital determinants of health, such as digital literacy and the need for broad access to digital infrastructure, as well as commercial and economic factors. Addressing these challenges and designing unbiased systems of care are essential to …

Alternative Polyadenylation Signatures Distinguish Maladaptive Right Ventricular Remodeling In Pulmonary Hypertension: Implications For Rna-Based Diagnostics And Therapeutics, Janani Subramaniam, Venkata Jonnakuti, Scott D Collum, Sandra Martineau, Kai-Lieh Huang, Sandra Breuils-Bonnet, Andrea L Frump, Bindu H Akkanti, Jayeshkumar A Patel, Manish K Patel, Ismael Salas De Armas, Isabella N Lefebvre, Rajko Radovancevic, Elvin Blanco, Eric J Wagner, Igor Gregoric, Sriram Nathan, Biswajit Kar, Steeve Provencher, Sebastien Bonnet, François Potus, Hari Krishna Yalamanchili, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

Increased pulmonary vascular pressures due to vascular remodeling, elevated vascular resistance, and vasoconstriction characterize Pulmonary Arterial Hypertension (PAH). The narrowing of the pulmonary arteries and obstruction of blood flow increase the Right Ventricular (RV) afterload, forcing the RV to undergo structural and functional changes. While adaptive remodeling leads to RV compensation by maintaining function, maladaptive remodeling leads to RV decompensation, characterized by worsening function and eventual failure. At present, there is no effective treatment for these patients as therapies for left ventricular failure are ineffectual, and there are no therapies specifically targeting the RV. Therefore, there is a clear need …

Test-Retest Apparent Diffusion Coefficient Reproducibility In Head And Neck Cancer Using A 15-T Mr-Linac, Brigid A Mcdonald, Dina El-Habashy, Renjie He, Sam Mulder, Sarah Mirbahaeddin, Abdallah S R Mohamed, Sara Ahmed, Yao Ding, Jihong Wang, Stephen Y Lai, Alex Dresner, John Christodouleas, Clifton D Fuller

Faculty, Staff and Student Publications

Purpose

To evaluate the reproducibility of apparent diffusion coefficient (ADC) measurements in head and neck squamous cell carcinoma (HNSCC) using a 1.5-T MR-linac (MRI-guided linear accelerator) system.

Materials and Methods

In this retrospective study, conducted between February 2021 and January 2024, patients with HNSCC lesions underwent echo-planar imaging diffusion-weighted MRI on a 1.5-T MR-linac system at two time points before the start of radiation therapy. Mean and median ADC values and volumes were measured for each lesion. Absolute and percent reproducibility coefficients (RCs) were calculated. Linear regression analyses and F tests were performed to determine whether the lesion volume or …

Cerebellar Motor And Non-Motor Contributions To Dystonia Pathophysiology And Treatment, Linda H Kim, Cheryl Brandenburg, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Dystonia is a complex neurological disorder characterized by sustained or intermittent abnormal movements and/or postures. However, dystonia's non-motor symptoms, particularly the sleep disturbances, are critical yet underexplored concerns that affect all ages. Here, we synthesize current knowledge on the motor and non-motor domains of dystonia, emphasizing the functional interconnections and plasticity within cerebellar motor, cognitive, and sleep-associated circuits to motivate more comprehensive and effective treatments that improve overall quality of life.

Organ Chips And Translational Research: Identifying And Examining New Ethical Issues, Melanie Jeske

Center for Medical Ethics and Health Policy Staff Publications

Organ chips, also known as organ-on-a-chip devices, tissue chips, or microphysiological systems, have emerged over the last decade as a promising translational technology amidst growing concern about the translational crisis between laboratory research and patient bedside. Pointing to high rates of failure between nonhuman animal models and safety and efficacy in humans, organ chips and similar new approach methods have attracted substantial public and private investment. As human-cell-based alternatives to animal models, organ chips promise more predictive, efficient, and ethical platforms for pharmaceutical and toxicity testing. Engineered cultivation systems that enable cells to assemble into tissue-like structures (e.g. kidney, brain, …

Anything But Endo: Diagnostic Buck-Passing In Endometriosis Diagnosis, Rita Dexter, Megan Kitts, Heather Welty, Melanie Jeske

Center for Medical Ethics and Health Policy Staff Publications

People living with endometriosis, a disease in which tissue similar to the lining of the uterus grows elsewhere in the body, often experience prolonged diagnostic journeys because of symptom variability, normalisation of period pain and other symptoms, and lack of awareness of the condition. In this article, we analyse the endometriosis diagnostic journey through the lens of epistemic injustice. Drawing on in-depth interviews with 52 people living with endometriosis in the United States, we introduce the concept of diagnostic buck-passing to characterise the phenomenon wherein individuals who seek treatment for their symptoms end up stuck in a cycle of seeing …

Differences Between Government, Consortium, And Private Database Stewards Impacting The Genomic Data Market: A Survey Of U.S. Academic Genetic Researchers., Amanda K Greene, J Denard Thomas, Kaitlyn Jaffe, Luyun Chen, Kerry A Ryan, Brian J Zikmund-Fisher, J Scott Roberts, Amy L Mcguire, Katherine Hendy, Kayte Spector-Bagdady

Center for Medical Ethics and Health Policy Staff Publications

Background: Despite major shifts in U.S. federal government data sharing requirements, their impact, and relation to researcher choice of database, are underexplored. This study surveyed genetic researchers regarding trends, priorities, perceptions of quality, impact on research outcomes, and genomic data sharing and use across government, consortium, and private databases.

Methods: As part of an exploratory sequential mixed methods project, we surveyed 294 U.S.-based genomic academic researchers.

Results: Genetic researchers generally have a choice between databases, which allows them to prioritize data quality. This might explain recent trends toward the use of government and consortium databases away from private ones. Respondents …

Can I Get A Witness? The Ethical Dimensions Of Family Presence In Patient Suffering, Jennifer Blumenthal-Barby, Trevor M Bibler, Holland Kaplan, Adam Omelianchuk, Joanna Smolenski

Center for Medical Ethics and Health Policy Staff Publications

For patients who are suffering, the bedside presence of a family member can provide comfort, and many people hold that there is moral value in being present with a conscious, suffering patient. Yet what is the moral significance of the absence of family members when a patient is minimally conscious or unconscious and not aware of their absence? Clinicians are often troubled when family members and surrogate decision-makers who are able to spend a significant amount of time at an unconscious, seriously ill patient's bedside do not do so. Clinicians feel frustrated that they must bear the burden of witnessing …

Toward Ethical Provenance Tracking: The Ga4gh Model Data Access Agreement (Daa), Alexander Bernier, Bartha Maria Knoppers, Jonathan Lawson, Robyn Mcdougall, Maili Raven-Adams, Vasiliki Rahimzadeh

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Standardizing contractual clauses that govern data access enables research institutions to responsibly steward genomic and related health data while enabling its efficient downstream reuse.

Methods: We describe a document analysis study using both qualitative and comparative law analytical approaches to identify the most common categories of clauses from 29 different data access agreements used by human biomedical research consortia globally. We furthermore characterized the legal positions and standard practices for each common element of the agreement and synthesized across them to develop model clauses. A total of 3 discussion sessions were organized virtually to refine the clauses among members …