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Uncertainty In The Physical Basis Of Estimates Of Relative Biological Effectiveness In Carbon Radiotherapy, Shannon Hartzell, Shannon Hartzell Ph.D.

Dissertations and Theses (Open Access)

Carbon ion radiotherapy is a novel modality used for the treatment of tumors that are unresectable, close to critical structures, or resistant to standard radiotherapy. A unique benefit of this therapy is the relative biological effectiveness (RBE) of the beam (i.e., how biologically potent carbon ions are as compared to x-rays), which is significantly elevated. This RBE also varies as a function of many parameters, and there are currently several models implemented in clinical and research-based treatment planning systems with which to predict RBE. These algorithms are computationally expensive and there are currently no means of validating their implementation within …

Role Of Il-17/Il-17ra Signaling In The Pancreatic Tumor Microenvironment, Susana Castro Pando, Susana Castro Pando

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related deaths. PDAC is characterized by the early establishment of a highly immunosuppressive fibro-cellular tumor microenvironment (TME). Our research has revealed the important role of IL-17 in the development and progression of pancreatic cancer, yet the specific cellular compartment responsible for IL-17-mediated tumor promotion remains unknown. We generated a transgenic mouse model with pancreatic KrasG12D activation and selective deletion of IL-17RA in the epithelial vs. immune component using either genetic manipulation or bone marrow transplantation. Deletion of IL17RA from the pancreatic epithelial compartment delayed premalignant lesion development …

Investigating The Role Of Il-10 Producing Nkt Cells In Prevention Of Graft Versus Host Disease, Drew Boagni

Dissertations and Theses (Open Access)

The standard curative treatment for hematologic malignancies is allogeneic stem cell transplantation (ASCT), in which the patient’s immune system is replaced with that of a healthy donor. This can lead to cure through the graft versus leukemia (GVL) effect but can also cause graft versus host disease (GVHD), which is characterized by systemic inflammation and organ damage mediated by dysregulated donor T cells. Preclinical studies have shown invariant natural killer T cells (iNKT) cells can prevent GVHD while preserving GVL. iNKT cells are unconventional T cells which recognize glycolipid antigens presented in the context of CD1d. Upon activation, they secrete …

Integrative Prognostic Machine Learning Models In Mantle Cell Lymphoma, Holly A Hill, Preetesh Jain, Chi Young Ok, Koji Sasaki, Han Chen, Michael L Wang, Ken Chen

Faculty, Staff and Student Publications

Patients with mantle cell lymphoma (MCL), an incurable B-cell malignancy, benefit from accurate pretreatment disease stratification. We curated an extensive database of 862 patients diagnosed between 2014 and 2022. A machine learning (ML) gradient-boosted model incorporated baseline features from clinicopathologic, cytogenetic, and genomic data with high predictive power discriminating between patients with indolent or responsive MCL and those with aggressive disease (AUC ROC = 0.83). In addition, we utilized the gradient-boosted framework as a robust feature selection method for multivariate logistic and survival modeling. The best ML models incorporated features from clinical and genomic data types highlighting the need for …

Upregulation Of Epac1 Promotes Pericyte Loss By Inducing Mitochondrial Fission, Reactive Oxygen Species Production, And Apoptosis, Wenli Yang, Fan Xia, Fang Mei, Shuizhen Shi, William G Robichaux, Wei Lin, Wenbo Zhang, Hua Liu, Xiaodong Cheng

The Brown Foundation: Institute of Molecular Medicine

PURPOSE: The pathogenic mechanisms behind the development of ischemic retinopathy are complex and poorly understood. This study investigates the involvement of exchange protein directly activated by cAMP (Epac)1 signaling in pericyte injury during ischemic retinopathy, including diabetic retinopathy, a disease that threatens vision.

METHODS: Mouse models of retinal ischemia-reperfusion injury and type 1 diabetes induced by streptozotocin were used to investigate the pathogenesis of these diseases. The roles of Epac1 signaling in the pathogenesis of ischemic retinopathy were determined by an Epac1 knockout mouse model. The cellular and molecular mechanisms of Epac1-mediated pericyte dysfunction in response to high glucose were …

Zeb1 Is Regulated By K811 Acetylation To Promote Stability, Nurd Complex Interactions, Emt, And Nsclc Metastasis, Mabel Perez-Oquendo, Roxsan Manshouri, Yanhua Tian, Jared J Fradette, B Leticia Rodriguez, Samrat T Kundu, Don L Gibbons

