Medical Specialties Commons^™

Rnai-Based Screen For Pigmentation In Drosophila Melanogaster Reveals Regulators Of Brain Dopamine And Sleep, Samantha L Deal, Danqing Bei, Shelley B Gibson, Harim Delgado-Seo, Yoko Fujita, Kyla Wilwayco, Elaine S Seto, Amita Sehgal, Shinya Yamamoto

Faculty, Staff and Students Publications

The dopaminergic system has a large role in behavior and neurological disease, and understanding dopamine level regulation in vivo is critical. To identify dopamine regulators, we utilized Drosophila melanogaster cuticle pigmentation, where dopamine is a precursor to melanin. We measured dopamine from known pigmentation mutants (e.g., tan, ebony, black) and performed an RNAi-based screen to identify additional regulators. We found 153 hits, enriched for developmental signaling pathways and mitochondria-associated proteins. From 35 prioritized candidates, 11 affected head dopamine levels. Effects on brain dopamine were mild, even knocking down the rate-limiting synthesis enzyme Tyrosine hydroxylase (TH), suggesting …

Epigenome-Wide Association Study Meta-Analysis Of Bmi In African Americans, Kendra Ferrier, Mariaelisa Graff, Iain R Konigsberg, Maggie Stanislawski, Heather M Highland, Laura M Raffield, April P Carson, Eric Boerwinkle, Jill M Norris, Chris R Gignoux, Audrey E Hendricks, Sridharan Raghavan, Kari E North, Kristin L Young, Anne E Justice, Matthew A Allison, Mathew J Budoff, Silva Kasela, François Aguet, Joshua J Joseph, Charles Kooperberg, Stephen S Rich, Jerome I Rotter, Ethan M Lange, Leslie A Lange

Faculty, Staff and Student Publications

Despite considerable advances in identifying risk factors for obesity, gaps remain in our understanding about its etiology. Genetic variants explain only a small portion of variation in obesity-related traits such as body mass index (BMI). Epigenetic regulation, which controls gene expression and is influenced by environmental and genetic factors, may account for additional variability in BMI. Epigenetic studies of BMI have largely been conducted in European ancestry populations, despite the disproportionate burden of obesity in African Americans (AAs). We conducted a sex-stratified BMI epigenome-wide association study meta-analysis in AA participants from the Jackson Heart Study (n = 1,604) and …

Dna Methyltransferase Inhibitors In Hematological Malignancies And Solid Tumors, Valentin Wenger, Guillermo Garcia-Manero, Robert Zeiser, Michael Lübbert

Faculty, Staff and Student Publications

Epigenetic modifications such as DNA methylation play a fundamental role in oncogenesis and the progression of neoplasms neoplasias. DNA methyltransferase inhibitors (DNMTi) constitute a family of therapeutic agents that impede the methylation at the 5-position on cytosine nucleotides, thereby modulating the epigenetic regulation of tumor suppressor genes, oncogenes, and other key regulatory genes. The first-generation DNMTi azacitidine and decitabine have demonstrated substantial efficacy in the treatment of medically non-fit, older patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy (IC), by virtue of their favorable safety profile. Despite these clinical achievements, however, single-agent DNMTi treatment …

C Elegans As A Tractable Infection Model For The Emerging Fungal Pathogen Candida Auris, Melissa Martinez, Melissa R Cruz, Danielle A Garsin, Michael C Lorenz

Faculty, Staff and Student Publications

Candida auris is an emerging multidrug-resistant fungal pathogen. The genetic factors contributing to the virulence, drug resistance, and stress-tolerant nature of C. auris are mostly unknown. Additional animal models of virulence are needed, especially those amenable to high-throughput analysis. The nematode Caenorhabditis elegans has been validated as an effective tool for studying multiple fungal and bacterial pathogens. We describe here a C. elegans infection model in which exposure to C. auris is lethal to worms with kinetics similar to killing by Candida albicans; in contrast to C. albicans, C. auris does not form hyphae, indicating distinct virulence mechanisms. …

Bdcd: A Comprehensive Brain Disease Cell-Cell Communication Database, Xinyi Liu, Citu Citu, Gang Qu, Wendao Liu, Nitesh Enduru, Andi Liu, Chia-Hao Tung, Zhongming Zhao

