Digital Commons Network^™

Myh11 Rare Variant Augments Aortic Growth And Induces Cardiac Hypertrophy And Heart Failure With Pressure Overload, Zhen Zhou, Kgosi Hughes, Nisha Saif, Hyoseon Kim, Michael P Massett, Mingjie Zheng, Alana C Cecchi, Dongchuan Guo, David R Murdock, Ping Pan, Jelita S Clinton, Jun Wang, John M Greally, Dianna M Milewicz

Faculty, Staff and Student Publications

Smooth muscle cell-specific myosin heavy chain, encoded by MYH11, is selectively expressed in smooth muscle cells (SMCs). Pathogenic variants in MYH11 predispose to a number of disorders, including heritable thoracic aortic disease associated with patent ductus arteriosus, visceral myopathy, and megacystis-microcolon-intestinal hypoperistalsis syndrome. Rare variants of uncertain significance occur throughout the gene, including MYH11 p.Glu1892Asp, and we sought to determine if this variant causes thoracic aortic disease in mice. Genomic editing was used to generate Myh11E1892D/E1892D mice. Wild-type (WT) and mutant mice underwent cardiovascular phenotyping with and without transverse aortic constriction (TAC). Myh11E1892D/E1892D and WT mice displayed …

Preventing Acute Kidney Injury And Its Longer-Term Impact In The Critically Ill, Alexander Zarbock, Lui Forni, Jay L Koyner, Hernando Gómez, Neesh Pannu, Marlies Ostermann, Rinaldo Bellomo, John A Kellum, Thilo Von Groote

Faculty, Staff and Student Publications

Acute kidney injury (AKI) is a heterogeneous syndrome that not only affects short-term morbidity and mortality but also influences long-term outcomes. AKI is part of acute kidney disease (AKD) that encompasses a range of different conditions and is characterized by a kidney dysfunction lasting 90 days or less after which time the term chronic kidney disease (CKD) applies. AKD may result in irreversible loss of nephrons and may lead to CKD. In this narrative review, an update on different aspects of AKI in critically ill patients will be provided. We discuss biomarkers for early diagnosis of AKI, sub-clinical AKI, as …

Long-Term Exposure To Multiple Air Pollutants And Multi-Level Socioeconomic Status: Joint Effects On Age-Related Macular Degeneration, Subsequent Ocular Comorbidity, And Death In Middle-Aged And Older Adults, Yang Yang, Liangkai Chen, Qichen Liu, Min Mu, Jing Huang, Guangming Zhang, Qianqian Song

Faculty, Staff and Student Publications

Background: Both air pollution and socioeconomic status (SES) are recognized as significant determinants of health outcomes. However, no study has explored the combined effects of air pollutants and SES on (1) age-related macular degeneration (AMD) incidence; (2) trajectories from baseline to AMD, subsequent ocular comorbidity (OCMD), and mortality; and (3) life expectancy in middle-aged and older adults.

Methods: Using UK Biobank data, we created two composite air pollution scores (APS) and assessed SES at individual and neighborhood levels. OCMD was defined as glaucoma or cataract occurrence after AMD diagnosis. Cox proportional hazard regression models, multistate models, and life tables were …

Switching From Adalimumab Reference Product To And Among Adalimumab Biosimilars Outside The Usa: Insights For Us Clinicians, John R P Tesser, Aline Charabaty, Adelaide A Hebert

Faculty, Staff and Student Publications

Ten adalimumab biosimilars have been introduced in the United States (USA) since 2023, while adalimumab biosimilars have been available for several years in other countries. These experiences of biosimilar uptake outside the USA can inform US-based healthcare professionals on switching in real-life practice settings. Considerations include how healthcare professionals might meaningfully address patient concerns about outcomes to improve patient satisfaction. A search of the MEDLINE database was used to identify publications on switching to and among adalimumab biosimilars in an ex-US setting, with no restriction on publication language and using a time frame of 1 January 2017 through 12 December …

Incomplete Toxicity Reporting And Use Of Toxicity-Minimizing Language In Phase Iii Oncology Trials, Avital M Miller, Adina H Passy, Alexander D Sherry, Ramez Kouzy, Joseph Abi Jaoude, Timothy A Lin, Gabrielle S Kupferman, Esther J Beck, Pavlos Msaouel, Ethan B Ludmir

Faculty, Staff and Student Publications

Purpose: This study aimed to determine complete toxicity reporting (CTR), and the use of subjective toxicity-minimizing language (TML) among phase III oncology trials.

