Biomedical Informatics Commons^™

Current Challenges In Image-Guided Magnetic Hyperthermia Therapy For Liver Cancer, Anirudh Sharma, Erik Cressman, Anilchandra Attaluri, Dara L Kraitchman, Robert Ivkov

Faculty, Staff and Student Publications

For patients diagnosed with advanced and unresectable hepatocellular carcinoma (HCC), liver transplantation remains the best option to extend life. Challenges with organ supply often preclude liver transplantation, making palliative non-surgical options the default front-line treatments for many patients. Even with imaging guidance, success following treatment remains inconsistent and below expectations, so new approaches are needed. Imaging-guided thermal therapy interventions have emerged as attractive procedures that offer individualized tumor targeting with the potential for the selective targeting of tumor nodules without impairing liver function. Furthermore, imaging-guided thermal therapy with added standard-of-care chemotherapies targeted to the liver tumor can directly reduce the …

A Comprehensive Search Of Non-Canonical Proteins In Non-Small Cell Lung Cancer And Their Impact On The Immune Response, Ehsan Irajizad, Johannes F Fahrmann, James P Long, Jody Vykoukal, Makoto Kobayashi, Michela Capello, Chuan-Yih Yu, Yining Cai, Fu Chung Hsiao, Nikul Patel, Soyoung Park, Qian Peng, Jennifer B Dennison, Taketo Kato, Mei Chee Tai, Ayumu Taguchi, Humam Kadara, Ignacio I Wistuba, Hiroyuki Katayama, Kim-Anh Do, Samir M Hanash, Edwin J Ostrin

Faculty, Staff and Student Publications

There is substantial interest in mining neoantigens for cancer applications. Non-canonical proteins resulting from frameshift mutations have been identified as neoantigens in cancer. We investigated the landscape of non-canonical proteins in non-small cell lung cancer (NSCLC) and their induced immune response in the form of autoantibodies. A database of cryptoproteins was computationally constructed and comprised all alternate open reading frames (altORFs) and ORFs identified in pseudogenes, noncoding RNAs, and untranslated regions of mRNAs that did not align with known canonical proteins. Proteomic profiles of seventeen lung adenocarcinoma (LUAD) cell lines were searched to evaluate the occurrence of cryptoproteins. To assess …

Oncogenic Collagen I Homotrimers From Cancer Cells Bind To Α3Β1 Integrin And Impact Tumor Microbiome And Immunity To Promote Pancreatic Cancer, Yang Chen, Sujuan Yang, Jena Tavormina, Desiree Tampe, Michael Zeisberg, Huamin Wang, Krishnan K Mahadevan, Chang-Jiun Wu, Hikaru Sugimoto, Chia-Chi Chang, Robert R Jenq, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

In contrast to normal type I collagen (Col1) heterotrimer (α1/α2/α1) produced by fibroblasts, pancreatic cancer cells specifically produce unique Col1 homotrimer (α1/α1/α1). Col1 homotrimer results from epigenetic suppression of the Col1a2 gene and promotes oncogenic signaling, cancer cell proliferation, tumor organoid formation, and growth via α3β1 integrin on cancer cells, associated with tumor microbiome enriched in anaerobic Bacteroidales in hypoxic and immunosuppressive tumors. Deletion of Col1 homotrimers increases overall survival of mice with pancreatic ductal adenocarcinoma (PDAC), associated with reprograming of the tumor microbiome with increased microaerophilic Campylobacterales, which can be reversed with broad-spectrum antibiotics. Deletion of Col1 homotrimers enhances …

Miracle Of Microrna-Driven Cancer Nanotherapeutics, Goknur Kara, Banu Arun, George A Calin, Bulent Ozpolat

Faculty, Staff and Student Publications

MicroRNAs (miRNAs) are non-protein-coding RNA molecules 20-25 nucleotides in length that can suppress the expression of genes involved in numerous physiological processes in cells. Accumulating evidence has shown that dysregulation of miRNA expression is related to the pathogenesis of various human diseases and cancers. Thus, stragegies involving either restoring the expression of tumor suppressor miRNAs or inhibiting overexpressed oncogenic miRNAs hold potential for targeted cancer therapies. However, delivery of miRNAs to tumor tissues is a challenging task. Recent advances in nanotechnology have enabled successful tumor-targeted delivery of miRNA therapeutics through newly designed nanoparticle-based carrier systems. As a result, miRNA therapeutics …