Faculty, Staff and Student Publications

Epithelial-to-mesenchymal transition results in loss of specialized epithelial cell contacts and acquisition of mesenchymal invasive capacity. The transcription repressor zinc finger E-box-binding homeobox 1 (ZEB1) binds to E-boxes of gene promoter regions to suppress the expression of epithelial genes. ZEB1 has inconsistent molecular weights, which have been attributed to posttranslational modifications (PTM). We performed mass spectrometry and identified K811 acetylation as a novel PTM in ZEB1. To define the role of ZEB1 acetylation in regulating function, we generated ZEB1 acetyl-mimetic (K811Q) and acetyl-deficient (K811R) mutant-expressing non-small cell lung cancer cell lines (NSCLC). We demonstrate that the K811R ZEB1 (125 kDa) …

Symptom Experience Of Patients With Advanced Melanoma Undergoing Immune Checkpoint Inhibitor Therapy, Natalie Jackson-Carroll

Dissertations and Theses (Open Access)

Background: Immune checkpoint inhibitors (ICIs) are novel therapeutic agents utilized in the management of advanced melanoma. Though generally well-tolerated, patients receiving ICIs experience treatment-related toxicities at varying onset and intensity. Assessment and evaluation of these toxicities and their impact on a quality of life is essential to comprehensive cancer care. Patient-reported outcomes (PRO) contribute vital data to a clinical assessment, supporting clinicians in their ability to improve outcomes. To date, there is no melanoma-specific or ICI-specific PRO measure of symptom burden available.

Purpose: The purpose of this study was to describe the symptom experience from the patient's perspective and how …

Analysis Of Genomic And Immune Intratumor Heterogeneity In Linitis Plastica Via Multiregional Exome And T-Cell Receptor Sequencing, Jin Huang, Guofeng Zhao, Qiu Peng, Xin Yi, Liyan Ji, Jing Li, Pansong Li, Yanfang Guan, Jie Ge, Ling Chen, Runzhe Chen, Xin Hu, Won-Chul Lee, Alexandre Reuben, P Andrew Futreal, Xuefeng Xia, Jian Ma, Jianjun Zhang, Zihua Chen

Faculty, Staff and Student Publications

The molecular landscape and the intratumor heterogeneity (ITH) architecture of gastric linitis plastica (LP) are poorly understood. We performed whole-exome sequencing (WES) and T-cell receptor (TCR) sequencing on 40 tumor regions from four LP patients. The landscape and ITH at the genomic and immunological levels in LP tumors were compared with multiple cancers that have previously been reported. The lymphocyte infiltration was further assessed by immunohistochemistry (IHC) in LP tumors. In total, we identified 6339 non-silent mutations from multi-samples, with a median tumor mutation burden (TMB) of 3.30 mutations per Mb, comparable to gastric adenocarcinoma from the Cancer Genome Atlas …

Brief Report: Clinical Response, Toxicity, And Resistance Mechanisms To Osimertinib Plus Met Inhibitors In Patients With Egfr-Mutant Met-Amplified Nsclc, Kaiwen Wang, Robyn Du, Sinchita Roy-Chowdhuri, Ziping T Li, Lingzhi Hong, Natalie Vokes, Yasir Y Elamin, Celyne Bueno Hume, Ferdinandos Skoulidis, Carl M Gay, George Blumenschein, Frank V Fossella, Anne Tsao, Jianjun Zhang, Niki Karachaliou, Aurora O'Brate, Claudia-Nanette Gann, Jeff Lewis, Waree Rinsurongkawong, J Jack Lee, Don Lynn Gibbons, Ara A Vaporciyan, John V Heymach, Mehmet Altan, Xiuning Le

Faculty, Staff and Student Publications

INTRODUCTION:MET amplification is a known resistance mechanism to EGFR tyrosine kinase inhibitor (TKI) treatment in EGFR-mutant NSCLC. Dual EGFR-MET inhibition has been reported with success in overcoming such resistance and inducing clinical benefit. Resistance mechanisms to dual EGFR-MET inhibition require further investigation and characterization.

METHODS: Patients with NSCLC with both MET amplification and EGFR mutation who have received crizotinib, capmatinib, savolitinib, or tepotinib plus osimertinib (OSI) after progression on OSI at MD Anderson Cancer Center were included in this study. Molecular profiling was completed by means of fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS). Radiological response …

Risk Of Cancer After Diagnosis Of Cardiovascular Disease, Caitlin F Bell, Xiudong Lei, Allen Haas, Richard A Baylis, Hua Gao, Lingfeng Luo, Sharon H Giordano, Mackenzie R Wehner, Kevin T Nead, Nicholas J Leeper

Faculty, Staff and Student Publications

BACKGROUND: Cardiovascular disease (CVD) and cancer share several risk factors. Although preclinical models show that various types of CVD can accelerate cancer progression, clinical studies have not determined the impact of atherosclerosis on cancer risk.

