Life Sciences Commons^™

Liger-Hn Phase Iii Trials Of Petosemtamab + Pembrolizumab And Petosemtamab Monotherapy In Recurrent Or Metastatic Hnscc, Jean-Pascal Machiels, Jérôme Fayette, Robert Haddad, Douglas Adkins, Maura Gillison, Sung-Bae Kim, Amanda Psyrri, Ari Rosenberg, Lillian L Siu, Makoto Tahara, William N William, Jim Ford, Shekeab Jauhari, Rebecca Pyle, Yu-Ming Shen, David Yao, Fabian Zohren, Everett Vokes

Faculty, Staff and Student Publications

Patients with recurrent/metastatic (r/m) head and neck squamous cell carcinoma (HNSCC) have limited treatment options and a dismal prognosis, especially when their cancer is resistant to standard treatments like anti-programmed cell death protein 1 and platinum-based therapies. Petosemtamab - a human, common light chain, bispecific antibody with enhanced antibody-dependent cellular cytotoxicity targeting epidermal growth factor receptor (EGFR) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) - demonstrated antitumor activity in r/m HNSCC. In many tumor types, including HNSCC, EGFR is an oncogenic driver, while LGR5 is upregulated. LGR5 can potentiate the wingless-type integration site (WNT)/β-catenin signaling pathway in response to …

Hyalinization-Based Pathologic Response And Immune Infiltration Following Neoadjuvant Radiotherapy With Or Without Immune-Checkpoint Blockade In Localized Undifferentiated Pleomorphic Sarcoma, R S Traweek, M Zoghbi, R Lazcano, B M Cope, A J Bishop, D Mitra, B A Guadagnolo, D R Ingram, K Wani, D Shamsutdinova, A J Lazar, W-L Wang, C P Scally, E Z Keung, K E Torres, K K Hunt, R Ratan, J A Livingston, M S Nakazawa, D M Araujo, S Patel, V Ravi, A P Conley, M A Zarzour, N Somaiah, C L Roland, E F Nassif Haddad

Faculty, Staff and Student Publications

BACKGROUND: Standard-of-care treatment of localized undifferentiated pleomorphic sarcoma (UPS) involves preoperative radiotherapy (RT) and surgery. Combination of RT with immune-checkpoint blockade (ICB) represents a promising new strategy.

METHODS: Our primary objective was to assess survival outcomes and pathologically documented response in patients receiving RT with or without ICB or chemotherapy.

RESULTS: In a retrospective cohort of 68 patients with primary or locally recurrent UPS who received neoadjuvant RT with or without ICB, the ICB group had greater tumor hyalinization than the non-ICB group (89% compared with 30%, P = 0.018). In the non-ICB group, 19/37 patients (51%) achieved hyalinization-based pathologic …

Cdemapper: Enhancing National Institutes Of Health Common Data Element Use With Large Language Models, Yujia Zhou, Xubing Hao, Pritham Ram, Lingfei Qian, Qianqian Xie, Ruey-Ling Weng, Fongci Lin, Yan Hu, Licong Cui, Xiaoqian Jiang, Hua Xu, Na Hong

Faculty, Staff and Student Publications

Objective: Common Data Elements (CDEs) standardize data collection and sharing across studies, enhancing data interoperability and improving research reproducibility. However, implementing CDEs presents challenges due to the broad range and variety of data elements. This study aims to develop a CDE mapping tool to bridge the gap between local data elements and National Institutes of Health (NIH) CDEs.

Methods: We propose CDEMapper, a large language model (LLM)-powered mapping tool designed to assist in mapping local data elements to NIH CDEs. CDEMapper has 3 core modules: (1) CDE indexing and embeddings. NIH CDEs were indexed and embedded to support semantic search; …

Evaluating Large Language Model Performance To Support The Diagnosis And Management Of Patients With Primary Immune Disorders, Cullen Dutmer, Jocelyn R Farmer, Kirk Roberts, Guergana Savova, Mei-Sing Ong

Faculty, Staff and Student Publications

Background: Generative artificial intelligence (GAI) is transforming health care in a variety of ways; however, the present utility of GAI for supporting clinicians who treat rare disease such as primary immune disorders (PIs) is not well studied. We evaluated the ability of 6 state-of-the-art large language models (LLMs) for providing clinical guidance about PIs.

Objective: To quantitatively and qualitatively measure the utility of current, open-source LLMs for diagnosing and providing helpful clinical decision support about PIs.

