Genetic Phenomena Commons^™

Controlled Delivery Of Rosuvastatin Or Rapamycin Through Electrospun Bismuth Nanoparticle-Infused Perivascular Wraps Promotes Arteriovenous Fistula Maturation, Allan John R Barcena, Joy Vanessa D Perez, Marvin R Bernardino, Erin Marie D San Valentin, Jossana A Damasco, Carleigh Klusman, Benjamin Martin, Karem A Court, Biana Godin, Gino Canlas, Natalie Fowlkes, Richard R Bouchard, Jizhong Cheng, Steven Y Huang, Marites P Melancon

Faculty, Staff and Student Publications

In the context of arteriovenous fistula (AVF) failure, local delivery enables the release of higher concentrations of drugs that can suppress neointimal hyperplasia (NIH) while reducing systemic adverse effects. However, the radiolucency of polymeric delivery systems hinders long-term in vivo surveillance of safety and efficacy. We hypothesize that using a radiopaque perivascular wrap to deliver anti-NIH drugs could enhance AVF maturation. Through electrospinning, we fabricated multifunctional perivascular polycaprolactone (PCL) wraps loaded with bismuth nanoparticles (BiNPs) for enhanced radiologic visibility and drugs that can attenuate NIH—rosuvastatin (Rosu) and rapamycin (Rapa). The following groups were tested onto the AVFs of a total …

Loss Of The Dna Repair Gene Rnase H2 Identifies A Unique Subset Of Ddr-Deficient Leiomyosarcomas, Michael S Nakazawa, Ian M Silverman, Victoria Rimkunas, Artur Veloso, Dominik Glodzik, Adrienne Johnson, Toshiro K Ohsumi, Shreyaskumar R Patel, Anthony P Conley, Christina L Roland, Pamela T Soliman, Hannah C Beird, Chia-Chin Wu, Davis R Ingram, Rossana Lazcano, Dawon Song, Khalida M Wani, Alexander J Lazar, Timothy A Yap, Wei-Lien Wang, J Andrew Livingston

Faculty, Staff and Student Publications

Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR-targeted treatments. Therefore, we designed a protein- and genomic-based RNase H2 screening assay to determine its prevalence and prognostic significance. Using a selective RNase H2 antibody on a pan-tumor microarray (TMA), RNase H2 loss was more common in LMS (11.5%, 9/78) than across all tumors (3.8%, 32/843). In a separate LMS cohort, RNase H2 deficiency was confirmed in uterine LMS (U-LMS, 21%, 23/108) and soft-tissue LMS (ST-LMS; 30%, 39/102). In …

Inhibition Of Malt1 And Bcl2 Induces Synergistic Antitumor Activity In Models Of B-Cell Lymphoma, Joshua P Plotnik, Adam E Richardson, Haopeng Yang, Estela Rojas, Velitchka Bontcheva, Colleen Dowell, Sydney Parsons, Ashley Wilson, Vida Ravanmehr, Christine Will, Paul Jung, Haizhong Zhu, Sarathy Karunan Partha, Sanjay C Panchal, Raghuveer Singh Mali, Frederick J Kohlhapp, Ryan A Mcclure, Cyril Y Ramathal, Mariam D George, Manisha Jhala, Nathaniel L Elsen, Wei Qiu, Russell A Judge, Chin Pan, Anthony Mastracchio, Jared Henderson, Jonathan A Meulbroek, Michael R Green, William N Pappano

Faculty, Staff and Student Publications

The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 …

Epigenetic Regulation Of Heart Failure, Manisha Deogharia, Priyatansh Gurha

Faculty, Staff and Student Publications

Purpose of review: The studies on chromatin-modifying enzymes and how they respond to different stimuli within the cell have revolutionized our understanding of epigenetics. In this review, we provide an overview of the recent studies on epigenetic mechanisms implicated in heart failure.