OBJECTIVES: The objective of this study was to determine whether CVD, especially atherosclerotic CVD, is independently associated with incident cancer.

METHODS: Using IBM MarketScan claims data from over 130 million individuals, 27 million cancer-free subjects with a minimum of 36 months of follow-up data were identified. Individuals were stratified by presence or absence of CVD, time-varying analysis with multivariable adjustment for cardiovascular risk factors was …

Framework For Quality Assurance Of Ultrahigh Dose Rate Clinical Trials Investigating Flash Effects And Current Technology Gaps, Wei Zou, Rongxiao Zhang, Emil Schüler, Paige A Taylor, Anthony E Mascia, Eric S Diffenderfer, Tianyu Zhao, Ahmet S Ayan, Manju Sharma, Shu-Jung Yu, Weiguo Lu, Walter R Bosch, Christina Tsien, Murat Surucu, Julianne M Pollard-Larkin, Jan Schuemann, Eduardo G Moros, Magdalena Bazalova-Carter, David J Gladstone, Heng Li, Charles B Simone, Kristoffer Petersson, Stephen F Kry, Amit Maity, Billy W Loo, Lei Dong, Peter G Maxim, Ying Xiao, Jeffrey C Buchsbaum

Faculty, Staff and Student Publications

FLASH radiation therapy (FLASH-RT), delivered with ultrahigh dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared with currently used conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology …

Divergent Structures Of Mammalian And Gammaherpesvirus Uracil Dna Glycosylases Confer Distinct Dna Binding And Substrate Activity, Yunxiang Mu, Monika A Zelazowska, Zaowen Chen, Joshua B Plummer, Qiwen Dong, Laurie T Krug, Kevin M Mcbride

Faculty, Staff and Student Publications

Uracil DNA glycosylase (UNG) removes mutagenic uracil base from DNA to initiate base excision repair (BER). The result is an abasic site (AP site) that is further processed by the high-fidelity BER pathway to complete repair and maintain genome integrity. The gammaherpesviruses (GHVs), human Kaposi sarcoma herpesvirus (KSHV), Epstein-Barr virus (EBV), and murine gammaherpesvirus 68 (MHV68) encode functional UNGs that have a role in viral genome replication. Mammalian and GHVs UNG share overall structure and sequence similarity except for a divergent amino-terminal domain and a leucine loop motif in the DNA binding domain that varies in sequence and length. To …

Life-Threatening Hemoptysis In Patients With Metastatic Kidney Cancer, Viral M Patel, Roy Elias, Annapoorani Asokan, Akanksha Sharma, Alana Christie, Ivan Pedrosa, Hsienchang Chiu, Scott Reznik, Raquibul Hannan, Robert Timmerman, James Brugarolas

Faculty, Staff and Student Publications

Hemoptysis is a complication of intrathoracic tumors, both primary and metastatic, and the risk may be increased by procedural interventions as well as Stereotactic Ablative Radiation (SAbR). The risk of hemoptysis with SAbR for lung cancer is well characterized, but there is a paucity of data about intrathoracic metastases. Here, we sought to evaluate the incidence of life-threatening/fatal hemoptysis (LTH) in patients with renal cell carcinoma (RCC) chest metastases with a focus on SAbR. We systematically evaluated patients with RCC at UT Southwestern Medical Center (UTSW) Kidney Cancer Program (KCP) from July 2005 to March 2020. We queried Kidney Cancer …

Image-Based Quantification Of Histological Features As A Function Of Spatial Location Using The Tissue Positioning System, Ruichen Rong, Yonglong Wei, Lin Li, Tao Wang, Hao Zhu, Guanghua Xiao, Yunguan Wang

Faculty, Staff and Student Publications

Background: Tissues such as the liver lobule, kidney nephron, and intestinal gland exhibit intricate patterns of zonated gene expression corresponding to distinct cell types and functions. To quantitatively understand zonation, it is important to measure cellular or genetic features as a function of position along a zonal axis. While it is possible to manually count, characterize, and locate features in relation to the zonal axis, it is labor-intensive and difficult to do manually while maintaining precision and accuracy.

Methods: We addressed this challenge by developing a deep-learning-based quantification method called the "Tissue Positioning System" (TPS), which can automatically analyze zonation …

Mitotic Rate In Primary Cutaneous Melanoma: Cell Division Matters, Jeffrey E Gershenwald

Faculty, Staff and Student Publications

No abstract provided.