Methods: Two-arm superiority-design phase III oncology trials published from 2002 to 2020 were reviewed for toxicity data. CTR was defined as reporting total adverse events (TAEs), total serious adverse events (SAEs), total deaths, and study therapy discontinuations because of toxicity. Guideline concordance was defined according to guidelines published in the BMJ (defined as reporting total SAEs, total deaths, and study therapy discontinuations because of toxicity). TML was defined as a set of terms that subjectively downplay the …

The Landscape Of Malignant Transition: Unraveling Cancer Cell-Of-Origin And Heterogeneous Tissue Microenvironment, Ruihan Luo, Jiajia Liu, Tiangang Wang, Weiling Zhao, Yanfei Wang, Jianguo Wen, Hongyu Wang, Shanli Ding, Xiaobo Zhou

Faculty, Staff and Student Publications

Understanding disease progression and sophisticated tumor ecosystems is imperative for investigating tumorigenesis mechanisms and developing novel prevention strategies. Here, we dissected heterogeneous microenvironments during malignant transitions by leveraging data from 1396 samples spanning 13 major tissues. Within transitional stem-like subpopulations highly enriched in precancers and cancers, we identified 30 recurring cellular states strongly linked to malignancy, including hypoxia and epithelial senescence, revealing a high degree of plasticity in epithelial stem cells. By characterizing dynamics in stem-cell crosstalk with the microenvironment along the pseudotime axis, we found differential roles of ANXA1 at different stages of tumor development. In precancerous stages, reduced …

Involved But Not Essential: Cognitive Activity In Periventricular Nodules And Neuropsychological Outcomes Following Their Ablation, Yosefa A Modiano, Oscar Woolnough, Ryan M Mccormack, Kathryn Snyder, Ellery Wheeler, Samden D Lhatoo, Nuria Lacuey, Sandipan Pati, Katherine Harris, Jay Gavvala, Jessica A Johnson, Nitin Tandon

Faculty, Staff and Student Publications

Objective: Periventricular nodular heterotopia (PVNH) is a malformation of cortical development with high rates of epilepsy. The extent to which nodules participate in normal cerebral functions in addition to pathological processes is unclear. The authors assessed the functional utility (i.e., cognitive impacts) of surgically ablated epileptogenic PVNH tissue via comprehensive neuropsychological testing.

Methods: The sample included 32 patients with PVNH who underwent presurgical neuropsychological evaluation and a subsample of 16 patients who underwent MR-guided laser interstitial thermal therapy (MRgLITT) of nodules, with postsurgical neuropsychological testing. In 11 patients in whom intracranial recordings were performed, reading and naming tasks were tested …

Diagnostic Guidance For Chronic Complex Regional Pain Syndrome Type I And Type Ii From The American Society Of Interventional Physicians (Asipp), Christopher Gharibo, Miles Day, Steve M Aydin, Alan D Kaye, Salahadin Abdi, Sudhir Diwan, Lisa V Doan, Danielle Feng, Kris Ferguson, Kirolos Georges, Andrew Kaufman, Nebojsa Nick Knezevic, Sean Li, Franzes A Liongson, Devi Nampiaparampil, Annu Navani, Mahendra Sanapati, Michael E Schatman, Amol Soin, Peter S Staats, Giustino Varrassi, Jing Wang, Laxmaiah Manchikanti

Faculty, Staff and Student Publications

Background: Complex Regional Pain Syndrome (CRPS) is a challenging and often disabling condition marked by persistent pain, most commonly in a limb following injury or surgery. It presents with a wide array of symptoms, including intense pain, swelling, alterations in skin color and temperature, motor dysfunction, and trophic changes such as skin and tissue atrophy. While the precise cause of CRPS is not fully understood, it is thought to stem from abnormal nervous system activity, leading to heightened pain sensitivity and inflammatory responses. A thorough understanding of CRPS is essential for accurate diagnosis, effective treatment, and enhancing patients' quality of …

Chronic Pain Is Associated With Greater Brain Entropy In The Prefrontal Cortex, Gianpaolo Del Mauro, Yiran Li, Jiaao Yu, Peter Kochunov, Landrew Samuel Sevel, Jeff Boissoneault, Shuo Chen, Ze Wang