Recent findings: We focus on the major mechanisms and the conceptual advances in epigenetics as evidenced by studies in humans and mouse models of heart failure. The significance of epigenetic modifications and the enzymes that catalyze them is also discussed. New findings from the studies of histone lysine demethylases demonstrate their significance in regulating fetal gene expression, as …

Sequencing Of Kaposi’S Sarcoma Herpesvirus (Kshv) Genomes From Persons Of Diverse Ethnicities And Provenances With Kshv-Associated Diseases Demonstrate Multiple Infections, Novel Polymorphisms, And Low Intra-Host Variance, Vickie A Marshall, Elena M Cornejo Castro, Charles A Goodman, Nazzarena Labo, Isabella Liu, Nicholas C Fisher, Kyle N Moore, Ananthakrishnan Nair, Taina Immonen, Brandon F Keele, Mark N Polizzotto, Thomas S Uldrick, Yunxiang Mu, Tanuja Saswat, Laurie T Krug, Kevin M Mcbride, Kathryn Lurain, Ramya Ramaswami, Robert Yarchoan, Denise Whitby

Faculty, Staff and Student Publications

Recently published near full-length KSHV genomes from a Cameroon Kaposi sarcoma case-control study showed strong evidence of viral recombination and mixed infections, but no sequence variations associated with disease. Using the same methodology, an additional 102 KSHV genomes from 76 individuals with KSHV-associated diseases have been sequenced. Diagnoses comprise all KSHV-associated diseases (KAD): Kaposi sarcoma (KS), primary effusion lymphoma (PEL), KSHV-associated large cell lymphoma (KSHV-LCL), a type of multicentric Castleman disease (KSHV-MCD), and KSHV inflammatory cytokine syndrome (KICS). Participants originated from 22 different countries, providing the opportunity to obtain new near full-length sequences of a wide diversity of KSHV genomes. …

Ccr2+ Monocytes Promote White Matter Injury And Cognitive Dysfunction After Myocardial Infarction, Edward B Thorp, Mallory Filipp, Maria Dima, Chunfeng Tan, Matthew Feinstein, Brian Popko, Matthew Deberge

Faculty, Staff and Student Publications

Survivors of myocardial infarction are at increased risk for vascular dementia. Neuroinflammation has been implicated in the pathogenesis of vascular dementia, yet little is known about the cellular and molecular mediators of neuroinflammation after myocardial infarction. Using a mouse model of myocardial infarction coupled with flow cytometric analyses and immunohistochemistry, we discovered increased monocyte abundance in the brain after myocardial infarction, which was associated with increases in brain-resident perivascular macrophages and microglia. Myeloid cell recruitment and activation was also observed in post-mortem brains of humans that died after myocardial infarction. Spatial and single cell transcriptomic profiling of brain-resident myeloid cells …

Exploring The Landscape Of Somatic Asxl2 Mutations In Myeloid Neoplasms: Frequency And Clinical Implications, Tareq Abuasab, Gautam Borthakur, Rashmi Kanagal-Shamanna, Lucia Masarova, Keyur Patel, Koichi Takahashi, Prithviraj Bose, John Villarreal, Sherry Pierce, Tapan Kadia, Guillermo Garcia-Manero, Nicholas J Short, Courtney Dinardo, Naval Daver, Farhad Ravandi, Hagop Kantarjian, Srdan Verstovsek, Musa Yilmaz

Faculty, Staff and Student Publications

No abstract provided.

Automated Quantification Of Measurable Residual Disease In Chronic Lymphocytic Leukemia Using An Artificial Intelligence-Assisted Workflow, Alexandre Bazinet, Alan Wang, Xinmei Li, Fuli Jia, Huan Mo, Wei Wang, Sa A Wang

Faculty, Staff and Student Publications

Detection of measurable residual disease (MRD) in chronic lymphocytic leukemia (CLL) is an important prognostic marker. The most common CLL MRD method in current use is multiparameter flow cytometry, but availability is limited by the need for expert manual analysis. Automated analysis has the potential to expand access to CLL MRD testing. We evaluated the performance of an artificial intelligence (AI)-assisted multiparameter flow cytometry (MFC) workflow for CLL MRD. We randomly selected 113 CLL MRD FCS files and divided them into training and validation sets. The training set (n = 41) was gated by expert manual analysis and used to …

Behavioral Therapies Targeting Reward Mechanisms In Substance Use Disorders, Margaret C Wardle, Heather E Webber, Jin H Yoon, Angela M Heads, Angela L Stotts, Scott D Lane, Joy M Schmitz