Faculty, Staff and Student Publications

Dysregulated cell–cell communication (CCC) is increasingly recognized as a driver of brain disease pathology, contributing to neuroinflammation, synaptic dysfunction, and neurodegeneration. Nevertheless, existing resources remain limited in brain specificity, regional coverage, and functional annotation. To address this gap, we develop the Brain Disease Cell-cell communication Database (BDCD), the first comprehensive resource focused on CCC networks across major brain diseases. BDCD integrates 38 manually curated datasets, comprising 8 519 425 single cells from single-cell RNA-seq studies and 140 744 spots from spatial transcriptomic maps, spanning 14 brain regions and 13 canonical cell types covering Alzheimer’s disease, Parkinson’s disease, schizophrenia, bipolar disorder, …

Bridging Hypoxia And Vision Loss: The Emerging Role Of Connexins In Local And Systemic Eye Diseases, Xianping Zhang, Yalong Cheng, Jean X Jiang, Yuting Li

Faculty, Staff and Student Publications

Hypoxic eye diseases represent a pivotal yet often underappreciated contributor to the onset and progression of many retinal disorders. When hypoxia persists or exceeds the tissue's compensatory capacity, it triggers pathological retinal neovascularization, blood-retinal barrier disruption, and neuronal apoptosis, ultimately resulting in irreversible visual impairment. Connexins (Cxs) form gap junction channels and hemichannels and regulate retinal cell proliferation, differentiation, and survival, thereby playing a central regulatory role in the pathogenesis of hypoxic ocular diseases. In addition to gap junctions, Cx hemichannels promote transmission of molecules between intra- and extracellular environments, further influencing retinal homeostasis under hypoxic stress. This review synthesizes …

The Impact Of Indigenous American-Like Ancestry On The Risk Of Acute Lymphoblastic Leukemia In Hispanic/Latino Children, Jalen Langie, Tsz Fung Chan, Wenjian Yang, Alice Y Kang, Libby Morimoto, Daniel O Stram, Nicholas Mancuso, Xiaomei Ma, Catherine Metayer, Philip J Lupo, Karen R Rabin, Michael E Scheurer, Joseph L Wiemels, Jun J Yang, Adam J De Smith, Charleston W K Chiang

Faculty, Staff and Students Publications

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with Hispanic/Latino children having a higher incidence of ALL than other racial/ethnic groups. Among the genetic variants previously implicated in ALL risk, a number of them were found to be enriched in Indigenous American (IA)-like ancestries and inherited by many Hispanic/Latino individuals. However, due to potential confounding from environmental factors, the association between IA-like ancestry and risk for ALL has remained unclear. In this study, we characterized the impact of IA-like ancestry on overall ALL risk and on the frequency and effect size of known risk alleles, while accounting for …

Ophiobolin A Impacts Mitochondrial Redox Biology In An Epithelial-Mesenchymal Transition (Emt)-Specific Manner, Haleigh N Parker, Yongfeng Tao, Jenna Tobin, Kayla L Haberman, Samantha Davis, Emily York, Alysia Martinez, Nobuyuki Matsumoto, Jaquelin Aroujo, Jun Hyoung Park, Bernd Zechmann, Benny Abraham Kaipparettu, Angela Boari, Christie M Sayes, Antonio Evidente, Alexander Kornienko, Benjamin Cravatt, Daniel Romo, Joseph H Taube

Faculty, Staff and Students Publications

Breast cancer progression is facilitated by the epithelial to mesenchymal transition (EMT), generating cancer cells with enhanced metastatic capacity and resistance to chemotherapeutics. The fungus-derived sesterterpenoid natural produce compound, ophiobolin A (OpA), possesses nanomolar cytotoxic activity and a high therapeutic index, although its molecular targets and mechanism of action are not well characterized. Herein, we utilized a model of mammary epithelial cells and breast cancer cell lines with and without EMT features to characterize the mechanism of selectivity towards EMT(+) cells by OpA. Proteins interacting with OpA in EMT(+) cells, including mitochondrial glutathione transporter SLC25A40, were identified through via mass …

Progress And Challenges In Profiling Protein-Rna And Protein-Associated Rna-Rna Interactions, Zhuoyi Song, Eric L Van Nostrand