Definitive Liver Radiotherapy For Intrahepatic Cholangiocarcinoma With Extrahepatic Metastases, Brian De, Rituraj Upadhyay, Kaiping Liao, Tiffany Kumala, Christopher Shi, Grace Dodoo, Joseph Abi Jaoude, Kelsey L Corrigan, Gohar S Manzar, Kathryn E Marqueen, Vincent Bernard, Sunyoung S Lee, Kanwal P S Raghav, Jean-Nicolas Vauthey, Ching-Wei D Tzeng, Hop S Tran Cao, Grace Lee, Jennifer Y Wo, Theodore S Hong, Christopher H Crane, Bruce D Minsky, Grace L Smith, Emma B Holliday, Cullen M Taniguchi, Albert C Koong, Prajnan Das, Milind Javle, Ethan B Ludmir, Eugene J Koay

Faculty, Staff and Student Publications

INTRODUCTION: Tumor-related liver failure (TRLF) is the most common cause of death in patients with intrahepatic cholangiocarcinoma (ICC). Though we previously showed that liver radiotherapy (L-RT) for locally advanced ICC is associated with less frequent TRLF and longer overall survival (OS), the role of L-RT for patients with extrahepatic metastatic disease (M1) remains undefined. We sought to compare outcomes for M1 ICC patients treated with and without L-RT.

METHODS: We reviewed ICC patients that found to have M1 disease at initial diagnosis at a single institution between 2010 and 2021 who received L-RT, matching them with an institutional cohort by …

Smooth Muscle Α-Actin Missense Variant Promotes Atherosclerosis Through Modulation Of Intracellular Cholesterol In Smooth Muscle Cells, Kaveeta Kaw, Abhijnan Chattopadhyay, Pujun Guan, Jiyuan Chen, Suravi Majumder, Xue-Yan Duan, Shuangtao Ma, Chen Zhang, Callie S Kwartler, Dianna M Milewicz

Faculty, Staff and Student Publications

AIMS: The variant p.Arg149Cys in ACTA2, which encodes smooth muscle cell (SMC)-specific α-actin, predisposes to thoracic aortic disease and early onset coronary artery disease in individuals without cardiovascular risk factors. This study investigated how this variant drives increased atherosclerosis.

METHODS AND RESULTS: Apoe-/- mice with and without the variant were fed a high-fat diet for 12 weeks, followed by evaluation of atherosclerotic plaque formation and single-cell transcriptomics analysis. SMCs explanted from Acta2R149C/+ and wildtype (WT) ascending aortas were used to investigate atherosclerosis-associated SMC phenotypic modulation. Hyperlipidemic Acta2R149C/+Apoe-/- mice have a 2.5-fold increase in atherosclerotic plaque burden compared to Apoe-/- mice …

Heterozygous Midnolin Knockout Attenuates Severity Of Nonalcoholic Fatty Liver Disease In Mice Fed A Western-Style Diet High In Fat, Cholesterol, And Fructose, Soo-Mi Kweon, Jose Irimia-Dominguez, Gayeoun Kim, Patrick T Fueger, Kinji Asahina, Keith K Lai, Daniela S Allende, Quincy R Lai, Chih-Hong Lou, Walter M Tsark, Ju Dong Yang, Dominic S Ng, Ju-Seog Lee, Patrick Tso, Wendong Huang, Keane K Y Lai

Faculty, Staff and Student Publications

Although midnolin has been studied for over 20 years, its biological roles in vivo remain largely unknown, especially due to the lack of a functional animal model. Indeed, given our recent discovery that the knockdown of midnolin suppresses liver cancer cell tumorigenicity and that this antitumorigenic effect is associated with modulation of lipid metabolism, we hypothesized that knockout of midnolin in vivo could potentially protect from nonalcoholic fatty liver disease (NAFLD) which has become the most common cause of chronic liver disease in the Western world. Accordingly, in the present study, we have developed and now report on the first …

Vincristine Enhances The Efficacy Of Mek Inhibitors In Preclinical Models Of Kras-Mutant Colorectal Cancer, Susmita Ghosh, Fan Fan, Reid T Powell, Jason Roszik, Yong Sung Park, Clifford Stephan, Manu Sebastian, Lin Tan, Alexey V Sorokin, Philip L Lorenzi, Scott Kopetz, Lee M Ellis, Rajat Bhattacharya

Faculty, Staff and Student Publications

Mutations in KRAS are found in more than 50% of tumors from patients with metastatic colorectal cancer (mCRC). However, direct targeting of most KRAS mutations is difficult; even the recently developed KRASG12C inhibitors failed to show significant benefit in patients with mCRC. Single agents targeting mitogen-activated protein kinase kinase (MEK), a downstream mediator of RAS, have also been ineffective in colorectal cancer. To identify drugs that can enhance the efficacy of MEK inhibitors, we performed unbiased high-throughput screening using colorectal cancer spheroids. We used trametinib as the anchor drug and examined combinations of trametinib with the NCI-approved Oncology Library version …

Myelodysplastic Syndromes: 2023 Update On Diagnosis, Risk-Stratification, And Management, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Disease overview: The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy.