Methods: Five expert clinical immunologists each provided 5 real-world, anonymized PI case vignettes via multi-turn prompting to 6 LLMs (OpenAI GPT-4o, Llama-3.1-8B-Instruct, Llama-3.1-70B-Instruct, Mistral-7B-Instruct-v0.3, …

Wnt-Directed Cxcl12-Expressing Apical Papilla Progenitor Cells Drive Tooth Root Formation, Hiroaki Manabe, Angel Ka Yan Chu, Ramandeep Kaur, Meer Ali, Yuntao Yang, Chiaki Tsutsumi-Arai, Yuta Nakai, Yuki Matsushita, Nicha Tokavanich, W Jim Zheng, Joshua D Welch, Noriaki Ono, Wanida Ono

Faculty, Staff and Student Publications

The tooth root is a critical component of the tooth anchored to surrounding alveolar bones. Tooth root formation is driven by cells in the apical papilla (AP) that generate new dentin-forming odontoblasts at the root-forming front. Mesenchymal stem cells have been isolated from AP for regenerative use; however, how AP cells physiologically coordinate tooth root formation remains undefined. We find that CXCL12+ cells emerge in AP under hypoxic environments at the onset of tooth root formation. Using Cxcl12-creER-based cell-lineage analysis, we further find that CXCL12+ AP cells contribute not only to odontoblasts but also to cementum-forming cementoblasts of the elongating …

Phase Ii Basket Trial Of Dual Anti-Ctla-4 And Anti-Pd-1 Blockade In Rare Tumors (Dart) Swog S1609: Pancreatic Neuroendocrine Neoplasm (Pnen) Cohort, Sandip Pravin Patel, Jillian Fisher, Young Kwang Chae, Luisa Solis Soto, Anup Kasi, Mark Walshauser, Jiexin Zhang, Caroline Duault, Edgar Gonzalez-Kozlova, Ganiraju Manyam, Jianhua Zhang, Hong Chen, Dzifa Yawa Duose, Caddie Laberiano Fernandez, Raja Luthra, Gheath Al-Atrash, Seunghee Kim-Schulze, Holden T Maecker, Ignacio I Wistuba, Sacha Gnjatic, J Jack Lee, Jianjun Zhang, Christine M Magner, Helen X Chen, Elad Sharon, Megan Othus, Christopher W Ryan, Charles Blanke, Cara L Haymaker, Razelle Kurzrock

Faculty, Staff and Student Publications

Purpose: SWOG S1609 Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) studied the efficacy of ipilimumab combined with nivolumab across multiple rare tumor types. We report the results of the pancreatic neuroendocrine neoplasm (PNEN) cohort.

Experimental design: Treatment consisted of ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR) (Response Evaluation Criteria In Solid TumorsRECIST V.1.1). Secondary endpoints include progression-free survival (PFS), overall survival (OS), and toxicity. Clinical benefit rate (includes ORR plus stable disease (SD)>6 months was examined. Correlative …

Bayesian-Weighted Mendelian Randomization Reveals Sleep Apnea Syndrome Mediates The Bmi-Chronic Pain Link, Wenbao Shi, Jing Luo, Liu Yang, Dalin Chen, Yongqin Zhang, Kurt Ruetzler, Hua Jin

Faculty, Staff and Student Publications

Background: Body mass index (BMI) has a complex association with a variety of chronic pain conditions, which may be influenced by sleep apnea syndrome (SAS). However, the role of SAS within the causal pathway linking BMI to chronic pain remains unconfirmed. This study explored whether and to what extent SAS serves as a mediator between BMI and chronic pain using Bayesian-weighted Mendelian randomization (BWMR) techniques.

Methods: This study utilized genome-wide association study (GWAS) summary data for BMI (N=461,460) and SAS (N=476,853; based on ICD-10 code diagnostic registries) from the IEU OpenGWAS database, along with chronic pain GWAS data (ICD-10 code-based …

Incidental Findings In Female Pelvis Mri Performed For Gynaecological Malignancies, Silvia Bottazzi, Roberta V Ninkova, Luca Russo, Andrea Ponsiglione, Benedetta Gui, Massimo Imbriaco, Evis Sala, Stephanie Nougaret, Lucia Manganaro, Stefania Rizzo