Faculty, Staff and Students Publications

RNA binding proteins (RBPs) play essential roles in post-transcriptional gene regulation by interacting with a wide range of RNA targets. In addition to regulating RNA processing via individual RBP-RNA interactions, there is a growing appreciation of the regulatory impact of protein-associated RNA-RNA interactions that include both well-studied examples of small regulatory RNAs (e.g. microRNAs, snRNAs, snoRNAs, piRNAs) guiding ribonucleoprotein complexes to their targets as well as structured RNA elements defining the interaction landscape for an RBP. To elucidate the full scope of RBP-RNA interactions, CLIP ( crosslinking and immunoprecipitation)-based methods have emerged as powerful tools. Even with the wide application …

Prevalence And Outcomes Of Her2-Low Versus Her2-0 Status In Patients With Metastatic Breast Cancer, Akshara Singareeka Raghavendra, Diane D Liu, Senthil Damodaran, Sarah Pasyar, Yu Shen, Jason A Mouabbi, Carlos H Barcenas, Kelly K Hunt, Debu Tripathy

Faculty, Staff and Student Publications

Background: HER2-low breast cancer (HER2 immunohistochemical [IHC] score 1+, or IHC 2+ without HER2 gene amplification) is distinct from HER2-positive and HER2-0 breast cancer (IHC 0), with a differing prognosis and specific therapeutic options. The DESTINY-Breast04 trial demonstrated notable efficacy of the HER2 antibody-drug conjugate trastuzumab deruxtecan over standard chemotherapy in patients with metastatic breast cancer (MBC) defined as HER2-low. More recently, the DESTINY-Breast06 trial confirmed this benefit in hormone receptor-positive and HER2-ultralow (less than 1+, but with ≤10% of infiltrating cancer cells showing incomplete and faint/weak membrane staining) cases, prompting re-evaluation of HER2 diagnostic thresholds and treatment strategies.

Methods …

Understanding The Compatibility Of Fluoride-Based Radiopharmaceutical Reaction Solutions And Pdms, Mark Mc Veigh, Charles Frech, Mai Lin, Robert Ta, H Charles Manning, Leon M Bellan

Faculty, Staff and Student Publications

Microfluidic devices offer unique and exciting benefits when applied to radiopharmaceutical manufacturing, and these platforms are now starting to be integrated into commercial products. The field has strayed away from the use of polydimethylsiloxane (PDMS), the most common microfluidic device material, due to its suspected incompatibility with 18F, the most commonly used radionuclide. However, existing literature provides conflicting conclusions as to the existence and extent of this incompatibility. In this study, we use several analytical instruments to uncover the underlying interaction between fluoride and PDMS. SEM imaging and profilometry confirm the reactive relationship between the two materials and suggest that …

Autograft Enlargement After The Ross Procedure In Pediatric Patients: Somatic Growth Or Pathologic Dilatation?, Ioannis Zoupas, Alexander C Mills, Scott D Olson, Damien J Lapar

Faculty, Staff and Student Publications

Purpose of ReviewPulmonary autograft autotransplantation represents a popular surgical approach for pediatric patients requiring aortic valve replacement due to the potential for autograft enlargement to accommodate somatic growth. Nevertheless, autograft dilatation and the subsequent need for reintervention are quite common. Published data suggest that autograft enlargement may result from pathological passive remodeling rather than active somatic growth and vice versa. The present review serves to comprehensively evaluate available evidence related to the fate of the pulmonary autograft after the Ross procedure as it relates to the etiology, risk factors and patterns of autograft failure.ResultsStudies present conflicting results supporting both pathological …

Diet-Responsive Genetic Determinants Of Intestinal Colonization In The Yeast Candida Albicans, Musfirat Shubaita, Mazen Oneissi, Elena Lindemann-Pérez, Cecilia Fadhel Alvarez, Anne-Marie Krachler, Diana M Proctor, J Christian Pérez

Faculty, Staff and Student Publications

Dietary components influence microbial composition in the digestive tract. Although often viewed as energy sources, dietary components are likely to shape microbial determinants of intestinal colonization beyond metabolism. Here, we report that a dietary long-chain fatty acid enhances the yeast Candida albicans colonization of the murine gut partly by eliciting modifications to the fungal cell surface. Mice fed an oleic acid-rich diet were readily colonized by C. albicans and exhibited higher fungal load in feces compared with rodents fed an isocaloric control diet. Surprisingly, β-oxidation, a catabolic process to break down fatty acids for energy production, was dispensable for C. …

Resolution Of A Human Chromosomal Mystery: Evolutionary Complexity Revealed, Jeffrey Rogers

Faculty, Staff and Students Publications

The human complement of chromosomes differs from our closest primate relatives by virtue of a unique chromosome fusion event. In this issue of Cell Genomics, Yang et al. provide the first detailed analysis of the site of chromosome fusion and reconstruct the complex evolutionary relationships among the genomic elements within the human fusion site and their related sequences in our great ape relatives.

