Digital Commons Network^™

Risk Of Second Primary Lung Cancer Among Cancer Survivors Stratified By The Site Of First Primary Cancer And The Lung Cancer Screening Eligibility Status, Sara Nofal, Edwin J Ostrin, Jianjun Zhang, Jia Wu, Paul Scheet, Mara B Antonoff, John V Heymach, Iakovos Toumazis

Faculty, Staff and Student Publications

Personal history of cancer is an independent risk factor for developing lung cancer. However, it is not considered in the current US lung cancer screening (LCS) guidelines. In this study, we assessed the risk of developing lung cancer among cancer survivors across 24 different sites of first primary cancer stratified by their LCS eligibility status. Using data from the Patient History Database at the University of Texas MD Anderson Cancer Center, we calculated and compared the cumulative incidence of second primary lung cancer, the overall and the LCS eligibility status-specific, stratified by the site of first primary cancer among cancer …

Unbound Bilirubin And Risk Of Severe Neurodevelopmental Impairment In Extremely Low Birthweight Newborns, Cody C Arnold, Ivana Maric, Ronald J Wong, Jon E Tyson, David K Stevenson

Faculty, Staff and Student Publications

Background: Unbound bilirubin (UB) was measured on day 5 ± 1 in 1101 ELBW newborns in the Aggressive vs Conservative Phototherapy randomized controlled trial. We accessed this dataset to quantify the UB-mediated risk of severe neurodevelopmental impairment (sNDI) in extremely low birthweight (ELBW) newborns.

Methods: UB levels were standardized within laboratories as z-score percentiles. A dichotomous UB exposure variable was based on sharply increased risk of sNDI at the 85th percentile (UBz>85th). Targeted maximum likelihood estimation with ensemble machine learning (TMLE + ML) and logistic regression (LR) were used to estimate sNDI risk attributable to UBz>85th.

Results: UB …

Utility Of Whole-Slide Imaging For Rapid Evaluation Of Thyroid Fna: A Multireader Prospective Study, Mohammed S Ahmed, Dianna Klippel-Almaraz, Sara E Amin, Gloria H Sura, Uma Rani Kundu, Wendong Yu, Jogn M Stewart, Qiong Gan, Savitri Krishnamurthy

Faculty, Staff and Student Publications

Background: Rapid on-site evaluation (ROSE) of thyroid fine-needle aspiration biopsy (FNAB) improves diagnostic adequacy and facilitates ancillary molecular testing. In this prospective, multireader study, the authors evaluated the feasibility of using whole-slide images (WSIs) for ROSE to determine specimen adequacy and preliminary categorization (according to The Bethesda System for Reporting Thyroid Cytopathology [Bethesda]) of image-guided thyroid FNABs compared with conventional light-microscopic (LM) examination of the same specimens in a referral cancer center.

Methods: The authors evaluated 98 ultrasound-guided thyroid FNAB cases. Smears were stained with Papanicolaou and Diff-Quik and were scanned at ×20 magnification using a Leica Aperio CS2 scanner. …

Examining The Impact Of Area Deprivation On Endovascular Stroke Therapy Access, Joseph N Samaha, Ngoc Mai Le, Emmanuel C Ebirim, Rania Abdelkhaleq, Sergio A Salazar Marioni, Muhammad Bilal Tariq, Ananya Iyyangar, Anjan Nagesh, Hussain Azeem, Arash Niktabe, Sunil A Sheth

Faculty, Staff and Student Publications

Background: Equitable access to health care is heavily affected by socioeconomic factors. However, the effects of such disparities in accessing life-saving treatments remain incompletely characterized. Here we explore the impact of disparities on access to endovascular treatments for large vessel occlusion acute ischemic stroke.

Methods: From our prospectively maintained multihospital registry, we identified patients with large vessel occlusion acute ischemic stroke from January 2019-June 2020. Patient addresses and zip codes were matched to census-tract level area deprivation index (ADI) scores that were obtained from Neighborhood Atlas. ADI is a validated neighborhood-level measure that uses variables such as income, education, and …

Correction: Imaging In Pelvic Exenteration-A Multidisciplinary Practice Guide From The Esgar-Sar-Esur-Pelvex Collaborative Group, Stephanie Nougaret, Doenja M J Lambregts, Geerard L Beets, Regina G H Beets-Tan, Lennart Blomqvist, David Burling, Quentin Denost, Maria A Gambacorta, Benedetta Gui, Ann Klopp, Yulia Lakhman, Kate E Maturen, Riccardo Manfredi, Iva Petkovska, Luca Russo, Atul B Shinagare, James A Stephenson, Damian Tolan, Aradhana M Venkatesan, Aaron J Quyn, Rosemarie Forstner

Faculty, Staff and Student Publications

No abstract provided.