Faculty, Staff and Student Publications

Incidental findings on female pelvic MRI present diagnostic challenges and may have significant clinical implications. Defined as abnormalities unrelated to the primary imaging indication, these findings have become increasingly prevalent with the expanded use of MRI in gynaecological practice. Standard gynaecological MRI protocols, incorporating T1- and T2-weighted sequences, diffusion-weighted imaging, and contrast-enhanced sequences, facilitate the characterisation of numerous extra-gynaecological abnormalities, ranging from benign to critical lesions. This review proposes a compartment-based approach for identifying extra-gynaecological findings, discussing their imaging characteristics and differential diagnoses. This approach may help radiologists systematically assess incidental findings, potentially improving the recognition of clinically relevant abnormalities …

Letter Of Concern From The Association Of Academic Chairs Of Emergency Medicine Regarding Acgme Proposed Changes, Richard J Hamilton, Lance B Becker, Richard E Wolfe, D Adam Algren, Thomas Arnold, Ross P Berkeley, Chad M Cannon, Theodore J Corbin, Michael E Chansky, Harinder S Dhindsa, Charles L Emerman, David A Farcy, Chris Fox, Michael A Gibbs, Christopher S Goode, Steven Andy Godwin, Dietrich Jehle, David Johnson, Samuel M Keim, Babak Khazaeni, Barry J Knapp, Clint Hawthorne, John D Hoyle, Michael Christopher Kurz, Evan Leibner, Robert Mcnamara, Robert F Mccormack, Edward A Michelson, Chadwick Miller, Ashley Norse, Andrew Nugent, Brian J O'Neil, David T Overton, Edward A Panacek, William F Paolo, Denis R Pauzé, Amanda L Perez, Ralph J Riviello, Scott W Rodi, Peter S Pang, Juan A Gonzalez Sanchez, David Seaberg, Adam Schwartz, Stephen A Shiver, David P Sklar, Ben C Smith, Jeffrey R Stowell, Marc D Squillante, J Jeremy Thomas, Terry Vanden Hoek, Gregory A Volturo, E Lea Walters, Thomas E Wyatt, Donald M Yealy

Faculty, Staff and Student Publications

This letter, signed by over 50 academic chairs of emergency medicine, urges the ACGME to reconsider a proposed mandate requiring all emergency medicine residency programs to adopt a four-year training model. The authors argue that current three-year programs are supported by data demonstrating equivalent educational and clinical outcomes compared to four-year formats. They criticize the flawed survey methodology underpinning the proposal, note the loss of milestone-based training flexibility, and highlight the lack of added scholarly or clinical value in the fourth year. The letter also outlines negative consequences for fellowship participation, workforce development, trainee debt, and diversity. The signatories advocate …

Encorafenib, Cetuximab, And Mfolfox6 In Braf-Mutated Colorectal Cancer, Elena Elez, Takayuki Yoshino, Lin Shen, Sara Lonardi, Eric Van Cutsem, Tae Won Kim, Jayesh Desai, Fortunato Ciardiello, Rona Yaeger, Timothy S Maughan, Van K Morris, Christina Wu, Tiziana Usari, Robert Laliberte, Samuel S Dychter, Xiaosong Zhang, Josep Tabernero, Scott Kopetz, Breakwater Trial Investigators

Faculty, Staff and Student Publications

Background: First-line treatment with encorafenib plus cetuximab (EC) with or without chemotherapy (oxaliplatin, leucovorin, and fluorouracil [mFOLFOX6]) for BRAF V600E-mutated metastatic colorectal cancer, an aggressive subtype with a poor prognosis, was compared with standard care (chemotherapy with or without bevacizumab) in an open-label, phase 3 trial, which showed significance regarding one of the two primary end points, objective response according to blinded independent central review (odds ratio for EC+mFOLFOX6 vs. standard care, 2.44; one-sided P< 0.001). This result led to accelerated Food and Drug Administration approval of this investigational combination therapy for BRAF V600E-mutated metastatic colorectal cancer, including as first-line therapy. Data on progression-free survival (the second primary end point) and an updated interim analysis of overall …

Mis-Splicing-Derived Neoantigens And Cognate Tcrs In Splicing Factor Mutant Leukemias, Won Jun Kim, Edie I Crosse, Emma De Neef, Inaki Etxeberria, Erich Y Sabio, Eric Wang, Jan Philipp Bewersdorf, Kuan-Ting Lin, Sydney X Lu, Andrea Belleville, Nina Fox, Cynthia Castro, Pu Zhang, Takeshi Fujino, Jennifer Lewis, Jahan Rahman, Beatrice Zhang, Jacob H Winick, Alexander M Lewis, Robert F Stanley, Susan Dewolf, Brigita Meškauskaitė Urben, Meril Takizawa, Tobias Krause, Henrik Molina, Ronan Chaligne, Priya Koppikar, Jeffrey Molldrem, Mathieu Gigoux, Taha Merghoub, Anthony Daniyan, Smita S Chandran, Benjamin D Greenbaum, Christopher A Klebanoff, Robert K Bradley, Omar Abdel-Wahab