Faculty, Staff and Student Publications

Chronic pain is a debilitating clinical condition and a severe public health issue that demands to be addressed. Neuroimaging-based techniques have been widely adopted to investigate the neural underpinnings of chronic pain. Despite the efforts the complex nature of pain experience as well as the heterogeneity of chronic pain have made the identification of neuroimaging-based biomarkers extremely challenging. In this study, resting-state fMRI-based brain entropy, a measure reflecting the "irregularity" of brain activity, was adopted as a biomarker of chronic pain by comparing individuals with chronic pain and healthy controls in a sample of middle-to-old-age participants (n > 30,000) drawn from …

Assessment Of Complement Cascade Components In Patients With Major Depressive Disorder, Brandi Quintanilla, Dede Greenstein, Ashutosh Tripathi, Alona Bartosh, Peixiong Yuan, Carlos A Zarate, Anilkumar Pillai

Faculty, Staff and Student Publications

Recent evidence suggests that the rapid-acting antidepressant ketamine has immune regulatory functions. The complement system is an important component of the innate immune response and plays a key role in synaptic plasticity. An increase in complement component 3 (C3) expression was previously found in the prefrontal cortex of individuals with depression. Given the complement system's role in depression and ketamine's potential anti-inflammatory properties, there is reason to suspect overlap between the complement system and ketamine's mechanism of action. This post-hoc study analyzed data from 39 individuals with major depressive disorder (MDD) and 25 healthy volunteers who previously participated in a …

Interconnections Of Insulin/Igf-1 Signaling And Autophagy Abnormalities In Alzheimer’S Disease, Wang Liao, Jinfeng Xuan, Woo-In Ryu, Mariana K Bormann, Yoon Lee, Haley Dion, Elizabeth Evangelista, Ruiyi Li, Lucas Trambaiolli, Jun Liu, Arthur J Siegel, Brent P Forester, Bruce M Cohen, Kai-Christian Sonntag

Faculty, Staff and Student Publications

Introduction: Impaired insulin (INS) and insulin-like growth factor 1 (IGF-1) signaling are features of both brain aging and late-onset Alzheimer's disease (LOAD). However, their exact underlying mechanisms and cause-and-effect linkages, including the downstream regulation of endocytosis and autophagy, are still not well understood.

Methods: We investigated INS/IGF-1 signaling and its connection with endocytic and autophagic processes in fibroblasts from LOAD patients and healthy young or old control individuals.

Results: Compared to control old-age cells, protein levels in the INS/IGF-1 signaling cascade were elevated in LOAD cells, but activation of AKT was reduced. The activation of the INS/IGF-1/AKT/FOXO1 or mTOR axes …

Ovarian Cancer Risk And Survival According To Tumor Sex Hormone Receptor Expression: An Ovarian Cancer Association Consortium And Ovarian Tumor Tissue Analysis Consortium Pooled Analysis, Zhuxuan Fu, Lauren Borho, Sarah E Taylor, Linda E Kelemen, Anna Defazio, Penelope M Webb, Martin Köbel, Nicola S Meagher, Renhua Na, Antonis C Antoniou, Alison H Brand, Catherine J Kennedy, Nikilyn Nevins, Paul D P Pharoah, Yurii B Shvetsov, Stacey J Winham, Jennifer Alsop, Matthias W Beckmann, Adelyn Bolithon, Jessica Boros, David D L Bowtell, James D Brenton, Michael E Carney, Anita Chudecka-Głaz, Linda S Cook, Cezary Cybulski, Peter A Fasching, Sian Fereday, Renée T Fortner, María J García, Ellen L Goode, Marc T Goodman, Jacek Gronwald, Arndt Hartmann, Brenda Y Hernandez, Estrid Høgdall, David G Huntsman, Allan Jensen, Mercedes Jimenez-Linan, Janine M Joseph, Beth Y Karlan, Ewa Kaznowska, Susanne K Kjaer, Tomasz Kluz, Jennifer M Koziak, Jenny Lester, Teri A Longacre, Maria Lycke, Valerie Mcguire, Kirsten B Moysich, Rachel A Murphy, Sandra Orsulic, Susan J Ramus, Cristina Rodríguez-Antona, Joseph H Rothstein, Spinder Samra, Weiva Sieh, Helen Steed, Karin Sundfeldt, Aline Talhouk, Jan Uciński, Chen Wang, Nicolas Wentzensen, Alice S Whittemore, Lynne R Wilkens, Thomas Songer, Maria Mori Brooks, Lu Tang, Francesmary Modugno

Faculty, Staff and Student Publications

Objective: Many epithelial ovarian cancer (EOC) risk factors relate to sex hormones. The association between these factors and the expression of androgen receptor (AR), estrogen receptor-α (ER), and progesterone receptor (PR) in tumors is unknown.