Faculty, Staff and Student Publications

Behavioral therapies are considered best practices in the treatment of substance use disorders (SUD) and used as first-line approaches for SUDs without FDA-approved pharmacotherapies. Decades of research on the neuroscience of drug reward and addiction have informed the development of current leading behavioral therapies that, while differing in focus and technique, have in common the overarching goal of shifting reward responding away from drug and toward natural non-drug rewards. This review begins by describing key neurobiological processes of reward in addiction, followed by a description of how various behavioral therapies address specific reward processes. Based on this review, a conceptual …

Mitochondrial Health, Physical Functioning, And Daily Affect: Bioenergetic Mechanisms Of Dementia Caregiver Well-Being, E Lydia Wu-Chung, Luis D Medina, Jensine Paoletti-Hatcher, Vincent Lai, Jennifer M Stinson, Itee Mahant, Paul E Schulz, Cobi J Heijnen, Christopher P Fagundes

Faculty, Staff and Student Publications

Objective: Chronic stress adversely affects mental and physical well-being. However, health outcomes vary among people experiencing the same stressor. Individual differences in physical and emotional well-being may depend on mitochondrial biology, as energy production is crucial for stress regulation. This study investigated whether mitochondrial respiratory capacity corresponds to individual differences in dementia spousal caregivers' mental and physical health.

Methods: Spousal caregivers of individuals with Alzheimer's disease and related dementias ( N = 102, mean age = 71, 78% female, 83% White) provided peripheral blood samples and completed self-report questionnaires on quality of life, caregiver burden, and a 7-day affect scale. …

Hairy Cell Leukemia Variant And Who Classification Correspondence Re: 5th Edition Who Classification Haematolymphoid Tumors: Lymphoid Neoplasms, Michael Grever, Leslie Andritsos, Mirela Anghelina, Evgeny Arons, Versha Banerji, Jacqueline Barrientos, Seema A Bhat, James Blachly, Alessandro Broccoli, Timothy Call, Claire Dearden, Sascha Dietrich, Monica Else, Narendranath Epperla, Andrei Fagarasanu, Brunangelo Falini, Francesco Forconi, Alessandro Gozzetti, Paul Hampel, David J Hermel, Sunil Iyengar, James B Johnston, Gunnar Juliusson, Robert J Kreitman, Francesco Lauria, Gerard Lozanski, Christopher C Oakes, Sameer A Parikh, Jae Park, Graeme Quest, Kanti Rai, Farhad Ravandi, Tadeusz Robak, Kerry A Rogers, Alan Saven, John F Seymour, Tamar Tadmor, Martin S Tallman, Constantine S Tam, Enrico Tiacci, Xavier Troussard, Bernhard Wörmann, Clive S Zent, Thorsten Zenz, Pier Luigi Zinzani

Faculty, Staff and Student Publications

No abstract provided.

A Bayesian Latent-Subgroup Platform Design For Dose Optimization, Rongji Mu, Xiaojiang Zhan, Rui Sammi Tang, Ying Yuan

Faculty, Staff and Student Publications

The US Food and Drug Administration launched Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development, calling for the paradigm shift from finding the maximum tolerated dose to the identification of optimal biological dose (OBD). Motivated by a real-world drug development program, we propose a master-protocol-based platform trial design to simultaneously identify OBDs of a new drug, combined with standards of care or other novel agents, in multiple indications. We propose a Bayesian latent subgroup model to accommodate the treatment heterogeneity across indications, and employ Bayesian hierarchical models to borrow information within subgroups. At …

Response-Adapted Ultra-Low-Dose 4 Gy Radiation As Definitive Therapy Of Gastric Malt Lymphoma: A Single-Centre, Pilot Trial, Jillian R Gunther, Jie Xu, Manoop S Bhutani, Paolo Strati, Penny Q Fang, Susan Y Wu, Bouthaina S Dabaja, Wenli Dong, Priya R Bhosale, Christopher R Flowers, Ranjit Nair, Luis Malpica Castillo, Luis Fayad, Swaminathan P Iyer, Simrit Parmer, Michael Wang, Hun Ju Lee, Felipe Samaniego, Jason Westin, Sairah Ahmed, Chijioke C Nze, Preetesh Jain, Sattva S Neelapu, Maria A Rodriguez, Dai Chihara, Loretta J Nastoupil, Chelsea C Pinnix

Faculty, Staff and Student Publications

Background: Given the favourable prognosis of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, treatment-related toxicity should be minimised. We aimed to evaluate the efficacy of 4 Gy radiotherapy given in a response-adapted approach.