Diagnosis: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry, and molecular genetics is usually complementary and may help refine diagnosis. A new WHO classification of MDS was proposed in 2022. Under this classification, …

Pitfalls In Machine Learning-Based Assessment Of Tumor-Infiltrating Lymphocytes In Breast Cancer: A Report Of The International Immuno-Oncology Biomarker Working Group On Breast Cancer, Jeppe Thagaard, Glenn Broeckx, David B Page, Chowdhury Arif Jahangir, Sara Verbandt, Zuzana Kos, Rajarsi Gupta, Reena Khiroya, Khalid Abduljabbar, Gabriela Acosta Haab, Balazs Acs, Guray Akturk, Jonas S Almeida, Isabel Alvarado-Cabrero, Mohamed Amgad, Farid Azmoudeh-Ardalan, Sunil Badve, Nurkhairul Bariyah Baharun, Eva Balslev, Enrique R Bellolio, Vydehi Bheemaraju, Kim Rm Blenman, Luciana Botinelly Mendonça Fujimoto, Najat Bouchmaa, Octavio Burgues, Alexandros Chardas, Maggie Chon U Cheang, Francesco Ciompi, Lee Ad Cooper, An Coosemans, Germán Corredor, Anders B Dahl, Flavio Luis Dantas Portela, Frederik Deman, Sandra Demaria, Johan Doré Hansen, Sarah N Dudgeon, Thomas Ebstrup, Mahmoud Elghazawy, Claudio Fernandez-Martín, Stephen B Fox, William M Gallagher, Jennifer M Giltnane, Sacha Gnjatic, Paula I Gonzalez-Ericsson, Anita Grigoriadis, Niels Halama, Matthew G Hanna, Aparna Harbhajanka, Steven N Hart, Johan Hartman, Søren Hauberg, Stephen Hewitt, Akira I Hida, Hugo M Horlings, Zaheed Husain, Evangelos Hytopoulos, Sheeba Irshad, Emiel Am Janssen, Mohamed Kahila, Tatsuki R Kataoka, Kosuke Kawaguchi, Durga Kharidehal, Andrey I Khramtsov, Umay Kiraz, Pawan Kirtani, Liudmila L Kodach, Konstanty Korski, Anikó Kovács, Anne-Vibeke Laenkholm, Corinna Lang-Schwarz, Denis Larsimont, Jochen K Lennerz, Marvin Lerousseau, Xiaoxian Li, Amy Ly, Anant Madabhushi, Sai K Maley, Vidya Manur Narasimhamurthy, Douglas K Marks, Elizabeth S Mcdonald, Ravi Mehrotra, Stefan Michiels, Fayyaz Ul Amir Afsar Minhas, Shachi Mittal, David A Moore, Shamim Mushtaq, Hussain Nighat, Thomas Papathomas, Frederique Penault-Llorca, Rashindrie D Perera, Christopher J Pinard, Juan Carlos Pinto-Cardenas, Giancarlo Pruneri, Lajos Pusztai, Arman Rahman, Nasir Mahmood Rajpoot, Bernardo Leon Rapoport, Tilman T Rau, Jorge S Reis-Filho, Joana M Ribeiro, David Rimm, Anne Roslind, Anne Vincent-Salomon, Manuel Salto-Tellez, Joel Saltz, Shahin Sayed, Ely Scott, Kalliopi P Siziopikou, Christos Sotiriou, Albrecht Stenzinger, Maher A Sughayer, Daniel Sur, Susan Fineberg, Fraser Symmans, Sunao Tanaka, Timothy Taxter, Sabine Tejpar, Jonas Teuwen, E Aubrey Thompson, Trine Tramm, William T Tran, Jeroen Van Der Laak, Paul J Van Diest, Gregory E Verghese, Giuseppe Viale, Michael Vieth, Noorul Wahab, Thomas Walter, Yannick Waumans, Hannah Y Wen, Wentao Yang, Yinyin Yuan, Reena Md Zin, Sylvia Adams, John Bartlett, Sibylle Loibl, Carsten Denkert, Peter Savas, Sherene Loi, Roberto Salgado, Elisabeth Specht Stovgaard