Method: We linked epidemiologic, AR/ER/PR tumor expression, and survival data from 19 studies in the Ovarian Cancer Association Consortium (OCAC; 4762 cases, 20,888 controls) and the Ovarian Tumor Tissue Analysis (OTTA) consortium (5737 cases). We estimated odds ratios (ORs) and 95 % confidence intervals (CIs) between hormonally-linked factors and tumor AR/ER/PR expression using polytomous logistic regression. We assessed survival by AR/ER/PR tumor expression overall and …

Bayesian Inference Of Fitness Landscapes Via Tree-Structured Branching Processes, Xiang Ge Luo, Jack Kuipers, Kevin Rupp, Koichi Takahashi, Niko Beerenwinkel

Faculty, Staff and Student Publications

Motivation: The complex dynamics of cancer evolution, driven by mutation and selection, underlies the molecular heterogeneity observed in tumors. The evolutionary histories of tumors of different patients can be encoded as mutation trees and reconstructed in high resolution from single-cell sequencing data, offering crucial insights for studying fitness effects of and epistasis among mutations. Existing models, however, either fail to separate mutation and selection or neglect the evolutionary histories encoded by the tumor phylogenetic trees.

Results: We introduce FiTree, a tree-structured multi-type branching process model with epistatic fitness parameterization and a Bayesian inference scheme to learn fitness landscapes from single-cell …

Βiv Spectrin Abundancy, Cellular Distribution And Sensitivity To Akt/Gsk3 Regulation In Schizophrenia, Jessica Di Re, Michela Marini, Syed Ibrar Hussain, Aditya K Singh, Akshaya Venkatesh, Musaad A Alshammari, Tahani K Alshammari, Abdul-Rizaq Ali Hamoud, Ali Sajid Imami, Zahra Haghighijoo, Nickolas Fularcyzk, Laura Stertz, Derek Hawes, Angela Mosebarger, Jordan Jernigan, Claire Chaljub, Ralda Nehme, Consuelo Walss-Bass, Anton Schulmann, Marquis P Vawter, Robert Mccullumsmith, Robert D Damoiseaux, Agenor Limon, Demetrio Labate, Michael F Wells, Fernanda Laezza

Faculty, Staff and Student Publications

Schizophrenia (SCZ) is a complex psychiatric disorder with unclear biological mechanisms. Spectrins, cytoskeletal proteins linked to neurodevelopmental disorders, are regulated by the AKT/GSK3 pathway, which is implicated in SCZ. However, the impact of SCZ-related dysregulation of this pathway on spectrin expression and distribution remains unexplored. Here, we show that βIV spectrin protein levels were reduced in neurons of the dorsolateral prefrontal cortex in SCZ postmortem samples compared to healthy control (HC) from the Human Brain Collection Core (HBCC). To investigate potential links between βIV spectrin and the AKT/GSK3 pathway, we analyzed the PsychEncode dataset, revealing elevated SPTBN4 and AKT2 mRNA …

Targeting Cdk2 And Other Novel Cell Cycle Targets For Breast Cancer Therapy, Mei-Kuang Chen, Linjie Luo, Nicole Massoumi, Khandan Keyomarsi

Faculty, Staff and Student Publications

Introduction: The dysregulation of cyclin-dependent kinases (CDKs) is a key driver of cancer progression, making them attractive therapeutic targets. In CDK4/6 inhibitor (CDK4/6i)-resistant breast cancer, targeting CDK2 offers a promising approach. CDK2 is frequently hyperactivated due to cyclin E1 overexpression or retinoblastoma protein loss, acting as a mechanism that sustains proliferation despite CDK4/6 inhibition. CDK2 inhibitors (CDK2i) show strong anti-tumor activity, particularly in combination with CDK4/6i or immune checkpoint inhibitors.