Faculty, Staff and Student Publications

Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-MHC dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant. Neoantigen-reactive CD8+ T cells were present in the blood of patients with active cancer and had a distinct phenotype from virus-reactive T cells with evidence of impaired cytotoxic function. T cells engineered with TCRs recognizing …

A Conditional Point Cloud Diffusion Model For Deformable Liver Motion Tracking Via A Single Arbitrarily-Angled X-Ray Projection, Jiacheng Xie, Hua-Chieh Shao, Yunxiang Li, Shunyu Yan, Chenyang Shen, You Zhang

Faculty, Staff and Student Publications

Objective. Deformable liver motion tracking using a single x-ray projection enables real-time motion monitoring and treatment intervention. We introduce a conditional point cloud diffusion (PCD) model-based framework for accurate and robust liver motion tracking from arbitrarily angled single x-ray projections. Approach. We propose a conditional PCD model for liver motion tracking (PCD-Liver), which estimates volumetric liver motion by solving deformable vector fields (DVFs) of a prior liver surface point cloud, based on a single x-ray image. It is a patient-specific model of two main components: a rigid alignment model to estimate the liver’s overall shifts, and a conditional PCD …

Intratumoral Neutrophil-To-Lymphocyte Ratio Is Mirrored By Circulating Neutrophil-To-Lymphocyte Ratio In Non-Small Cell Lung Cancer, Kyle G Mitchell, Younghee Lee, Nathaniel Deboever, Marcelo V Negrao, Hai T Tran, Lauren Byers, Lorenzo Federico, Chantale Bernatchez, Jing Wang, Mara B Antonoff, Ara A Vaporciyan, Stephen G Swisher, Tina Cascone, Ignacio I Wistuba, John V Heymach, Don L Gibbons, Jianjun Zhang, Daniel J Mcgrail, Boris Sepesi, Cara L Haymaker

Faculty, Staff and Student Publications

Tumor-initiated emergency granulopoiesis results in expansion of the circulating neutrophil compartment and neutrophil recruitment into the tumor microenvironment (TME), which may in turn promote tumor progression. Although an elevated circulating neutrophil-to-lymphocyte ratio (cNLR) has repeatedly been demonstrated to be an adverse prognostic factor in patients with non-small cell lung cancer (NSCLC), whether this neutrophil expansion in circulation reflects a similar relative neutrophil abundance in the TME remains unclear. We sought to characterize the relationships between cNLR and the intratumoral neutrophil-to-lymphocyte ratio (tNLR), between tNLR and proteogenomic and immune features of NSCLC tumors, and between tNLR and prognosis.We analyzed tNLR (transcriptomic …

Cholesterol Metabolism Regulated By Camkk2-Creb Signaling Promotes Castration-Resistant Prostate Cancer, Chenchu Lin, Thomas L Pulliam, Jenny J Han, Jiaqian Xu, Carlos Vera Recio, Yan Shi, Sarah Bench, Eduardo Ruiz, Sanjanaa Senthilkumar, Jayasurya Dileep, Peter D A Shepherd, Nora M Navone, Albert R Klekers, Elizabeth M Whitley, Michael M Ittmann, Livia S Eberlin, Wenyi Wang, Daniel E Frigo

Faculty, Staff and Student Publications

Castration-resistant prostate cancer (CRPC) remains an incurable disease in need of improved treatments. CAMKK2 is an emerging therapeutic target whose oncogenic effects in prostate cancer have, to date, been largely attributed to its activation of AMP-activated protein kinase (AMPK). Here, we demonstrate that CAMKK2 promotes prostate cancer growth through an alternative downstream pathway involving CAMKI and CREB. Unbiased transcriptomics identify CREB-mediated transcription as a CAMKK2-regulated process, findings that we validate using diverse molecular, genetic, and pharmacological approaches in vitro and in vivo. CAMKK2 promotes CREB phosphorylation/activation through CAMKIα independently of AMPK, CAMKIV, or other CAMKI isoforms. Functionally, the CREB family …