Methods: We conducted a single-centre, single-arm, prospective trial at MD Anderson Cancer Center (Houston, TX, USA) of response-adapted ultra-low-dose radiotherapy. Eligible patients were 18 years or older and had newly diagnosed or relapsed Helicobacter pylori-negative gastric MALT lymphoma, with stage I-IV disease. Given the expected low toxicity profile of treatment, performance status was not an exclusion criterion. Patients received external beam photon-based radiotherapy for a total …

Identification Of A Clinically Efficacious Car T Cell Subset In Diffuse Large B Cell Lymphoma By Dynamic Multidimensional Single-Cell Profiling, Ali Rezvan, Gabrielle Romain, Mohsen Fathi, Darren Heeke, Melisa Martinez-Paniagua, Xingyue An, Irfan N Bandey, Melisa J Montalvo, Jay R T Adolacion, Arash Saeedi, Fatemeh Sadeghi, Kristen Fousek, Nahum Puebla-Osorio, Laurence J N Cooper, Chantale Bernatchez, Harjeet Singh, Nabil Ahmed, Mike Mattie, Adrian Bot, Sattva Neelapu, Navin Varadarajan

Faculty, Staff and Student Publications

Chimeric antigen receptor (CAR) T cells used for the treatment of B cell malignancies can identify T cell subsets with superior clinical activity. Here, using infusion products of individuals with large B cell lymphoma, we integrated functional profiling using timelapse imaging microscopy in nanowell grids with subcellular profiling and single-cell RNA sequencing to identify a signature of multifunctional CD8+ T cells (CD8-fit T cells). CD8-fit T cells are capable of migration and serial killing and harbor balanced mitochondrial and lysosomal volumes. Using independent datasets, we validate that CD8-fit T cells (1) are present premanufacture and are associated with clinical responses …

Health-Related Quality Of Life In Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma Treated With Daratumumab, Lenalidomide, Bortezomib, And Dexamethasone: Patient-Reported Outcomes From Griffin, Rebecca Silbermann, Jacob Laubach, Jonathan L Kaufman, Douglas W Sborov, Brandi Reeves, Cesar Rodriguez, Ajai Chari, Luciano J Costa, Larry D Anderson, Nitya Nathwani, Nina Shah, Naresh Bumma, Sarah A Holstein, Caitlin Costello, Andrzej Jakubowiak, Robert Z Orlowski, Kenneth H Shain, Andrew J Cowan, Katharine S Gries, Huiling Pei, Annelore Cortoos, Sharmila Patel, Thomas S Lin, Peter M Voorhees, Saad Z Usmani, Paul G Richardson

Faculty, Staff and Student Publications

In the phase 2 GRIFFIN trial (ClinicalTrials.gov identifier: NCT02874742), daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) improved depth of response and progression-free survival (PFS) versus lenalidomide, bortezomib, and dexamethasone (RVd) alone in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) collected using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30-item (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module 20-item (QLQ-MY20), and EuroQol 5-Dimension 5-Level (EQ-5D-5L) tools on day 1 of cycles 1, 2, and 3; on day 21 of cycle 4 (end of …

Molecular Characterization Of Metastatic Oncocytoma With Exceptional Response To Treatment: A Case Report, Bradley R Webster, Christopher J Ricketts, Cathy D Vocke, Dionna Gamble, Daniel R Crooks, Ye Yang, Lindsay Friedman, Antoun Toubaji, Pavlos Msaouel, Jonathan M Hernandez, W Marston Linehan, Mark W Ball

Faculty, Staff and Student Publications

Comprehensive molecular characterization and effective therapy in a rare case of metastatic renal oncocytoma.

Impact Of Apolipoprotein E Genotype On Neurocognitive Function In Patients With Brain Metastases: An Analysis Of Nrg Oncology's Rtog 0614, Jeffrey S Wefel, Snehal Deshmukh, Paul D Brown, David R Grosshans, Erik P Sulman, Jane H Cerhan, Minesh P Mehta, Deepak Khuntia, Wenyin Shi, Mark V Mishra, John H Suh, Nadia N Laack, Yuhchyau Chen, Amarinthia Amy Curtis, Joanna M Laba, Ahmed Elsayed, Anu Thakrar, Stephanie L Pugh, Deborah W Bruner

Faculty, Staff and Student Publications

Purpose: Whole-brain radiation therapy (WBRT) is a common treatment for brain metastases and is frequently associated with decline in neurocognitive functioning (NCF). The e4 allele of the apolipoprotein E (APOE) gene is associated with increased risk of Alzheimer disease and NCF decline associated with a variety of neurologic diseases and insults. APOE carrier status has not been evaluated as a risk factor for onset time or extent of NCF impairment in patients with brain metastases treated with WBRT.