Areas covered: This review explores the biological roles of CDK2 and its regulatory mechanisms. The review highlights the latest advancements in CDK2i, their mechanisms of action, and their potential in …

Long-Term Cytoreduction Outcomes With Or Without Heated Intraperitoneal Chemotherapy For Colorectal Peritoneal Metastases, Michael G White, Paula Marincola Smith, Neal Bhutiani, Beth Helmink, Norman Galbraith, Scott Kopetz, Michael Overman, Paul Mansfield, Keith Fournier, Abhineet Uppal

Faculty, Staff and Student Publications

Background: Patients with peritoneal metastases from colorectal adenocarcinoma (CRC) benefit from cytoreductive surgery (CRS). However, the role of heated intraperitoneal chemotherapy (HIPEC) remains unclear. We studied associations between HIPEC, peritoneal disease-free survival (PDFS), and overall survival (OS) in patients with CRC undergoing CRS.

Study design: All patients with CRC undergoing CRS between 2008 and 2023 were retrospectively identified at our center. Patient clinicodemographic factors were determined by chart review. OS and PDFS were evaluated using the Kaplan-Meier method. Associations between clinical factors and survival were determined using Cox proportional hazard models.

Results: A total of 147 patients were identified with …

Germline And Somatic Changes Associated With The Development Of Inherited And De Novo Pediatric Acute Myeloid Leukemia., Scott C. Smith, Lei Zhang

Manuscripts, Articles, Book Chapters and Other Papers

Acute myeloid leukemia (AML) accounts for only about 15-20% of pediatric leukemia and an overall incidence of 1.4 cases per 200,000 children under the age of 15 years. The majority of pediatric AML occurs de novo, often as the result of somatic first hits in utero. A minority of pediatric AML occurs in response to a predisposition syndrome, such as a bone marrow failure syndrome, or other inherited mutations and copy number changes. While the overall survival of pediatric patients with AML is approximately 70%, survival at the individual level is dependent on the abnormality detected either through cytogenomic analyses …

Pathologist-Read Vs Ai-Driven Assessment Of Tumor-Infiltrating Lymphocytes In Melanoma, Thazin N Aung, Matthew Liu, David Su, Saba Shafi, Ceren Boyaci, Sanna Steen, Nikolaos Tsiknakis, Joan Martinez Vidal, Nigel Maher, Goran Micevic, Samuel X Tan, Matthew D Vesely, Saeed Nourmohammadi, Yalai Bai, Dijana Djureinovic, Pok Fai Wong, Katherine Bates, Nay N N Chan, Niki Gavirelatou, Mengni He, Sneha Burela, Robert Barna, Martina Bosic, Konstantin Bräutigam, Irineu Illabochaca, Zhou Chenhao, Joao Gama, Bianca Kreis, Reka Mohacsi, Nir Pillar, Joao Pinto, Christos Poulios, Maria Angeliki Toli, Evangelos Tzoras, Yadriel Bracero, Francesca Bosisio, Gábor Cserni, Alis Dema, Francesco Fortarezza, Mercedes Solorzano Gonzalez, Irene Gullo, Francisco Javier Queipo Gutiérrez, Ezgi Hacihasanoglu, Viktor Jovic, Bianca Lazar, Maria Olinca, Christina Neppl, Rui Caetano Oliveira, Federica Pezzuto, Daniel Gomes Pinto, Vanda Plotar, Ovidiu Pop, Tilman Rau, Kristijan Skok, Wenwen Sun, Ezgi Dicle Serbes, Wiebke Solass, Olga Stanowska, Marcell Szasz, Krzysztof Szymonski, Franziska Thimm, Danielle Vignati, Alon Vigdorovits, Victor Prieto, Tobias Sinnberg, James Wilmott, Shawn Cowper, Jonathan Warrell, Yvonne Saenger, Johan Hartman, Jasmine Plummer, Iman Osman, David L Rimm, Balazs Acs

Faculty, Staff and Student Publications

Importance: Tumor-infiltrating lymphocytes (TILs) are a provocative biomarker in melanoma, influencing diagnosis, prognosis, and immunotherapy outcomes; however, traditional pathologist-read TIL assessment on hematoxylin and eosin-stained slides is prone to interobserver variability, leading to inconsistent clinical decisions. Therefore, development of newer TIL scoring approaches that produce more reliable and consistent readouts is important.