Spatial Colocalization And Molecular Crosstalk Of Myofibroblastic Cafs And Tumor Cells Shape Lymph Node Metastasis In Oral Squamous Cell Carcinoma, Ken Furudate, Shuya Kasai, Tadashi Yoshizawa, Yuya Sasaki, Kohei Fujikura, Shintaro Goto, Ryohei Ito, Koki Takagi, Tomoyuki Tanaka, Hiroshi Kijima, Kosei Kubota, Ken Itoh, Wataru Kobayashi, Koichi Takahashi

Faculty, Staff and Student Publications

Lymph node metastasis (LNM) is a critical prognostic factor for patients with oral squamous cell carcinoma (OSCC). Previous research has implicated the partial epithelial-to-mesenchymal transition of tumor cells and myofibroblastic cancer-associated fibroblasts (myCAFs) in the LNM process. However, the underlying molecular mechanisms remain poorly understood. Here, we conducted a comprehensive molecular analysis integrating original and publicly available OSCC data from bulk genome and transcriptome, single-cell transcriptome, and spatial transcriptome analyses. We found that myCAFs were quantitatively and functionally activated in LNM-positive samples and spatially colocalized with OSCC cells within the invasive tumor front (ITF), providing a niche that may facilitate …

Dna Methylation Cooperates With Genomic Alterations During Non-Small Cell Lung Cancer Evolution, Francisco Gimeno-Valiente, Carla Castignani, Elizabeth Larose Cadieux, Nana E Mensah, Xiaohong Liu, Kezhong Chen, Olga Chervova, Takahiro Karasaki, Clare E Weeden, Corentin Richard, Siqi Lai, Carlos Martínez-Ruiz, Emilia L Lim, Alexander M Frankell, Thomas B K Watkins, Georgia Stavrou, Ieva Usaite, Wei-Ting Lu, Daniele Marinelli, Sadegh Saghafinia, Gareth A Wilson, Pawan Dhami, Heli Vaikkinen, Jonathan Steif, Selvaraju Veeriah, Robert E Hynds, Martin Hirst, Crispin Hiley, Andrew Feber, Özgen Deniz, Mariam Jamal-Hanjani, Nicholas Mcgranahan, Tracerx Consortium, Stephan Beck, Jonas Demeulemeester, Miljana Tanić, Charles Swanton, Peter Van Loo, Nnennaya Kanu

Faculty, Staff and Student Publications

Aberrant DNA methylation has been described in nearly all human cancers, yet its interplay with genomic alterations during tumor evolution is poorly understood. To explore this, we performed reduced representation bisulfite sequencing on 217 tumor and matched normal regions from 59 patients with non-small cell lung cancer from the TRACERx study to deconvolve tumor methylation. We developed two metrics for integrative evolutionary analysis with DNA and RNA sequencing data. Intratumoral methylation distance quantifies intratumor DNA methylation heterogeneity. MR/MN classifies genes based on the rate of hypermethylation at regulatory (MR) versus nonregulatory (MN) CpGs to identify driver genes exhibiting recurrent functional …

In Situ Programming Of The Tumor Microenvironment To Alleviate Immunosuppression For Pancreatic Cancer Immunotherapy, Man Sun, Huan Zhang, Yarui Ma, Simiao Wang, Jiayi Chen, Yaxin Cui, Yun Zhang, Siyuan Hu, Dan Zhou, Pengchen Zhang, Yahui Liu, Betty Y S Kim, Wen Jiang, Xiaobing Wang, Zhaogang Yang