The Carsr Two-Component System Directly Controls Radd Expression As A Global Regulator That Senses Bacterial Coaggregation In Fusobacterium Nucleatum, Bibek G C, Chenggang Wu

Faculty, Staff and Student Publications

Two-component systems (TCS) enable bacteria to sense and respond to environmental signals, facilitating rapid adaptation. Fusobacterium nucleatum, a key oral pathobiont, employs the CarSR TCS to modulate coaggregation with various gram-positive partners by regulating the expression of radD, encoding a surface adhesion protein, as revealed by RNA-Seq analysis. However, the direct regulation of the radD-containing operon (radABCD) by the response regulator CarR, the broader CarR regulon, and the signals sensed by this system remain unclear. In this study, chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-seq) identified approximately 161 CarR-enriched loci across the genome and …

Protocol For Establishing Genetically Engineered Murine Lung Organoids Mimicking Cell Plasticity And Regeneration, Bongjun Kim, Jae-Il Park

Faculty, Staff and Student Publications

Lung endothelial cells (LuECs) play crucial roles in lung regeneration and support lung organoids (LOs). However, detailed guidelines for LO culture using LuECs have not been reported yet. Here, we present an efficient protocol for generating and culturing murine LOs that mimic regeneration. We describe steps for the isolation of LuECs and lung epithelial cells, followed by LO culture. We also describe how to establish genetically engineered LOs using viral transduction. For complete details on the use and execution of this protocol, please refer to Kim et al.

Protocol To Analyze Trna And Rrna Processing Using Biotin-Labeled Probes, Sseu-Pei Hwang, Katherine Barondeau, Catherine Denicourt

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Mature tRNAs and rRNAs are derived from larger precursor transcripts through intricate endo- and exonuclease processing steps. Here, we present a protocol to analyze rRNA and tRNA processing using total RNA extracted from human cells. We describe steps for separating RNA by denaturing electrophoresis, followed by northern blotting. We detail procedures for detecting pre-rRNA intermediates or specific tRNA species using biotin-labeled probes imaged via fluorescence or chemiluminescence. This non-radioactive, high-sensitivity assay enables the investigation of rRNA and tRNA expression dynamics. For complete details on the use and execution of this protocol, please refer to Hwang et al.

Usp37 Counteracts Hltf To Protect Damaged Replication Forks And Promote Survival Of Brca1-Deficient Cells And Parp Inhibitor Resistance, Mengfan Tang, Siting Li, Ziqiang Zhu, Chao Wang, Shuai Ding, Min Huang, Zhen Chen, Ling Yin, Litong Nie, Dan Su, Xu Feng, Junjie Chen

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase inhibitors (PARPi) have greatly improved survival of cancer patients harboring BRCA1 mutations. However, therapy resistance develops via either restoration of homologous recombination or replication fork stabilization. Therapeutic targets to overcome PARPi resistance are critically needed. We identified the deubiquitinase USP37 as a key determinant of PARPi toxicity in BRCA1-deficient cells via whole-genome CRISPR screens. USP37 ablation enhanced PARPi sensitivity in BRCA1-deficient cells and also overcame PARPi resistance due to 53BP1 loss. USP37 interacts with and deubiquitinates replication protein A (RPA) at stalled replication forks to limit excessive RPA accumulation, progressive RPA exhaustion, and the conversion of RPA-coated single-stranded …

Protocol For Assessing Mobilization Of Peritoneal B Cells To The Pre-Metastatic Omentum In An Orthotopic Mouse Model Of Ovarian Cancer, Wonjae Lee, Hironari Akasaka, Honami Naora

Faculty, Staff and Student Publications

The omentum is a visceral adipose tissue that undergoes dynamic immunological changes prior to and following metastasis. Here, we present a protocol for assessing the mobilization of peritoneal B cells to the pre-metastatic omentum in a mouse ovarian cancer model. We describe steps for isolation and adoptive transfer of peritoneal donor B cells and their detection in the omentum of recipient mice. This protocol could be utilized to study the mobilization of peritoneal B cells to the omentum in other pathological contexts. For complete details on the use and execution of this protocol, please refer to Lee et al.