Methods and materials: NRG/Radiation Therapy Oncology Group 0614 treated adult patients with brain metastases with 37.5 Gy of WBRT (+/- memantine), performed …

Technical Note: Radiological Clinical Equivalence For Phantom Materials In Carbon Ion Therapy, Paige A Taylor, Alfredo Mirandola, Mario Ciocca, Shannon Hartzell, Alessandro Vai, Paola Alvarez, Rebecca M Howell, Eugene J Koay, Christopher R Peeler, Christine B Peterson, Stephen F Kry

Faculty, Staff and Student Publications

Purpose: As carbon ion radiotherapy increases in use, there are limited phantom materials for heterogeneous or anthropomorphic phantom measurements. This work characterized the radiological clinical equivalence of several phantom materials in a therapeutic carbon ion beam.

Methods: Eight materials were tested for radiological material-equivalence in a carbon ion beam. The materials were computed tomography (CT)-scanned to obtain Hounsfield unit (HU) values, then irradiated in a monoenergetic carbon ion beam to determine relative linear stopping power (RLSP). The corresponding HU and RLSP for each phantom material were compared to clinical carbon ion calibration curves. For absorbed dose comparison, ion chamber measurements …

Cancer Incidence After Diagnosis Of Abdominal Aortic Aneurysm-Brief Report, Lingfeng Luo, Allen M Haas, Caitlin F Bell, Richard A Baylis, Shaunak S Adkar, Changhao Fu, Ivan Angelov, Sharon H Giordano, Derek Klarin, Nicholas J Leeper, Kevin T Nead

Faculty, Staff and Student Publications

Background: Epidemiological and mechanistic data support a potential causal link between cardiovascular disease (CVD) and cancer. Abdominal aortic aneurysms (AAAs) represent a common form of CVD with at least partially distinct genetic and biologic pathogenesis from other forms of CVD. The risk of cancer and how this risk differs compared with other forms of CVD, is unknown among AAA patients. We conducted a retrospective cohort study using the IBM MarketScan Research Database to test whether individuals with AAA have a higher cancer risk independent of traditional shared risk factors.

Methods: All individuals ≥18 years of age with ≥36 months of …

Breast Cancer (Bc) And Severe Covid-19 (C-19) Outcomes: A Matched Analysis, Marija Sullivan, Xiudong Lei, Sharon H Giordano, Mariana Chavez-Macgregor

Faculty, Staff and Student Publications

Purpose: Patients with cancer receiving anticancer treatment have a higher risk of severe COVID-19 (C-19) outcomes. We examine the association between breast cancer (BC), recent treatment (systemic therapy, surgery, radiation), and C-19 outcomes.

Methods: Retrospective matched cohort study using the Optum® de-identified C-19 Electronic Health Record dataset (2007-2022). Patients with C-19 were categorized into: no cancer, BC with recent treatment, and BC without recent treatment and matched based on age, C-19 diagnosis date, and comorbidity score. We evaluated 30-day mortality, mechanical ventilation, intensive care unit (ICU) stay, and hospitalization. A composite outcome including all outcomes was analyzed. Multivariable logistic regression …

Delivery Of Hereditary Cancer Genetics Services To Patients Newly Diagnosed With Ovarian And Endometrial Cancers At Three Gynecologic Oncology Clinics In The Usa, Brazil, And Mexico, Erica M Bednar, Keiry A Paiz, Karen H Lu, Aline Patricia Soares Dias De Souza, Gabriela Oliveira, Carlos E Eduardo Mattos Da Cunha Andrade, Lenny Gallardo, Jairo Rubio-Cordero, David Cantu-De-León, Jose Alejandro Rauh-Hain

Faculty, Staff and Student Publications

Objective: Three gynecologic oncology clinics located in the USA, Brazil, and Mexico collaborated to evaluate their delivery of hereditary cancer genetics services. This descriptive retrospective review study aimed to establish baseline rates and timeliness of guideline-recommended genetics service delivery to patients with ovarian, fallopian tube, primary peritoneal (ovarian), and endometrial cancers at each clinic.