Adaptation And Dosimetric Commissioning Of A Synchrotron-Based Proton Beamline For Flash Experiments, Ming Yang, Xiaochun Wang, Fada Guan, Uwe Titt, Kiminori Iga, Dadi Jiang, Takeshi Takaoka, Satoshi Tootake, Tadashi Katayose, Masumi Umezawa, Emil Schüler, Steven Frank, Steven H Lin, Narayan Sahoo, Albert C Koong, Radhe Mohan, X Ronald Zhu

Faculty, Staff and Student Publications

Objective. Irradiation with ultra-high dose rates (>40 Gy s^-1), also known as FLASH irradiation, has the potential to shift the paradigm of radiation therapy because of its reduced toxicity to normal tissues compared to that of conventional irradiations. The goal of this study was to (1) achieve FLASH irradiation conditions suitable for pre-clinicalin vitroandin vivobiology experiments using our synchrotron-based proton beamline and (2) commission the FLASH irradiation conditions achieved.

Approach. To achieve these suitable FLASH conditions, we made a series of adaptations to our proton beamline, including modifying the spill length …

The Value Of In Vivo Reflectance Confocal Microscopy As An Assessment Tool In Chemotherapy-Induced Peripheral Neuropathy: A Pilot Study, Sabrina R Ramnarine, Patrick M Dougherty, Roman Rolke, Linda J Williams, Christi Alessi-Fox, Andrew J Coleman, Caterina Longo, Lesley A Colvin, Marie T Fallon

Faculty, Staff and Student Publications

Background: There is a lack of standardized objective and reliable assessment tools for chemotherapy-induced peripheral neuropathy (CIPN). In vivo reflectance confocal microscopy (RCM) imaging offers a non-invasive method to identify peripheral neuropathy markers, namely Meissner's corpuscles (MC). This study investigated the feasibility and value of RCM in CIPN.

Patients and methods: Reflectance confocal microscopy was performed on the fingertip to evaluate MC density in 45 healthy controls and 9 patients with cancer (prior, during, and post-chemotherapy). Quantification was completed by 2 reviewers (one blinded), with maximum MC count/3 × 3 mm image reported. Quantitative Sensory Testing (QST; thermal and mechanical …

Risk Assessment With Low-Pass Whole-Genome Sequencing Of Cell-Free Dna Before Cd19 Car T-Cell Therapy For Large B-Cell Lymphoma, Hua-Jay J Cherng, Ryan Sun, Bryant Sugg, Russell Irwin, Haopeng Yang, Cao Cuong Le, Qing Deng, Luis Fayad, Nathan H Fowler, Simrit Parmar, Raphael Steiner, Fredrick Hagemeister, Ranjit Nair, Hun Ju Lee, Maria Rodriguez, Felipe Samaniego, Swaminathan P Iyer, Christopher R Flowers, Linghua Wang, Loretta J Nastoupil, Sattva S Neelapu, Sairah Ahmed, Paolo Strati, Michael R Green, Jason Westin

Faculty, Staff and Student Publications

Patients with relapsed or refractory large B-cell lymphomas (rrLBCL) can achieve long-term remission after CD19 chimeric antigen receptor T-cell therapy (CART19). However, more than half of recipients will experience treatment failure. Thus, approaches are needed to identify high-risk patients who may benefit from alternative or consolidative therapy. We evaluated low-pass whole-genome sequencing (lpWGS) of cell-free DNA (cfDNA) before CART19 as a new approach for risk stratification. We performed lpWGS on pretreatment plasma samples from 122 patients at time of leukapheresis who received standard-of-care CART19 for rrLBCL to define DNA copy number alterations (CNAs). In multivariable selection, high focal CNA score …

Primary Cutaneous Lymphoma: Recommendations For Clinical Trial Design And Staging Update From The Iscl, Usclc, And Eortc, Elise A Olsen, Sean Whittaker, Rein Willemze, Lauren Pinter-Brown, Francine Foss, Larisa Geskin, Lawrence Schwartz, Steven Horwitz, Joan Guitart, John Zic, Youn H Kim, Gary S Wood, Madeleine Duvic, Wei Ai, Michael Girardi, Alejandro Gru, Emmanuella Guenova, Emmilia Hodak, Richard Hoppe, Werner Kempf, Ellen Kim, Mary Jo Lechowicz, Pablo Ortiz-Romero, Evangelia Papadavid, Pietro Quaglino, Mark Pittelkow, H Miles Prince, Jose Antonio Sanches, Makoto Sugaya, Maarten Vermeer, Jasmine Zain, Robert Knobler, Rudolf Stadler, Martine Bagot, Julia Scarisbrick