Characterization And Clinical Implications Of P53 Dysfunction In Patients With Myelodysplastic Syndromes, Matteo Zampini, Elena Riva, Luca Lanino, Elisabetta Sauta, Rita Antunes Dos Reis, Giulia Maggioni, Alessandra Merlotti, Alessia Campagna, Lorenzo Dall'olio, Austin Kulasekararaj, Michela Calvi, Clara Di Vito, Arturo Bonometti, Daoud Rahal, Giorgio Croci, Emanuela Boveri, Umberto Gianelli, Maurilio Ponzoni, Rossella Caselli, Serena Albertazzi, Gabriele Todisco, Marta Ubezio, Laura Crisafulli, Alessandro Frigo, Enrico Lugli, Ettore Mosca, Pamela Acha, Serena Ghisletti, Francesco Nicassio, Armando Santoro, Maria Diez-Campelo, Francesc Solé, Lionel Ades, Uwe Platzbecker, Valeria Santini, Pierre Fenaux, Torsten Haferlach, David Sallman, Guillermo Garcia-Manero, Domenico Mavilio, Daniel Remondini, Gastone Castellani, Saverio D'Amico, Amer M Zeidan, Rami Komrokji, Shahram Kordasti, Francesca Ficara, Matteo Giovanni Della Porta, Calr Consortium

Faculty, Staff and Student Publications

Purpose: Tumor Protein 53 (p53) expressed from gene TP53 is a seminal tumor suppressor. We aimed to characterize mutational and nonmutational mechanisms of p53 dysfunction in myelodysplastic syndromes (MDS) and to investigate their clinical effect.

Patients and methods: We analyzed a cohort of 6,204 patients with MDS and subsets of patients with available information on RNA sequencing of tumor cells (n = 109), high-dimensional phenotype of immune cells (n = 77), and multiomics analysis (RNA sequencing and proteomics) on single cells (n = 15). An independent validation was performed on 914 patients.

Results: Biallelic TP53 inactivation was a powerful driver …

Blood-Based Proteomic Profiling Identifies Osmr As A Novel Biomarker Of Aml Outcomes, Patrick K Reville, Bofei Wang, Jennifer Marvin-Peek, Bin Yuan, Yu-An Kuo, Jessica Root, Andrea Arruda, Ivo Veletic, Yiwei Liu, Nicholas J Short, Courtney D Dinardo, Tapan M Kadia, Naval G Daver, Philip L Lorenzi, Koji Sasaki, Steven Kornblau, Mark D Minden, Farhad Ravandi, Hagop M Kantarjian, Hussein A Abbas

Faculty, Staff and Student Publications

Inflammation is increasingly recognized as a critical factor in acute myeloid leukemia (AML) pathogenesis. We performed blood-based proteomic profiling of 251 inflammatory proteins in 543 patients with newly diagnosed AML. Using a machine learning model, we derived an 8-protein prognostic score termed the leukemia inflammatory risk score (LIRS). Individual proteins were evaluated in multivariable Cox models, and model performance was assessed by cumulative concordance index. Findings were validated in internal and external cohorts across 2 institutions. Blood-based LIRS significantly outperformed the European LeukemiaNet 2022 risk model and was independently prognostic of overall survival after accounting for known clinical and molecular …

Therapy, Safety, And Logistics Of Preoperative Vs Postoperative Stereotactic Radiation Therapy: A Preliminary Analysis Of A Randomized Clinical Trial, Debra Nana Yeboa, Jing Li, Ruitao Lin, Sujit S Prabhu, Thomas H Beckham, Todd Allen Swanson, Xuemei Wang, Xiaohan Chi, Chinenye Lynette Ejezie, Dima Suki, Chenyang Wang, Chibawanye Ene, Ian E Mccutcheon, Susan Mcgovern, Mary Frances Mcaleer, Martin Tom, Amol Ghia, Subha Perni, Wen Jiang, Brian De, Caroline Chung, Betty Y S Kim, Barbara J O'Brien, Jason T Huse, Jeffrey S Wefel, Laurence Court, Hussein Tawbi, Filip Janku, Nandita Guha-Thakurta, J Matthew Debnam, Jason Johnson, Ceylan Altintas Taslicay, Christopher Alvarez-Breckenridge, Shaan M Raza, Amy B Heimberger, Franco Demonte, Robert North, Tina M Briere, John F De Groot, Raymond Sawaya, David Grosshans, Frederick F Lang, Ganesh Rao, Sherise D Ferguson

Faculty, Staff and Student Publications

Importance: Preoperative stereotactic radiation therapy (SRT) vs postoperative SRT logistics and toxic effects provides clinically significant data on management outcomes.

Objective: To determine preoperative SRT logistics and safety profile compared with postoperative in patients with brain metastases.