Faculty, Staff and Student Publications

Recent studies have highlighted the pivotal role of the cGAS‐STING pathway in cancer immunotherapy. However, clinical trials with cGAS‐STING pathway agonists have faced setbacks thanks to their short biological half‐life, lack of tumor specificity, and potential to promote tumor immune evasion. To address these challenges, a novel exosome‐based drug delivery platform, termed cmExoaCD11b is developed, designed to precisely target and reprogram the tumor microenvironment (TME) in situ for pancreatic cancer immunotherapy. cmExoaCD11b is engineered to encapsulate high copy numbers of IL‐12 mRNA and 2′3’‐cGAMP (cGAMP) and is functionalized with CD11b antibodies for targeted delivery to macrophages. Notably, cmExoaCD11b facilitated the …

Sex Disparities In Chlamydia And Gonorrhea Treatment In Us Adult Emergency Departments: A Systematic Review And Meta-Analysis, Rachel E Solnick, Rahi Patel, Ethan Chang, Carmen Vargas-Torres, Maaz Munawar, Carlin Pendell, Judith E Smith, Ethan Cowan, Keith E Kocher, Roland C Merchant

Faculty, Staff and Student Publications

BACKGROUND: Empiric antibiotic treatment for gonorrhea (GC) and chlamydia (CT) is common in U.S. emergency departments (EDs) due to the delayed availability of test results. Local studies have identified sex-based disparities in sexually transmitted infection (STI) care, with females potentially receiving less empiric treatment than males. This study evaluates how STI treatment aligns with laboratory-confirmed results to quantify potential overtreatment and undertreatment rates and investigates sex differences for these outcomes.

METHODS: We conducted a preregistered (PROSPERO #241429) systematic review and meta-analysis of studies published between January 2010 and January 2025 in U.S. EDs, excluding studies conducted exclusively in pediatric settings. …

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

Faculty, Staff and Student Publications

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

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

Faculty, Staff and Student Publications

No abstract provided.

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

Faculty, Staff and Student Publications

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

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

Faculty, Staff and Student Publications

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

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

Faculty, Staff and Student Publications

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

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

Faculty, Staff and Student Publications

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

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

Faculty, Staff and Student Publications

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

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

Faculty, Staff and Student Publications

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

Predictors Of Perceived Hiv Stigma Among People Who Inject Drugs In The United States, Itunu Sokale, Paige Wermuth, Johnny Wilkerson, Folefac Atem, Salma Khuwaja, Catherine Troisi

Faculty, Staff and Student Publications

Background: HIV stigma is a huge impediment to ending the HIV epidemic. To develop effective HIV interventions, we must determine factors associated with HIV stigma, particularly among high-risk groups like people who inject drugs (PWID). We aimed to identify predictors of perceived HIV stigma (PHS) among a sample of PWID from 23 U.S. cities.

Methods: We analyzed the 2018 National HIV Behavioral Surveillance data on PWID aged ≥ 18 years. PHS was assessed using a validated survey that measured four PHS constructs: perceived unfriendliness, perceived discrimination, perceived punishment, and perceived support. We created a composite PHS index score by summing …

Zika In Infants And Pregnancy (Zip) Study: Results From A Prospective International Cohort Study Of Prenatal Zika Virus Infection And Adverse Fetal And Infant Outcomes, Jill Farnell Lebov, Martha Nason, Kristen B Stolka, Ricardo Ximenes, Marisa M Mussi-Pinhata, Jack Moye, Carmen D Zorrilla, Carmen M Velez Vega, José F Cordero, Deolinda M F Scalabrin, Albert I Ko, Maria Elisabeth Lopes Moreira, Luiz Augusto Galvão, William Britt, Ernesto T A Marques, Angel Balmaseda, Eva Harris, Juan F Arias, Stacey Schultz-Cherry, Ana Lucía Garces, Nancy F Krebs, Theresa J Ochoa, César Augusto Ugarte-Gil, Elizabeth Fogleman, Erin Gabriel, Michael Welton, Carmen M Irizarry, Silvia Biason De Moura Negrini, Conrado Milani Coutinho, Demócrito De Barros Miranda-Filho, Ulisses Ramos Montarroyos, Marli Tenorio Cordeiro, Anna Gajewski, Jorge E Osorio, Lester Figueroa

Faculty, Staff and Student Publications

Background: Before Zika virus (ZIKV) infections were observed in the Americas, an association between ZIKV and microcephaly or other congenital malformations was not well documented. Initial reports suggested strong associations between ZIKV and congenital malformations, but plausible estimates of causal effects from prospective studies with adequate sample size and covariate data were few.