Faculty, Staff and Student Publications

The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. …

Spatial Analyses Of Immune Cell Infiltration In Cancer: Current Methods And Future Directions: A Report Of The International Immuno-Oncology Biomarker Working Group On Breast Cancer, David B Page, Glenn Broeckx, Chowdhury Arif Jahangir, Sara Verbandt, Rajarsi R Gupta, Jeppe Thagaard, Reena Khiroya, Zuzana Kos, Khalid Abduljabbar, Gabriela Acosta Haab, Balazs Acs, Guray Akturk, Jonas S Almeida, Isabel Alvarado-Cabrero, Farid Azmoudeh-Ardalan, Sunil Badve, Nurkhairul Bariyah Baharun, Enrique R Bellolio, Vydehi Bheemaraju, Kim Rm Blenman, Luciana Botinelly Mendonça Fujimoto, Najat Bouchmaa, Octavio Burgues, Maggie Chon U Cheang, Francesco Ciompi, Lee Ad Cooper, An Coosemans, Germán Corredor, Flavio Luis Dantas Portela, Frederik Deman, Sandra Demaria, Sarah N Dudgeon, Mahmoud Elghazawy, Scott Ely, Claudio Fernandez-Martín, Susan Fineberg, Stephen B Fox, William M Gallagher, Jennifer M Giltnane, Sacha Gnjatic, Paula I Gonzalez-Ericsson, Anita Grigoriadis, Niels Halama, Matthew G Hanna, Aparna Harbhajanka, Alexandros Hardas, Steven N Hart, Johan Hartman, Stephen Hewitt, Akira I Hida, Hugo M Horlings, Zaheed Husain, Evangelos Hytopoulos, Sheeba Irshad, Emiel Am Janssen, Mohamed Kahila, Tatsuki R Kataoka, Kosuke Kawaguchi, Durga Kharidehal, Andrey I Khramtsov, Umay Kiraz, Pawan Kirtani, Liudmila L Kodach, Konstanty Korski, Anikó Kovács, Anne-Vibeke Laenkholm, Corinna Lang-Schwarz, Denis Larsimont, Jochen K Lennerz, Marvin Lerousseau, Xiaoxian Li, Amy Ly, Anant Madabhushi, Sai K Maley, Vidya Manur Narasimhamurthy, Douglas K Marks, Elizabeth S Mcdonald, Ravi Mehrotra, Stefan Michiels, Fayyaz Ul Amir Afsar Minhas, Shachi Mittal, David A Moore, Shamim Mushtaq, Hussain Nighat, Thomas Papathomas, Frederique Penault-Llorca, Rashindrie D Perera, Christopher J Pinard, Juan Carlos Pinto-Cardenas, Giancarlo Pruneri, Lajos Pusztai, Arman Rahman, Nasir Mahmood Rajpoot, Bernardo Leon Rapoport, Tilman T Rau, Jorge S Reis-Filho, Joana M Ribeiro, David Rimm, Anne Vincent-Salomon, Manuel Salto-Tellez, Joel Saltz, Shahin Sayed, Kalliopi P Siziopikou, Christos Sotiriou, Albrecht Stenzinger, Maher A Sughayer, Daniel Sur, Fraser Symmans, Sunao Tanaka, Timothy Taxter, Sabine Tejpar, Jonas Teuwen, E Aubrey Thompson, Trine Tramm, William T Tran, Jeroen Van Der Laak, Paul J Van Diest, Gregory E Verghese, Giuseppe Viale, Michael Vieth, Noorul Wahab, Thomas Walter, Yannick Waumans, Hannah Y Wen, Wentao Yang, Yinyin Yuan, Sylvia Adams, John Mark Seaverns Bartlett, Sibylle Loibl, Carsten Denkert, Peter Savas, Sherene Loi, Roberto Salgado, Elisabeth Specht Stovgaard

Faculty, Staff and Student Publications

Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical …

Predictive Model Of Liver Toxicity To Aid The Personalized Selection Of Proton Versus Photon Therapy In Hepatocellular Carcinoma, Ibrahim Chamseddine, Yejin Kim, Brian De, Issam El Naqa, Dan G Duda, John A Wolfgang, Jennifer Pursley, Jennifer Y Wo, Theodore S Hong, Harald Paganetti, Eugene J Koay, Clemens Grassberger

Faculty, Staff and Student Publications

Purpose: Our objective was to develop an externally validated model for predicting liver toxicity after radiation therapy in patients with hepatocellular carcinoma (HCC) that can integrate both photon and proton dose distributions with patient-specific characteristics.