Methods: Patients who were newly diagnosed with ovarian and endometrial cancers between September 1, 2018 and December 31, 2020 were identified from the medical records of the clinics. Genetics service delivery metrics included the rates of mismatch repair deficiency tumor testing for patients with endometrial cancer …

Evaluating The Relationship Between Magnetic Resonance Image Quality Metrics And Deep Learning-Based Segmentation Accuracy Of Brain Tumors, Rajarajeswari Muthusivarajan, Adrian Celaya, Joshua P Yung, James P Long, Satish E Viswanath, Daniel S Marcus, Caroline Chung, David Fuentes

Faculty, Staff and Student Publications

Background: Magnetic resonance imaging (MRI) scans are known to suffer from a variety of acquisition artifacts as well as equipment-based variations that impact image appearance and segmentation performance. It is still unclear whether a direct relationship exists between magnetic resonance (MR) image quality metrics (IQMs) (e.g., signal-to-noise, contrast-to-noise) and segmentation accuracy.

Purpose: Deep learning (DL) approaches have shown significant promise for automated segmentation of brain tumors on MRI but depend on the quality of input training images. We sought to evaluate the relationship between IQMs of input training images and DL-based brain tumor segmentation accuracy toward developing more generalizable models …

Pten Deficiency Induces An Extrahepatic Cholangitis-Cholangiocarcinoma Continuum Via Aurora Kinase A In Mice, Yan Yang, Jiale Wang, Jianhua Wan, Qianqian Cheng, Zenong Cheng, Xueli Zhou, Oliver Wang, Kelvin Shi, Lingxiang Wang, Bin Wang, Xiaohui Zhu, Jiaxiang Chen, Dongfeng Feng, Yang Liu, Yasmin Jahan-Mihan, Ashley N Haddock, Brandy H Edenfield, Guang Peng, Jessica D Hohenstein, Chantal E Mccabe, Daniel R O'Brien, Chen Wang, Sumera I Ilyas, Liuyan Jiang, Michael S Torbenson, Huamin Wang, Raouf E Nakhleh, Xuemei Shi, Ying Wang, Yan Bi, Gregory J Gores, Tushar Patel, Baoan Ji

Faculty, Staff and Student Publications

Background & aims: The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aimed to evaluate the role of PTEN in the pathogenesis of eCCA and identify novel therapeutic targets for this disease.

Methods: The Pten gene was genetically deleted using the Cre-loxp system in biliary epithelial cells. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry, reverse-transcription PCR, cell culture, and RNA sequencing. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. We also tested the …

Defining The Subset Of Mutations In Polymerase Epsilon (Pole) Associated With Loss-Of-Proofreading (Lop) Functionality, G Maddalena, F A Zeineddine, S Rivero-Hinojosa, V N Aushev, S Chowdhury, M A Zeineddine, A M Yousef, T A Yap, A C Einaggar, M C Liu, M White, M J Overman, S Kopetz, J P Shen

Faculty, Staff and Student Publications

No abstract provided.

Navigating The Critical Translational Questions For Implementing Flash In The Clinic, Billy W Loo, Ioannis I Verginadis, Brita Singers Sørensen, Anthony E Mascia, John P Perentesis, Albert C Koong, Emil Schüler, Erinn B Rankin, Peter G Maxim, Charles L Limoli, Marie-Catherine Vozenin

Faculty, Staff and Student Publications

The "FLASH effect" is an increased therapeutic index, that is, reduced normal tissue toxicity for a given degree of anti-cancer efficacy, produced by ultra-rapid irradiation delivered on time scales orders of magnitude shorter than currently conventional in the clinic for the same doses. This phenomenon has been observed in numerous preclinical in vivo tumor and normal tissue models. While the underlying biological mechanism(s) remain to be elucidated, a path to clinical implementation of FLASH can be paved by addressing several critical translational questions. Technological questions pertinent to each beam type (eg, electron, proton, photon) also dictate the logical progression of …

The Dynamic Trpv2 Ion Channel Proximity Proteome Reveals Functional Links Of Calcium Flux With Cellular Adhesion Factors Ncam And L1cam In Neurite Outgrowth, Pamela N Gallo, Elaine Mihelc, Robyn Eisert, Gary A Bradshaw, Florian Dimek, Andreas Leffler, Marian Kalocsay, Vera Moiseenkova-Bell