Faculty, Staff and Student Publications

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), …

Microenvironmental Landscape Of Human Melanoma Brain Metastases In Response To Immune Checkpoint Inhibition, Christopher Alvarez-Breckenridge, Samuel C Markson, Jackson H Stocking, Naema Nayyar, Matt Lastrapes, Matthew R Strickland, Albert E Kim, Magali De Sauvage, Ashish Dahal, Juliana M Larson, Joana L Mora, Andrew W Navia, Robert H Klein, Benjamin M Kuter, Corey M Gill, Mia Bertalan, Brian Shaw, Alexander Kaplan, Megha Subramanian, Aarushi Jain, Swaminathan Kumar, Husain Danish, Michael White, Osmaan Shahid, Kristen E Pauken, Brian C Miller, Dennie T Frederick, Christine Hebert, Mckenzie Shaw, Maria Martinez-Lage, Matthew Frosch, Nancy Wang, Elizabeth Gerstner, Brian V Nahed, William T Curry, Bob Carter, Daniel P Cahill, Genevieve Marie Boland, Benjamin Izar, Michael A Davies, Arlene H Sharpe, Mario L Suvà, Ryan J Sullivan, Priscilla K Brastianos, Scott L Carter

Faculty, Staff and Student Publications

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM …

Robust And Efficient Assessment Of Potency (Reap) As A Quantitative Tool For Dose-Response Curve Estimation, Shouhao Zhou, Xinyi Liu, Xinying Fang, Vernon M Chinchilli, Michael Wang, Hong-Gang Wang, Nikolay V Dokholyan, Chan Shen, J Jack Lee

Faculty, Staff and Student Publications

The median-effect equation has been widely used to describe the dose-response relationship and identify compounds that activate or inhibit specific disease targets in contemporary drug discovery. However, the experimental data often contain extreme responses, which may significantly impair the estimation accuracy and impede valid quantitative assessment in the standard estimation procedure. To improve the quantitative estimation of the dose-response relationship, we introduce a novel approach based on robust beta regression. Substantive simulation studies under various scenarios demonstrate solid evidence that the proposed approach consistently provides robust estimation for the median-effect equation, particularly when there are extreme outcome observations. Moreover, simulation …

Muscle And Adipose Tissue Segmentations At The Third Cervical Vertebral Level In Patients With Head And Neck Cancer, Kareem A Wahid, Brennan Olson, Rishab Jain, Aaron J Grossberg, Dina El-Habashy, Cem Dede, Vivian Salama, Moamen Abobakr, Abdallah S R Mohamed, Renjie He, Joel Jaskari, Jaakko Sahlsten, Kimmo Kaski, Clifton D Fuller, Mohamed A Naser

Faculty, Staff and Student Publications

The accurate determination of sarcopenia is critical for disease management in patients with head and neck cancer (HNC). Quantitative determination of sarcopenia is currently dependent on manually-generated segmentations of skeletal muscle derived from computed tomography (CT) cross-sectional imaging. This has prompted the increasing utilization of machine learning models for automated sarcopenia determination. However, extant datasets currently do not provide the necessary manually-generated skeletal muscle segmentations at the C3 vertebral level needed for building these models. In this data descriptor, a set of 394 HNC patients were selected from The Cancer Imaging Archive, and their skeletal muscle and adipose tissue was …

Building Consensus For A Shared Definition Of Adverse Events: A Case Study In The Profession Of Dentistry, Amy Franklin, Elsbeth Kalenderian, Nutan Hebballi, Veronique Delattre, Jini Etoule, Joel White, Ram Vaderhobli, Denice Stewart, Karla Kent, Alfa Yansane, Muhammad Walji

Faculty, Staff and Student Publications

BACKGROUND: To achieve high-quality health care, adverse events (AEs) must be proactively recognized and mitigated. However, there is often ambiguity in applying guidelines and definitions. We describe the iterative calibration process needed to achieve a shared definition of AEs in dentistry. Our alignment process includes both independent and consensus building approaches.

OBJECTIVE: We explore the process of defining dental AEs and the steps necessary to achieve alignment across different care providers.