Therapeutic Responses In Patients With Advanced Nsclc Enrolled In Early-Phase Clinical Trials At Md Anderson, Jeong Uk Lim, Heather Y Lin, Lei Kang, Hung Le, Tin-Yun Tang, Stephane Champiat, Ecaterina Elena Dumbrava, Xiuning Le, Aung Naing, Sarina A Piha-Paul, Jordi Rodon Ahnert, Apostolia Maria Tsimberidou, Timothy A Yap, Siqing Fu, Funda Meric-Bernstam, David S Hong

Faculty, Staff and Student Publications

We evaluated clinical outcomes and safety profiles in patients with non-small cell lung cancer (NSCLC) treated in early-phase trials. A retrospective review of 546 NSCLC cases treated from January 2016 to December 2024 at The University of Texas MD Anderson Cancer Center was performed using the MD Anderson CHIMERA database. Patients were categorized into seven groups based on treatment regimen. The overall objective response rate (ORR) was 19.9%, and the highest ORRs were in the targeted combination (30.8%) and targeted monotherapy (29.7%) groups. Gene alteration–matched therapy, serum albumin level, metastatic burden, treatment group, and liver metastasis were independently associated with …

Genome-Wide Gene By Sleepiness Interaction Analysis For Sleep Apnea, Pavithra Nagarajan, Nuzulul Kurniansyah, Jiwon Lee, Sina A Gharib, Yushan Xu, Yiyan Zhang, Brian Spitzer, Tariq Faquih, Hufeng Zhou, Eric Boerwinkle, Han Chen, Daniel J Gottlieb, Xiuqing Guo, Nancy L Heard-Costa, Bertha A Hidalgo, Daniel Levy, Peter Y Liu, Hao Mei, Rebecca Montalvan, Sutapa Mukherjee, Kari E North, George T O'Connor, Lyle J Palmer, Sanjay R Patel, Bruce M Psaty, Shaun M Purcell, Laura M Raffield, Stephen S Rich, Jerome I Rotter, Richa Saxena, Albert V Smith, Katie L Stone, Xiaofeng Zhu, Topmed Sleep Trait Working Group, Brian E Cade, Tamar Sofer, Susan Redline, Heming Wang

Faculty, Staff and Student Publications

Study objectives: Excessive daytime sleepiness (EDS), influenced by environmental and social-behavioral factors, is reported by a subset of patients with sleep apnea-a group that may be at elevated cardiovascular risk. However, it is unclear whether sleep apnea with and without EDS have distinct genetic underpinnings. In this study, we perform gene-by-EDS interaction analyses for apnea hypopnea index, a diagnostic marker of sleep apnea severity, to understand EDS's influence on its underlying genetic risk.

Methods: Discovery interaction analyses for common variants and gene-based rare variants were conducted respectively using multi-ethnic Trans-Omics for Precision Medicine (N = 11 619) data, followed by …

Workflow Improvements From Automated Large Vessel Occlusion Detection Algorithms Are Dependent On Care Team Engagement, Emmanuel C Ebirim, Ngoc Mai Le, Joseph N Samaha, Hussain Azeem, Ananya Iyyangar, Anjan N Ballekere, Saagar Dhanjani, Luca Giancardo, Eunyoung Lee, Sunil A Sheth

Faculty, Staff and Student Publications

Background: Automated machine learning (ML)-based large vessel occlusion (LVO) detection algorithms have been shown to improve in-hospital workflow metrics including door-to-groin time (DTG). The degree to which care team engagement and interaction are required for these benefits remains incompletely characterized.