Design, setting, and participants: This single-institution phase 3 randomized clinical trial included patients 18 years and older and undergoing a planned surgical resection. Patients were required to have an Eastern Cooperative Oncology Group Performance Status score of 2 or greater and be candidates for SRT within 30 days of surgical resection. Patients with radiosensitive histologies (eg, small cell lung cancer and lymphoma), brain …

The Multilayered Control Of Acetylation During Adenovirus-Based Immunotherapy Of Cancer, Akhila Parthasarathy, Maria Frost, Andrew G Gillard, Marta M Alonso, Candelaria Gomez-Manzano

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Adenoviruses are highly immunogenic agents that have shown promise first as gene delivery vectors and later as oncolytic viruses. Currently, oncolytic adenoviruses are featured in over 30% of cancer virotherapy clinical trials. Due to their effective cellular uptake and hijack of cellular machinery, replication-competent adenoviruses are promising therapeutic agents for treating a wide range of tumors. Adenoviral influence on host cell acetylome regulation has regained attention, as these viruses redirect or suppress acetylation during replication, making them potentially desirable therapeutic agents for cancers driven by epigenetic modifications. In this review, we aim to cover the viral processes influencing the acetylome …

Aso Visual Abstract: Characterization Of The Germline Pathogenic Mutational Landscape And Oncologic Outcomes Among 877 Patients With Invasive Lobular Carcinoma, Victoria D Huynh, Jason Mouabbi, Henry M Kuerer, Kerollos Nashat Wanis, Hiam M Abdel-Salam, Helen M Johnson, Kelly K Hunt, Banu K Arun

Faculty, Staff and Student Publications

No abstract provided.

Education Improves Perceived Control But Not Risk Identification In Adolescents Regarding Fentanyl, Tiffany Champagne-Langabeer

Faculty, Staff and Student Publications

Background/objectives: In 2022, 2.2 million adolescents were diagnosed with substance use disorders, including 265,000 with opioid use disorder. The National Survey on Drug Use and Health revealed that 130,000 adolescents misused prescription pain medications, often obtaining them from friends or relatives. This age group perceives weekly heroin use as less risky than those younger or older.

Methods: A questionnaire was developed for 7th to 12th graders in a rural Texas school district as part of a fentanyl awareness curriculum. The questionnaire included Likert scale, multiple choice, and yes/no questions. The participants were categorized into younger (grades 7th and 8th) and …

Identification Of Hypoxia-Inducible Factor Hif1a As A Therapeutic Target During Sars-Cov-2-Associated Lung Injury, Jieun Kim, Yanyu Wang, In Hyuk Bang, David Robinson, Paulina B Sergot, Steven K Burke, Tingting Mills, Constanza De Dios, Robert Suchting, George W Williams, Adit A Ginde, Yafen Liang, Hongfang Liu, Charles Green, Marie-Francoise Doursout, Alparslan Turan, Daniel I Sessler, Xiaoyi Yuan, Holger K Eltzschig

Faculty, Staff and Student Publications

Hypoxia-inducible factors (HIFs) promote lung protection and pathogen eradication during acute lung injury. We therefore tested the theory that pharmacologic stabilization of HIFs dampens lung injury during SARS-CoV-2 pneumonia. Initial studies in murine SARS-CoV-2 models showed improved outcomes after treatment with the FDA-approved HIF-stabilizer vadadustat. Subsequent studies in genetic models implicated alveolar-expressed Hif1a in mediating lung protection. Therefore, we performed a randomized, double-blinded, multicenter phase 2 trial in patients admitted for SARS-CoV-2 infection and concomitant hypoxia (SpO2 ≤ 94%). Patients (n=448) were randomized to oral vadadustat (900 mg/day) or placebo for up to 14 days. Safety events were similar between …

Dosimetric Advantage Of Scanning Beam Proton Therapy In Gynecologic Patients Receiving Adjuvant Radiotherapy, Rachel B Ger, Jarrod M Lentz, Joshua S Niedzielski, Sujay A Vora, Martin Bues, Justin D Anderson, Christie A Schulz, Pedro R Lara, Ana K Ridgway, Pamela R Lemish, Justin D Gagneur, Aman Anand

Faculty, Staff and Student Publications

Background/Objectives: Adjuvant radiation for gynecologic malignancies often exposes organs at risk (OARs), such as the bone marrow, bowel, rectum, and bladder, to radiation, leading to toxicities that impact treatment tolerance and patient quality of life. Scanning proton beam therapy, particularly with Individual Field Simultaneous Optimization (IFSO), may offer dosimetric and biological advantages over volumetric modulated arc therapy (VMAT). This study evaluates the clinical impact of IFSO-based proton planning in post-operative gynecologic cancer patients.