Methods and materials: Training data consisted of all patients with HCC treated between 2008 and 2019 at our institution (n = 117, 60%/40% photon/proton). We developed a shallow convolutional neural network (CNN) to predict posttreatment liver dysfunction from the differential dose-volume histogram (DVH) and baseline liver metrics. To reduce bias and improve robustness, we used ensemble learning (CNNE). After a preregistered study analysis plan, we …

Ultrasensitive Ngs Mrd Assessment In Ph+ All: Prognostic Impact And Correlation With Rt-Pcr For Bcr::Abl1, Nicholas J Short, Elias Jabbour, Walid Macaron, Farhad Ravandi, Nitin Jain, Rashmi Kanagal-Shamanna, Keyur P Patel, Sanam Loghavi, Fadi G Haddad, Musa Yilmaz, Ghayas C Issa, Partow Kebriaei, Steven M Kornblau, Sarah Pelletier, Wilmer Flores, Jairo Matthews, Rebecca Garris, Hagop Kantarjian

Faculty, Staff and Student Publications

Reverse transcription polymerase chain reaction (RT-PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL); however, RT-PCR may not be an optimal measure of MRD in many cases of Ph+ ALL. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay (sensitivity of 10-6 ) and its correlation with RT-PCR for BCR::ABL1 in patients with Ph+ ALL. Overall, 32% of patients had a discordance between MRD assessment by RT-PCR and NGS, and 31% of patients who achieved NGS MRD negativity were …

A Spatiotemporal Notch Interaction Map From Plasma Membrane To Nucleus, Alexandre P Martin, Gary A Bradshaw, Robyn J Eisert, Emily D Egan, Lena Tveriakhina, Julia M Rogers, Andrew N Dates, Gustavo Scanavachi, Jon C Aster, Tom Kirchhausen, Marian Kalocsay, Stephen C Blacklow

Faculty, Staff and Student Publications

Notch signaling relies on ligand-induced proteolysis of the transmembrane receptor Notch to liberate a nuclear effector that drives cell fate decisions. Upon ligand binding, sequential cleavage of Notch by the transmembrane protease ADAM10 and the intracellular protease γ-secretase releases the Notch intracellular domain (NICD), which translocates to the nucleus and forms a complex that induces target gene transcription. To map the location and timing of the individual steps required for the proteolysis and movement of Notch from the plasma membrane to the nucleus, we used proximity labeling with quantitative, multiplexed mass spectrometry to monitor the interaction partners of endogenous NOTCH2 …

Retrospective Analysis Of Retroperitoneal-Abdominal-Pelvic Ganglioneuromas: An International Study By The Transatlantic Australasian Retroperitoneal Sarcoma Working Group (Tarpswg), Sangkyu Noh, Carolyn Nessim, Emily Z Keung, Christina L Roland, Dirk Strauss, Gausihi Sivarajah, Marco Fiore, Davide Biasoni, Stefano Piero Bernardo Cioffi, Winta Mehtsun, Ferdinando Carlo Maria Cananzi, Federico Sicoli, Vittorio Quagliuolo, Jun Chen, Chenghua Luo, Rebecca A Gladdy, Carol Swallow, Wendy Johnston, Samuel J Ford, Caroline Evenden, Fabio Tirotta, Max Almond, Laura Nguyen, Piotr Rutkowski, Maria Krotewicz, Elisabetta Pennacchioli, Kenneth Cardona, Adriana Gamboa, Daphne Hompes, Marleen Renard, Attila Kollár, Christoph O Ryser, Nikolaos Vassos, Chandrajit P Raut, Mark Fairweather, Dagmar Adamkova Krakorova, Sergio Quildrian, Andraz Perhavec, Eran Nizri, Jeffrey M Farma, Stephanie H Greco, Bruno Vincenzi, José Antonio González Lopez, Mireia Solans Solerdecoll, Shintaro Iwata, Suguru Fukushima, Teresa Kim, Francesco Tolomeo, Hayden Snow, Ynez Howlett-Jansen, Dimitri Tzanis, Maxim Nikulin, Alessandro Gronchi, Jason K Sicklick, Transatlantic Australasian Retroperitoneal Sarcoma Working Group

Faculty, Staff and Student Publications

OBJECTIVE: The Transatlantic Australasian Retroperitoneal Sarcoma Working Group conducted a retrospective study on the disease course and clinical management of ganglioneuromas.

BACKGROUND: Ganglioneuromas are rare tumors derived from neural crest cells. Data on these tumors remain limited to case reports and single-institution case series.