Methods: This analysis was conducted as a pre-planned post-hoc analysis of a randomized prospective clinical trial. ML-based LVO detection software was implemented at four comprehensive stroke centers (CSCs) from January 1, 2021, to February 27, 2022. Patients were included if they underwent endovascular thrombectomy for LVO acute ischemic stroke. ML software utilization was quantified as the total number of active …

Mini-Hyper-Cvd Plus Venetoclax And Navitoclax For Relapsed/Refractory Acute Lymphoblastic Leukemia, Nicholas J Short, Hagop Kantarjian, Nitin Jain, Tapan M Kadia, Jayastu Senapati, Fadi G Haddad, Manuel M Maroun, Koji Sasaki, Lianchun Xiao, Xuelin Huang, Omer Karrar, Regina Abramova, Min Zhao, Rebecca Garris, Marina Konopleva, Farhad Ravandi, Elias Jabbour

Faculty, Staff and Student Publications

No abstract provided.

The Biomedical Landscape Of Genomic Structural Variation In The Qatari Population, Elbay Aliyev, Najeeb Syed, Alessia Visconti, Taghi Aliyev, Aziz Belkadi, Mohammadmersad Ghorbani, Niccolò Rossi, Haroon Naeem, Geethanjali Devadoss Gandhi, Gaurav Thareja, Aljazi Al-Maraghi, Waleed Aamer, Amal Abdulsalam Ibrahim, Rulan Shaath, Farooq Omar Al-Ajli, Rozaimi Mohamad Razali, Fritz J Sedlazeck, Sonia Davila, Ammira Akil, Karsten Suhre, Younes Mokrab, Mario Falchi, Khalid A Fakhro

Faculty, Staff and Students Publications

We present a large-scale study of structural variation (SV) in the Qatari population, based on short-read whole-genome sequencing (WGS) of 6,141 individuals, identifying 153,946 variants across 5 classes reflecting the region's diversity and evolutionary history. Leveraging consanguinity and biobank phenotypes, we identify >180 putative gene knockouts, and use proteomics to show functional consequences in homozygotes. Conversely, 52 genes show significant depletion of homozygous deletions, eight of which cause severe pediatric disease or murine embryonic lethality. Examining phenotypic extremes uncovers several non-exonic homozygous deletions with large effect, including in SPIRE2 (creatinine), MAGI2 (leanness) and a chr19 microRNA cluster (extreme obesity). Further, …

Spatial Omics At The Forefront: Emerging Technologies, Analytical Innovations, And Clinical Applications, Yunhe Liu, Yibo Dai, Linghua Wang

Faculty, Staff and Student Publications

Spatial omics transforms our understanding of cancer by revealing how tumor cells and the microenvironment are organized, interact, and evolve within tissues. Here, we synthesize advances in spatial technologies that map tumor ecosystems with unprecedented fidelity. We highlighted analytical breakthroughs-including multimodal integration and emerging spatial foundation models-that resolve functional niches and spatial communities, converting spatial patterns into mechanistic insights. We summarize how spatially organized features, from immune hubs to microbiota and neural interfaces, shape tumor evolution and clinical outcomes. We then outline how spatial approaches illuminate precancer biology, metastatic adaptation, and therapy response. Bridging discovery and translation, we provide a …

Tet2-Mutant Clonal Hematopoiesis Enhances Macrophage Antigen Presentation And Improves Immune Checkpoint Therapy In Solid Tumors, Shelley Herbrich, Mehdi Chaib, Swetha Anandhan, Samuel W Andrewes, Ashwat Nagarajan, Baoxiang Guan, Nishant Gandhi, Jared Gilliam, Milan Radovich, Padmanee Sharma

Faculty, Staff and Student Publications

Clonal hematopoiesis (CH) is detectable in upwards of 20% of patients with solid tumors and is associated with worsened prognosis; however, its role in tumor immunology and immune checkpoint therapy (ICT) is unknown. Using a bone marrow chimera model of Tet2+/mut CH in mice with solid tumors, we found the Tet2-mutant myeloid cells are abundant in the tumor microenvironment and contributed to an improved response to ICT. Mechanistically, Tet2+/mut macrophages inside the tumor act as immunogenic antigen-presenting cells that more effectively cross-prime naive CD8+ T cells in response to IFNγ. In human cohorts of 35,971 non-small cell lung cancer patients …

Tumor-Infiltrating Bacteria Disrupt Cancer Epithelial Cell Interactions And Induce Cell-Cycle Arrest, Jorge Luis Galeano Niño, Falk Ponath, Victor A Ajisafe, Clara R Becker, Andrew G Kempchinsky, Martha A Zepeda-Rivera, Javier A Gomez, Hanrui Wu, Jessica G Terrazas, Heather Bouzek, Elizabeth Cromwell, Pritha Chanana, Matthew Wong, Ashish Damania, Michael G White, Y Nancy You, Scott Kopetz, Nadim J Ajami, Jennifer A Wargo, Christopher D Johnston, Susan Bullman