Objective: To evaluate the analytical and clinical validity of a machine learning algorithm for TIL quantification in melanoma compared with traditional pathologist-read methods.

Design, setting, and participants: This multioperator, global, multi-institutional prognostic study compared TIL scoring reproducibility between traditional pathologist-read methods and an artificial intelligence (AI)-driven approach. The …

Adtnorm: Robust Integration Of Single-Cell Protein Measurement Across Cite-Seq Datasets, Ye Zheng, Daniel P Caron, Ju Yeong Kim, Seong-Hwan Jun, Yuan Tian, Florian Mair, Kenneth D Stuart, Peter A Sims, Raphael Gottardo

Faculty, Staff and Student Publications

Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) enables paired measurement of surface protein and mRNA expression in single cells using antibodies conjugated to oligonucleotide tags. Due to the high copy number of surface protein molecules, sequencing antibody-derived tags (ADTs) allows for robust protein detection, improving cell-type identification. However, variability in antibody staining leads to batch effects in the ADT expression, obscuring biological variation, reducing interpretability, and obstructing cross-study analyses. Here, we present ADTnorm, a normalization and integration method designed explicitly for ADT abundance. Benchmarking against 14 existing scaling and normalization methods, we show that ADTnorm accurately aligns populations …

The Landmark Series: Therapeutic Cancer Vaccine Strategies For Cold Tumors, Alex B Blair, Lei Zheng, Kevin C Soares

Faculty, Staff and Student Publications

Immunologically cold tumors present a significant challenge in cancer treatment due to their limited baseline immune infiltration and resistance to immunotherapy. Cancer vaccines offer a promising strategy to overcome this barrier by introducing high-quality, tumor-relevant antigens that can stimulate an effective anti-tumor immune response. Therapeutic cancer vaccines are being explored in the neoadjuvant, adjuvant, and minimal residual disease contexts to enhance immune activation and promote immune cell infiltration and function, with the goal to eradicate malignant cells and improve patient survival. Critical hurdles remain in optimizing antigen selection, determining the most effective vaccine formulations, and defining the ideal clinical setting …

The Evolution Of Multidisciplinary Head And Neck Cancer Treatment, Kevin J Contrera, Pooja D Reddy, Vanessa Helou, Jeffrey N Myers, Heath D Skinner, Renata Ferrarotto, Eugene N Myers

Faculty, Staff and Student Publications

Objective: The management of head and neck squamous cell carcinoma (HNSCC) has substantially changed over the past two centuries. This review explores the historical progression of HNSCC management focusing on the multidisciplinary treatment paradigm.

Data sources: This review synthesizes data from historical and current clinical trials, books, scientific reports, public documents, and other written material relevant to HNSCC management.

Review methods: Historical review.

Results: Although surgery was initially the only treatment available, radiation, chemotherapy, and immunotherapy have expanded the treatment landscape for HNSCC. Despite continuous evolution, modern treatment of HNSCC remains rooted in a multidisciplinary, personalized approach. This review highlights …

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, Kevin J Harrington, Sung-Bae Kim, Christophe Le Tourneau, 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 …

Developing Reference Plans For Evaluating Global Clinical Trials Credentialing And Psqa Systems, Fre'etta M D Brooks, Mohammad Hussein, Jessica Lye, Christopher L Nelson, Nakamura Mitsuhiro, Mallory C Glenn, Patricia Diez, Rushil Patel, Maddison Shaw, Ileana Silvestre Patallo, Miriam Barry, Catharine H Clark, Joerg Lehmann, Stephen F Kry

Faculty, Staff and Student Publications

Purpose: To develop a practical framework for creating a diverse set of validated reference plans (varying in complexity) and implement a workflow to introduce beam modeling, calibration, and delivery errors into the reference cohort to test and compare various dosimetry audit methodologies.