METHODS: Patients of all ages with pathologically confirmed primary retroperitoneal, intra-abdominal, and pelvic ganglioneuromas between January 1, 2000, and January 1, 2020, were included. We examined demographic, clinicopathologic, and radiologic characteristics, as well as clinical management.

RESULTS: Overall, 328 patients from 29 institutions were included. The median age at diagnosis was 37 years with 59.1% of …

Artificial Mirnas Derived From Mir-181 Family Members Have Potential In Cancer Therapy Due To An Altered Spectrum Of Target Mrnas, Sergiu Chira, Cristina Ciocan, Cecilia Bica, George A Calin, Ioana Berindan-Neagoe

Faculty, Staff and Student Publications

miRNAs are a class of noncoding RNAs with gene regulation properties, and they function as key factors in cell homeostasis. The interaction of miRNAs with their target mRNAs is largely considered to rely on sequence complementarity; however, some evidence indicates that mature miRNAs can adopt diverse conformations with implications for their function. Using the oncogenic miR-181 family as a study model, we suggest that a potential relationship between the primary sequence and secondary structure of miRNAs may have an impact on the number and spectrum of targeted cellular transcripts. We further emphasize that specific alterations in miR-181 primary sequences might …

Combining Voltage-Sensitive Dye, Carbon Fiber Array, And Extracellular Nerve Electrodes Using A 3-D Printed Recording Chamber And Manipulators, Curtis L Neveu, Yu Huan, Yuto Momohara, Paras R Patel, Hillel J Chiel, Cynthia A Chestek, John H Byrne

Faculty, Staff and Student Publications

BACKGROUND: The analyses of neuronal circuits require high-throughput technologies for stimulating and recording many neurons simultaneously with single-neuron precision. Voltage-sensitive dyes (VSDs) have enabled the monitoring of membrane potentials of many (10-100 s) neurons simultaneously. Carbon fiber electrode (CFE) arrays allow for stimulation and recording of many neurons simultaneously, including intracellularly.

NEW METHOD: Combining CFE with VSD leverages the advantages of both technologies, allowing for stimulation of single neurons while recording the activity of the entire network. 3-D printing technology was used to develop a chamber to simultaneously perform VSD imaging, CFE array recording, and extracellular recording from individual glass …

Predicting Severity Of Radiation Induced Lymphopenia In Individual Proton Therapy Patients For Varying Dose Rate And Fractionation Using Dynamic 4-Dimensional Blood Flow Simulations, Lucas Mccullum, Jungwook Shin, Stella Xing, Chris Beekman, Jan Schuemann, Theodore Hong, Dan Duda, Radhe Mohan, Steven H Lin, Camilo M Correa-Alfonso, Sean Domal, Julia Withrow, Wesley Bolch, Harald Paganetti, Clemens Grassberger

Faculty, Staff and Student Publications

PURPOSE: Radiation-induced lymphopenia has gained attention recently as the result of its correlation with survival in a range of indications, particularly when combining radiation therapy (RT) with immunotherapy. The purpose of this study is to use a dynamic blood circulation model combined with observed lymphocyte depletion in patients to derive the in vivo radiosensitivity of circulating lymphocytes and study the effect of RT delivery parameters.

METHODS AND MATERIALS: We assembled a cohort of 17 patients with hepatocellular carcinoma treated with proton RT alone in 15 fractions (fx) using conventional dose rates (beam-on time [BOT], 120 seconds) for whom weekly absolute …

Tp53 Gain-Of-Function Mutation Modulates The Immunosuppressive Microenvironment In Non-Hpv-Associated Oral Squamous Cell Carcinoma, Yewen Shi, Xiaoyong Ren, Shaolong Cao, Xi Chen, Bo Yuan, Fabio Henrique Brasil Da Costa, Alanis E Rodriguez Rosario, Arnoldo Corona, Chieko Michikawa, Ratna Veeramachaneni, Abdullah A Osman, Tongxin Xie, Wenyi Wang, Andrew G Sikora, Jeffrey N Myers, Roberto Rangel

Faculty, Staff and Student Publications

BACKGROUND: TP53, the most mutated gene in solid cancers, has a profound impact on most hallmarks of cancer. Somatic TP53 mutations occur in high frequencies in head and neck cancers, including oral squamous cell carcinoma (OSCC). Our study aims to understand the role of TP53 gain-of-function mutation in modulating the tumor immune microenvironment (TIME) in OSCC.

METHODS: Short hairpin RNA knockdown of mutant p53R172H in syngeneic oral tumors demonstrated changes in tumor growth between immunocompetent and immunodeficient mice. HTG EdgeSeq targeted messenger RNA sequencing was used to analyze cytokine and immune cell markers in tumors with inactivated mutant p53R172H …