Faculty, Staff and Student Publications

Tumor-infiltrating bacteria are increasingly recognized as modulators of cancer progression and therapy resistance. We describe a mechanism by which extracellular intratumoral bacteria, including Fusobacterium, modulate cancer epithelial cell behavior. Spatial imaging and single-cell spatial transcriptomics show that these bacteria predominantly localize extracellularly within tumor microniches of colorectal and oral cancers, characterized by reduced cell density, transcriptional activity, and proliferation. In vitro, Fusobacterium nucleatum disrupts epithelial contacts, inducing G0-G1 arrest and transcriptional quiescence. This state confers 5-fluorouracil resistance and remodels the tumor microenvironment. Findings were validated by live-cell imaging, spatial profiling, mouse models, and a 52-patient colorectal cancer cohort. Transcriptomics reveals …

Adipose Stromal Cell-Derived Cancer-Associated Fibroblasts Promote Pancreatic Adenocarcinoma Progression Through Sfrp4 Signaling, Joseph Rupert, Lingyi Cai, Alexes C Daquinag, Dimitris Anastassiou, Mikhail G Kolonin

Faculty, Staff and Student Publications

Background/objectives: Progression of pancreatic ductal adenocarcinoma (PDAC) and other carcinomas relies on cancer-associated fibroblasts (CAFs). A subset of CAFs is derived from adipose stromal cells (ASCs) recruited by tumors and the ASC-CAF conversion has been associated with invasiveness and poor prognosis.

Methods: To explore the underlying molecular mechanisms, we used a model based on primary ASCs derived from human visceral adipose tissue co-cultured with human PDAC cell line Capan-1. To investigate cancer progression in vivo, we also used mice orthotopically grafted with mouse KPC cells.

Results: Genomic analysis revealed that Capan-1 co-culture induces Wnt and TGFβ signaling and extracellular matrix …

Chek2 Loss Endows Chemotherapy Resistance To Hematopoietic Stem Cells, Jing Zhou, Tianyuan Hu, Dian Li, Sanming Li, Minhua Li, Xiangguo Shi, Daisuke Nakada

Faculty, Staff and Students Publications

Individuals with history of chemo- or radiotherapy frequently exhibit somatic mosaicism in the blood, often involving mutations in genes responsible for DNA damage responses (DDR), such as CHEK2. However, the mechanisms by which CHEK2 mutations promote the expansion of mutant cells following chemo- or radiotherapy remain poorly understood. Here, we demonstrate that loss of CHEK2 confers resistance to chemotherapy in hematopoietic stem and progenitor cells (HSPCs). Through a CRISPR-based screen, we identified CHEK2 as a gene whose loss enhances resistance to cytotoxic chemotherapies. A complementary drug screen revealed that CHEK2-mutant cells are also resistant to DNA hypomethylating agents. Chek2-deficient HSPCs …

Il-18 Metabolically Reprograms Car-Expressing Natural Killer T Cells And Enhances Their Antitumor Activity, Gabriel A Barragán Bravo, David A De La Cerda, Elisa Landoni, Kshiti Dholakia, Piotr Humeniuk, Leidy D Caraballo Galva, Ying Wang, Gengwen Tian, Boning Yang, Linjie Guo, Michael S Wood, Xavier Rios, Xin Xu, Amy N Courtney, Erica J Di Pierro, Joan Jacob, Yi-Han Li, Akshaya Adaikkalavan, Norihiro Watanabe, Sufeng Mao, George Miles, Gianpietro Dotti, Leonid S Metelitsa

Faculty, Staff and Students Publications

Invariant natural killer T cells (NKTs) have intrinsic anti-tumor properties that make them promising candidates for chimeric antigen receptor (CAR) immunotherapies. Transgenic cytokine expression can enhance cellular therapy potency, and we hypothesized that co-expressing IL-18 alone or with IL-15 would boost CAR-NKT therapeutic potential. To test this, we generated retroviral constructs expressing IL-15 and/or IL-18 with an inducible caspase 9 safety switch and co-transduced them with a GD2-specific CAR into human NKTs. Co-expression of IL-18 or IL-15/IL-18 increased CAR-NKT cytotoxicity, proliferation, and cytokine secretion in vitro compared to IL-15 alone. IL-18 also enhanced GPC3.CAR and CD19.CAR NKT activity against hepatocellular …