Methods: Sixteen IMRT and VMAT reference plans were created, using RayStation software, for four phantom geometries based on established credentialing cases from participating Global Harmonization Group (GHG) members. These reference plans were first validated in a multi-ion-chamber phantom. Nine dosimetric errors (perturbations) were introduced into the plans by modifying beam model and/or delivery parameters (MLC-offset, MLC-transmission, leaf-tip-width, PDD, …

Mutation Dynamics From Diagnosis To Relapse In Acute Myeloid Leukemia With Chromosomal 7 Deletions, Eitan Kugler, Enes Dasdemir, Alex Bataller, Bofei Wang, Courtney D Dinardo, Naval Daver, Musa Yilmaz, Nicholas J Short, Gautam Borthakur, Tapan M Kadia, Koji Sasaki, Danielle Hammond, Alexandre Bazinet, Ehsan Irajizad, Beenu Thakral, Sherry Pierce, Patrick Reville, Farhad Ravandi, Hussein A Abbas

Faculty, Staff and Student Publications

Monosomy 7 and 7q deletions (-7/del(7q)) are the most common adverse cytogenetic event in acute myeloid leukemia (AML), linked to high relapse rates. We analyzed 115 AML patients with -7/del(7q) who achieved remission after induction therapy to characterize the mutational landscape from diagnosis to relapse. Median overall survival (OS) was 10.4 months, with improved survival in patients without TP53 mutation (13.04 vs. 8.6 months) or complex karyotype (12.4 vs. 8.6 months). TP53 mutations were most frequent (67% of cases at diagnosis) and persisted in 97% of patients at relapse. At time of relapse, patients with TP53 mutations had fewer co-occurring …

A Visual-Omics Foundation Model To Bridge Histopathology With Spatial Transcriptomics, Weiqing Chen, Pengzhi Zhang, Tu N Tran, Yiwei Xiao, Shengyu Li, Vrutant V Shah, Hao Cheng, Kristopher W Brannan, Keith Youker, Li Lai, Longhou Fang, Yu Yang, Nhat-Tu Le, Jun-Ichi Abe, Shu-Hsia Chen, Qin Ma, Ken Chen, Qianqian Song, John P Cooke, Guangyu Wang

Faculty, Staff and Student Publications

Artificial intelligence has revolutionized computational biology. Recent developments in omics technologies, including single-cell RNA sequencing and spatial transcriptomics, provide detailed genomic data alongside tissue histology. However, current computational models focus on either omics or image analysis, lacking their integration. To address this, we developed OmiCLIP, a visual-omics foundation model linking hematoxylin and eosin images and transcriptomics using tissue patches from Visium data. We transformed transcriptomic data into 'sentences' by concatenating top-expressed gene symbols from each patch. We curated a dataset of 2.2 million paired tissue images and transcriptomic data across 32 organs to train OmiCLIP integrating histology and transcriptomics. Building …

Blood Bacterial Dna Signatures In A Prospective Cohort Of Patients With Masld Cirrhosis, Suet-Ying Kwan, Lillian I Dolapchiev, Caren I Sanchez, Tiffany L Calderone, Jessica I Sanchez, Megha B Bhongade, Ahmed El Sabagh, Darrel W Cleere, Nakul Gupta, Prasun K Jalal, David W Victor, Laura Beretta

Faculty, Staff and Student Publications

Background: Predictive biomarkers are needed to identify individuals with metabolic dysfunction-associated steatotic liver disease (MASLD), at high risk for HCC. Our study aimed to determine whether the detection of circulating bacterial DNA could be associated with HCC development in MASLD patients with liver cirrhosis.

Methods: We developed a multicenter prospective cohort of patients with cirrhosis undergoing surveillance for HCC by contrast-enhanced magnetic resonance imaging. In a nested cohort study, we performed 16S rRNA sequencing of cell-free DNA extracted from 343 longitudinal plasma samples collected from 151 MASLD patients with cirrhosis. Among the 151 patients, 25 developed HCC during follow-up.

Results: …

Technical Development And In Silico Implementation Of Syntheticmr In Head And Neck Adaptive Radiation Therapy: A Prospective R-Ideal Stage 0/1 Technology Development Report, Lucas Mccullum, Samuel L Mulder, Natalie A West, Robert Aghoghovbia, Alaa Mohamed Shawky Ali, Hayden Scott, Travis C Salzillo, Yao Ding, Alex Dresner, Ergys Subashi, Dan Ma, R Jason Stafford, Ken-Pin Hwang, Clifton D Fuller

Faculty, Staff and Student Publications

Background: SyntheticMR has the capability of generating quantitative relaxometry maps and synthetic contrast-weighted MRI images in rapid acquisition times. Recently, it has gained attention in the diagnostic community, however, no studies have investigated its feasibility on the MR-Simulation or MR-Linac systems, especially as part of the head and neck adaptive radiation oncology workflow.