Materials and Methods: Fourteen patients receiving adjuvant proton therapy to 45 Gy in 25 fractions were retrospectively analyzed. Comparison VMAT plans were generated on the same datasets. …

The Tumor Suppressor Hnrnpk Induces P53-Dependent Nucleolar Stress To Drive Ribosomopathies, Pedro Aguilar-Garrido, María Velasco-Estévez, Miguel Ángel Navarro-Aguadero, Álvaro Otero-Sobrino, Marta Ibáñez-Navarro, María Hernández-Sánchez, Ashley Rodriguez, Oscar Benitez, Xiaroui Zhang, Marisa Jl Aitken, Alejandra Ortiz-Ruiz, Diego Megías, Manuel Pérez, Gadea Mata, Jesús Gomez, Miguel Lafarga, Orlando Domínguez, Osvaldo Graña-Castro, Eduardo Caleiras, Pilar Ximénez-Embun, Marta Isasa, Paloma Jimena De Andres, Sandra Rodríguez-Perales, Raúl Torres-Ruiz, Enrique Revilla, Rosa María García-Martín, Daniel Azorín, Josune Zubicaray, Julián Sevilla, Oleksandra Sirozh, Vanesa Lafarga, Joaquín Martínez-López, Sean M Post, Miguel Gallardo

Faculty, Staff and Student Publications

The nucleolus is a membraneless organelle and an excellent stress sensor. Any changes in its architecture or composition lead to nucleolar stress, resulting in cell cycle arrest and interruption of ribosomal activity, critical factors in aging and cancer. In this study, we identified and described the pivotal role of the RNA-binding protein HNRNPK in ribosome and nucleolar dynamics. We developed an in vitro model of endogenous HNRNPK overexpression and an in vivo mouse model of ubiquitous HNRNPK overexpression. These models showed disruptions in translation as the HNRNPK overexpression caused alterations in the nucleolar structure, resulting in p53-dependent nucleolar stress, cell …

Blastemia Portrays A Poor Prognosis In Acute Leukemia Patients With Invasive Pulmonary Aspergillosis, Sung-Yeon Cho, Sebastian Wurster, Ying Jiang, Alexandre Bazinet, Yang Hui, Takahiro Matsuo, Guillermo Garcia-Manero, Dimitrios P Kontoyiannis

Faculty, Staff and Student Publications

Objectives: Severe and prolonged neutropenia is associated with poor outcomes of invasive pulmonary aspergillosis (IPA) in leukemia patients. Given the high frequency of IPA in patients with relapsed/refractory leukemia, we studied the association of peripheral blood blast burden (blastemia), IPA outcomes, and antifungal immune failure, even without neutropenia.

Methods: We retrospectively reviewed adult patients with acute leukemia (AL) or myelodysplastic syndrome and culture-positive proven/probable IPA (2011-2022). Blast and neutropenia indices were calculated and incorporated into multi-variable prognostic models. The impact of blasts on immune cell-mediated fungal clearance was studied in vitro.

Results: Among 74 patients, 69% had neutropenia and 57% …

Technical And Clinical Validity Of Assessing Measurable Residual Disease By Multicolor Flow Cytometry In An Unselected Acute Myeloid Leukemia Patient Cohort, Sa A Wang, Shaoying Li, Wei Wang, Jie Xu, Beenu Thakral, Chi Young Ok, Jeffrey L Jorgensen, L Jeffrey Medeiros, Farhad Ravandi, Nicholas J Short, Sanam Loghavi

Faculty, Staff and Student Publications

Context.—: Following the validation of a multicolor flow cytometry (MFC) assay for measurable residual disease (MRD) in acute myeloid leukemia (AML), this study examines its clinical applicability.

Objective.—: To evaluate the practicality and performance of MFC-based MRD detection in AML.

Design.—: Prospectively assessed AML MRD MFC in unselected AML patients achieving morphologic remission with follow-up studies, molecular genetics, and survival data.

Results.—: Among 379 patient bone marrow samples in this cohort, an interpretable result was obtained in 359 (95%). A total of 57 of the 359 cases (16%) were positive for MRD, and the most frequently observed immunophenotype was CD34+CD117+ …