Flipi24: A Modern Prognostic Model And Clinical Trial Enrichment Tool For Newly Diagnosed Follicular Lymphoma, Matthew J Maurer, Vit K Prochazka, Tarec Christoffer El-Galaly, Christopher R Flowers, Diego Villa, Emmanuel Bachy, Elliot J Cahn, Marguerite Fournier, Melissa C Larson, Caroline E Dietrich, Lasse Hjort Jakobsen, Hervé Ghesquières, Robert Kridel, Maher K Gandhi, Chan Y Cheah, Eliza A Hawkes, John F Seymour, Ciara L Freeman, Michael R Clausen, Björn E Wahlin, Jonathan W Friedberg, Carla Casulo, Thomas M Habermann, Yucai Wang, Loretta J Nastoupil, Peter De Nully Brown, David Belada, Andrea Janíková, Heidi Mocikova, Tomáš Fürst, Pierre Feugier, Hervé Tilly, Corinne Haioun, Andrew J Davies, Guillaume Cartron, Richard Burack, Dai Chihara, Peter Martin, Jonathon B Cohen, Izidore S Lossos, Brad S Kahl, Laurie H Sehn, Karin E Smedby, Gilles Salles, Marek Trneny, Brian K Link, Franck Morschhauser, James R Cerhan

Faculty, Staff and Student Publications

Purpose: Although most patients with follicular lymphoma (FL) can expect an indolent course, progressive lymphoma remains the primary cause of death during the first decade after diagnosis. Progression of disease within 24 months (POD24) of starting first-line (1L) immunochemotherapy defines a high-risk population with poor survival, but better risk stratification at diagnosis is needed.

Methods: The FLIPI24 model was developed and internally validated to predict 24-month event rates using individual data from 4,485 patients treated with 1L immunochemotherapy from 10 observational cohorts of FL. Overall and cause-specific survival was further evaluated in FLIPI24 risk groups. External validation in the 1L …

Proton Versus Photon Radiotherapy For Patients With Oropharyngeal Cancer In The Usa: A Multicentre, Randomised, Open-Label, Non-Inferiority Phase 3 Trial, Steven J Frank, Paul M Busse, J Jack Lee, David I Rosenthal, Mike Hernandez, David M Swanson, Adam S Garden, G Brandon Gunn, Samir H Patel, James W Snider, Daniel J Ma, Jason K Molitoris, Nancy Y Lee, Upendra Parvathaneni, Mark W Mcdonald, Noah S Kalman, Alexander Lin, Nasiruddin Mohammed, Christina Henson, Christian Hyde, Gopal K Bajaj, Sanford R Katz, Roi Dagan, William H Morrison, Jay P Reddy, C David Fuller, Shalin J Shah, Jack Phan, Gregory M Chronowski, Lauren Mayo, Erich M Sturgis, Renata Ferrarotto, Xiaorong R Zhu, Xiaodong Zhang, Li Wang, Katherine A Hutcheson, Adel K El-Naggar, Amy C Moreno, Anna Lee, Michael T Spiotto, Neil D Gross, Stephen Y Lai, Jay J Liao, Jonathan Paly, Zhongxing Liao, Robert L Foote

Faculty, Staff and Student Publications

Background: Radiotherapy is an integral component of treatment for oropharyngeal cancer. Toxicity from the current state-of-the-art photon radiotherapy, intensity-modulated radiation therapy (IMRT), has prompted the search for alternative, less toxic therapies. One such alternative that might de-intensify treatment is proton therapy. In this trial, we aimed to directly compare IMRT with intensity-modulated proton therapy (IMPT), both concurrent with systemic therapy, hypothesising comparable disease control and survival and lower toxicity.