Purpose: Demonstrating its feasibility will facilitate rapid quantitative biomarker extraction, which can be leveraged to guide adaptive radiation therapy decision making.

Methods: Two phantoms, two healthy volunteers, and one patient were scanned using SyntheticMR on the MR-Simulation and MR-Linac devices with scan times between 4 to 6 …

Long-Term Transfusion Independence With Luspatercept Versus Epoetin Alfa In Erythropoiesis-Stimulating Agent-Naive, Lower-Risk Myelodysplastic Syndromes In The Commands Trial, Guillermo Garcia-Manero, Valeria Santini, Amer M Zeidan, Rami S Komrokji, Veronika Pozharskaya, Shelonitda Rose, Karen Keeperman, Yinzhi Lai, Sameer Kalsekar, Barkha Aggarwal, Dimana Miteva, David Valcárcel, Pierre Fenaux, Jake Shortt, Matteo Giovanni Della Porta, Uwe Platzbecker

Faculty, Staff and Student Publications

Introduction: The efficacy of erythropoiesis-stimulating agents (ESAs) for transfusion-dependent (TD) anemia in lower-risk myelodysplastic syndromes (LR-MDS) is limited. Luspatercept achieved significantly greater rates of red blood cell (RBC) transfusion independence (TI) versus epoetin alfa (an ESA) in the phase 3 COMMANDS trial. This analysis assessed long-term RBC-TI, cumulative response, and safety with luspatercept in COMMANDS.

Methods: Eligible patients aged ≥ 18 years, with ESA-naive, RBC TD LR-MDS were randomized 1:1 to receive luspatercept (1.0 mg/kg, titration to 1.75 mg/kg permitted) or epoetin alfa (450 IU/kg, titration to 1050 IU/kg). Disease assessment was carried out at week 24 (day 169) and …

Impacts Of Radiation On Metabolism And Vascular Cell Senescence, Junichi Abe, Khanh Chau, Anahita Mojiri, Guangyu Wang, Masayoshi Oikawa, Venkata S K Samanthapudi, Abigail M Osborn, Keila C Ostos-Mendoza, Karla N Mariscal-Reyes, Tammay Mathur, Abhishek Jain, Joerg Herrmann, Syed Wamique Yusuf, Sunil Krishnan, Anita Deswal, Steven H Lin, Sivareddy Kotla, John P Cooke, Nhat-Tu Le

Faculty, Staff and Student Publications

Significance: This review investigates how radiation therapy (RT) increases the risk of delayed cardiovascular disease (CVD) in cancer survivors. Understanding the mechanisms underlying radiation-induced CVD is essential for developing targeted therapies to mitigate these effects and improve long-term outcomes for patients with cancer.

Recent Advances: Recent studies have primarily focused on metabolic alterations induced by irradiation in various cancer cell types. However, there remains a significant knowledge gap regarding the role of chronic metabolic alterations in normal cells, particularly vascular cells, in the progression of CVD after RT.

Critical Issues: This review centers on RT-induced metabolic alterations in vascular cells …

Heat Shock Induces Alternative Polyadenylation Through Dynamic Dna Methylation And Chromatin Looping, Emily E Fink, Yi Zhang, Briana Santo, Anwita Siddavatam, Rosie Ou, Vishal Nanavaty, Byron H Lee, Angela H Ting

Faculty, Staff and Student Publications

Alternative cleavage and polyadenylation (APA) is a gene regulatory mechanism used by cells under stress to upregulate proteostasis-promoting transcripts, but how cells achieve this remains poorly understood. Previously, we elucidated a DNA methylation-regulated APA mechanism, in which gene body DNA methylation enhances distal poly(A) isoform expression by blocking CCCTC-binding factor (CTCF) binding and chromatin loop formation at APA control regions. We hypothesized that DNA methylation-regulated APA is one mechanism cells employ to induce proteostasis-promoting poly(A) isoforms. At the DNAJB6 cochaperone locus, acute heat shock resulted in binding of stress response transcription factors heat shock factor 1, ATF6, and YY1 at …