Methods: From 2016-2018, the Zika in Infants and Pregnancy (ZIP) study enrolled pregnant people before 18 weeks gestation or with confirmed symptomatic ZIKV in a prospective cohort across 10 sites in South and Central America, and in Puerto Rico. Pregnancies were followed monthly through delivery and 6 …

Whole-Genome Sequence-Based Association Analysis Of African American Individuals With Bipolar Disorder And Schizophrenia, Runjia Li, Sarah A Gagliano Taliun, Kevin Liao, Matthew Flickinger, Janet L Sobell, Giulio Genovese, Adam E Locke, Rebeca Rothwell Chiu, Jonathon Lefaive, Jiongming Wang, Taylor Martins, Sinéad Chapman, Anna Neumann, Robert E Handsaker, Donna K Arnett, Kathleen C Barnes, Eric Boerwinkle, David Braff, Brian E Cade, Myriam Fornage, Richard A Gibbs, Karin F Hoth, Lifang Hou, Charles Kooperberg, Ruth J F Loos, Ginger A Metcalf, Courtney G Montgomery, Alanna C Morrison, Zhaohui S Qin, Susan Redline, Alexander P Reiner, Stephen S Rich, Jerome I Rotter, Kent D Taylor, Karine A Viaud-Martinez, Tim B Bigdeli, Stacey Gabriel, Sebastian Zollner, Albert V Smith, Goncalo Abecasis, Steve A Mccarroll, Michele T Pato, Carlos N Pato, Michael Boehnke, James Knowles, Hyun Min Kang, Roel A Ophoff, Jason Ernst, Laura J Scott

Faculty, Staff and Student Publications

In studies of individuals of primarily European genetic ancestry, common and low-frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole-genome sequencing (∼27X) of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study). We increased power by incorporating 14,812 jointly called psychiatrically unscreened ancestry-matched controls from the Trans-Omics for Precision Medicine (TOPMed) Program for a total of …

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

Faculty, Staff and Student Publications

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

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

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

Faculty, Staff and Student Publications

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

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

Faculty, Staff and Student Publications

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

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

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

Faculty, Staff and Student Publications

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

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

Faculty, Staff and Student Publications

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

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

Faculty, Staff and Student Publications

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

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

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

Faculty, Staff and Student Publications

Not available.

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

Faculty, Staff and Student Publications

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

Low-Level Pm2.5 Exposure And Mortality In The Medicare Cohort: The Role Of Native American Beneficiaries, Judy Wendt Hess, Wenyaw Chan

Faculty, Staff and Student Publications

Fine particulate matter (PM2.5) has been associated with mortality at low concentrations, with higher per-unit risk at lower exposure levels, and no threshold of effect. We examined characteristics of Medicare decedents living in zip codes at the lowest end of the U.S. PM2.5 exposure distribution to determine whether there is a demographic, health or exposure profile of beneficiaries for whom even low PM2.5 exposure is associated with increased mortality. The study included 2,773,647 decedent cases and 27,736,470 non-decedent controls, matched on decile of long-term PM2.5 exposure from among 36 million Medicare fee-for-service beneficiaries enrolled 2015–2016. Outcomes of the study included …

Exploring Lingering Covid-19 Vaccine Hesitancy In Three Diverse U.S. States: Alabama, Illinois, And Texas, Sinan Almukhtar, Noah Mcwhirter, Anaïs Mendiola, Shekwonya Samuel, Olivia Dominguez, Danielle Pester Boyd, Stephen Flores, Pooja Gandhi, Francis Kazungu, Manorama Khare, Paula Cuccaro, Maria E Fernández, Ronald C Hershow, Sage Kim, Emily Stiehl

Faculty, Staff and Student Publications

During the COVID-19 pandemic, vaccine uptake was slower than expected, with some people experiencing concern about the safety and effectiveness of the COVID-19 vaccine even after being vaccinated. This manuscript explores a phenomenon called lingering hesitancy, or the concern that people experience even after receiving an initial dose of a vaccine. Leveraging survey findings from three individual Prevention Research Centers (PRCs) in Alabama, Illinois, and Texas, we compare the attitudes of individuals across three vaccine status groups: those who received their complete COVID-19 vaccine series, those who received an initial dose but no subsequent doses (lingering hesitancy), and those who …