Methods: This randomised, multicentre, open-label, non-inferiority, phase 3 trial was conducted in 21 sites (cancer centres or universities) in the USA. Patients (aged ≥18 years) with stage III or stage IV …

Identification Of Cadm1 As An Immunotherapeutic Target And Evaluation Of A Novel Cadm1-Targeting Antibody-Drug Conjugate In Preclinical Osteosarcoma Models, Yifei Wang, Zhongting Zhang, Caterina Longo, Wendong Zhang, Qi Wang, Amer Najjar, Xiangjun Tian, Rossana N Lazcano Segura, Michael E Roth, Jonathan Gill, Douglas J Harrison, Zhaohui Xu, Yanhua Yi, Xin Zhou, Sylvester Jusu, Timothy M Stearns, Steven B Neuhauser, Carol J Bult, Jing Wang, Alexander J Lazar, Richard Gorlick

Faculty, Staff and Student Publications

Due to the paucity of validated cell surface osteosarcoma-specific targets, patients with this condition have long been excluded from the benefits of antibody-drug conjugate (ADC) therapy observed in patients with several solid and hematologic malignancies. Our comprehensive surfaceome profiling approach previously identified osteosarcoma-specific cell-surface antigens that are highly expressed in osteosarcomas but minimally expressed in normal tissues. As a result, one such antigen, CADM1, was selected for the generation of an ADC. We tested a CADM1-targeting ADC with a tesirine payload (SG3249) in vitro in osteosarcoma, rhabdomyosarcoma, and neuroblastoma patient-derived xenograft cell lines. In vivo, we tested six CADM1-expressing osteosarcoma …

An Integrated Single-Cell And Spatial Transcriptomic Atlas Of Thyroid Cancer Progression Identifies Prognostic Fibroblast Subpopulations, Matthew A Loberg, George J Xu, Sheau-Chiann Chen, Hua-Chang Chen, Claudia C Wahoski, Kailey P Caroland, Megan L Tigue, Heather A Hartmann, Jean-Nicolas Gallant, Courtney J Phifer, Andres A Ocampo, Dayle K Wang, Reilly G Fankhauser, Kirti A Karunakaran, Chia-Chin Wu, Maxime Tarabichi, Sophia M Shaddy, James L Netterville, Sarah L Rohde, Carmen C Solórzano, Lindsay A Bischoff, Naira Baregamian, Barbara A Murphy, Jennifer H Choe, Jennifer R Wang, Eric C Huang, Quanhu Sheng, Luciane T Kagohara, Elizabeth M Jaffee, Ryan H Belcher, Ken S Lau, Fei Ye, Ethan Lee, Vivian L Weiss

Faculty, Staff and Student Publications

Although well-differentiated thyroid carcinoma (WDTC) is characterized by a robust treatment response, aggressive subtypes, such as anaplastic thyroid carcinoma (ATC), remain highly lethal. To understand thyroid cancer evolution in both children and adults, we analyzed single-cell transcriptomes of 423,733 cells from 81 samples and spatially resolved key tumor and microenvironment populations across 28 tumors with spatial transcriptomics, including rare and unique composite WDTC/ATC tumors and pediatric diffuse sclerosing thyroid carcinomas. Additionally, we identified gene signatures of stromal cell populations in 5 large thyroid cancer bulk RNA-sequencing cohorts. Through this multi-institutional effort, we defined a population of POSTN+ myofibroblast cancer-associated fibroblasts …

Clinical And Dosimetric Dataset Of Time-To-Event Normal Tissue Complication Probability For Osteoradionecrosis, Natalie A West, Serageldin Kamel, Andrew Wentzel, Zaphanlene Kaffey, Moamen Abdelaal, G Elisabeta Marai, Guadalupe Canahuate, Xinhua Zhang, Melissa M Chen, Kareem A Wahid, Jillian Rigert, Kristy K Brock, Mark Chambers, Adegbenga O Otun, Ruth Aponte-Wesson, Renjie He, Mohamed A Naser, Katherine A Hutcheson, Abdallah S R Mohamed, Lisanne V Van Dijk, Amy C Moreno, Stephen Y Lai, Clifton D Fuller, Laia Humbert-Vidan

Faculty, Staff and Student Publications

Osteoradionecrosis of the jaw (ORNJ) is a radiation-induced late toxicity that can dramatically decrease patients' quality of life. Recent increases in survival rates of head and neck cancers associated with human papillomavirus (HPV) infection have resulted in a higher frequency of radiation-induced toxicities, particularly ORNJ. Recent work with Normal Tissue Complication Probability (NTCP) models and a Weibull Accelerated Failure Time (WAFT) model have further developed our understanding of ORNJ clinical/dosimetric risk factors and longitudinal features, respectively. In this data descriptor, 1129 head and neck cancer (HNC) patients received curative intent radiotherapy (RT) at MD Anderson Cancer Center and were followed …