Faculty, Staff and Student Publications

TRPV2 voltage-insensitive, calcium-permeable ion channels play important roles in cancer progression, immune response, and neuronal development. Despite TRPV2's physiological impact, underlying endogenous proteins mediating TRPV2 responses and affected signaling pathways remain elusive. Using quantitative peroxidase-catalyzed (APEX2) proximity proteomics we uncover dynamic changes in the TRPV2-proximal proteome and identify calcium signaling and cell adhesion factors recruited to the molecular channel neighborhood in response to activation. Quantitative TRPV2 proximity proteomics further revealed activation-induced enrichment of protein clusters with biological functions in neural and cellular projection. We demonstrate a functional connection between TRPV2 and the neural immunoglobulin cell adhesion molecules NCAM and L1CAM. …

New Full-Counts Phase-Matched Data-Driven Gated (Ddg) Pet/Ct, Peng Sun, M Allan Thomas, Dershan Luo, Tinsu Pan

Faculty, Staff and Student Publications

Background: Data-driven gated (DDG) PET has gained clinical acceptance and has been shown to match or outperform external-device gated (EDG) PET. However, in most clinical applications, DDG PET is matched with helical CT acquired in free breathing (FB) at a random respiratory phase, leaving registration, and optimal attenuation correction (AC) to chance. Furthermore, DDG PET requires additional scan time to reduce image noise as it only preserves 35%-50% of the PET data at or near the end-expiratory phase of the breathing cycle.

Purpose: A new full-counts, phase-matched (FCPM) DDG PET/CT was developed based on a low-dose cine CT to improve …

Intratumoral Injection Of Immunotherapeutics: State Of The Art And Future Directions, Rahul A Sheth, Eric Wehrenberg-Klee, Sapna P Patel, Kristy K Brock, Nicos Fotiadis, Thierry De Baère

Faculty, Staff and Student Publications

Systemic immunotherapies have led to tremendous progress across the cancer landscape. However, several challenges exist, potentially limiting their efficacy in the treatment of solid tumors. Direct intratumoral injection can increase the therapeutic index of immunotherapies while overcoming many of the barriers associated with systemic administration, including limited bioavailability to tumors and potential systemic safety concerns. However, challenges remain, including the lack of standardized approaches for administration, issues relating to effective drug delivery, logistical hurdles, and safety concerns specific to this mode of administration. This article reviews the biologic rationale for the localized injection of immunotherapeutic agents into tumors. It also …

Evaluation Of Major Pathologic Response And Pathologic Complete Response As Surrogate End Points For Survival In Randomized Controlled Trials Of Neoadjuvant Immune Checkpoint Blockade In Resectable In Nsclc, Jacobi B Hines, Robert B Cameron, Alessandra Esposito, Leeseul Kim, Luca Porcu, Antonio Nuccio, Giuseppe Viscardi, Roberto Ferrara, Giulia Veronesi, Patrick M Forde, Janis Taube, Everett Vokes, Christine M Bestvina, James M Dolezal, Matteo Sacco, Marta Monteforte, Tina Cascone, Marina C Garassino, Valter Torri

Faculty, Staff and Student Publications

Introduction: Controversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate end points for event-free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable NSCLC.

Methods: A search of PubMed and archives of international conference abstracts was performed from June 2017 through October 31, 2023. Studies incorporating a neoadjuvant arm with immune checkpoint blockade alone or in combination with chemotherapy were included. Those not providing information regarding pCR, MPR, EFS, or OS were excluded. For trial-level surrogacy, log ORs for pCR and MPR and log hazard ratios for EFS and OS were …

Mycophenolate Mofetil Is Associated With Inferior Overall Survival In Cytomegalovirus-Seropositive Patients With Acute Myeloid Leukemia Undergoing Hematopoietic Cell Transplantation, Rima M Saliba, Stephanie J Lee, Paul A Carpenter, Geoffrey R Hill, Catherine J Lee, Amin Alousi, May Daher, George Chen, Richard E Champlin, Katayoun Rezvani, Elizabeth J Shpall, Rohtesh S Mehta

Faculty, Staff and Student Publications

No abstract provided.