METHODS: Teams from 4 dental institutions across the United States iteratively reviewed patient records after identification of charts using an automated trigger tool. Calibration across teams was supported through …

Knowledge Representation And Management: Notable Contributions In 2021, Licong Cui, Ferdinand Dhombres, Jean Charlet

Faculty, Staff and Student Publications

OBJECTIVES: To select, present, and summarize the best papers in the field of Knowledge Representation and Management (KRM) published in 2021.

METHODS: Following the International Medical Informatics Association (IMIA) Yearbook guidelines, a comprehensive and standardized review of the biomedical informatics literature was performed to select the best KRM papers published in 2021, based on PubMed queries.

RESULTS: A total of 1,231 publications were retrieved from PubMed. We nominated 15 candidate best papers, and four of them were finally selected as the best papers in the KRM section. The topics covered by these papers include knowledge graph, ontology development, ontology alignment, …

Charting The Proteome Landscape In Major Psychiatric Disorders: From Biomarkers To Biological Pathways Towards Drug Discovery, Brisa S Fernandes, Yulin Dai, Peilin Jia, Zhongming Zhao

Faculty, Staff and Student Publications

Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are major mental disorders that affect a significant proportion of the global population. Advancing our knowledge of the pathophysiology of these disorders and identifying biomarkers are urgent needs for developing objective diagnostic tests and new therapeutics. In this study, we performed a systematic review and then extracted, curated, and analyzed proteomics data from published studies, aiming to assess the proteome in peripheral blood of individuals with SZ, BD, or MDD. Then, we performed pathway and network analyses to illuminate the biological themes concatenated by the differentially expressed proteins by systematically …

Genome-Wide Bidirectional Crispr Screens Identify Mucins As Host Factors Modulating Sars-Cov-2 Infection, Scott B Biering, Sylvia A Sarnik, Eleanor Wang, James R Zengel, Sarah R Leist, Alexandra Schäfer, Varun Sathyan, Padraig Hawkins, Kenichi Okuda, Cyrus Tau, Aditya R Jangid, Connor V Duffy, Jin Wei, Rodney C Gilmore, Mia Madel Alfajaro, Madison S Strine, Xammy Nguyenla, Erik Van Dis, Carmelle Catamura, Livia H Yamashiro, Julia A Belk, Adam Begeman, Jessica C Stark, D Judy Shon, Douglas M Fox, Shahrzad Ezzatpour, Emily Huang, Nico Olegario, Arjun Rustagi, Allison S Volmer, Alessandra Livraghi-Butrico, Eddie Wehri, Richard R Behringer, Dong-Joo Cheon, Julia Schaletzky, Hector C Aguilar, Andreas S Puschnik, Brian Button, Benjamin A Pinsky, Catherine A Blish, Ralph S Baric, Wanda K O'Neal, Carolyn R Bertozzi, Craig B Wilen, Richard C Boucher, Jan E Carette, Sarah A Stanley, Eva Harris, Silvana Konermann, Patrick D Hsu

Faculty, Staff and Student Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2-host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a …

Real-World Matching Performance Of Deidentified Record-Linking Tokens, Elmer V Bernstam, Reuben Joseph Applegate, Alvin Yu, Deepa Chaudhari, Tian Liu, Alex Coda, Jonah Leshin

Faculty, Staff and Student Publications

OBJECTIVE: Our objective was to evaluate tokens commonly used by clinical research consortia to aggregate clinical data across institutions.

METHODS: This study compares tokens alone and token-based matching algorithms against manual annotation for 20,002 record pairs extracted from the University of Texas Houston's clinical data warehouse (CDW) in terms of entity resolution.

RESULTS: The highest precision achieved was 99.9% with a token derived from the first name, last name, gender, and date-of-birth. The highest recall achieved was 95.5% with an algorithm involving tokens that reflected combinations of first name, last name, gender, date-of-birth, and social security number.

DISCUSSION: To protect …

Development Of A Quality Improvement Dental Chart Review Training Program, Elsbeth Kalenderian, Nutan B Hebballi, Amy Franklin, Alfa Yansane, Ana M Ibarra Noriega, Joel White, Muhammad F Walji

Faculty, Staff and Student Publications

INTRODUCTION: Chart review is central to understanding adverse events (AEs) in medicine. In this article, we describe the process and results of educating chart reviewers assigned to evaluate dental AEs.

METHODS: We developed a Web-based training program, "Dental Patient Safety Training," which uses both independent and consensus-based curricula, for identifying AEs recorded in electronic health records in the dental setting. Training included (1) didactic education, (2) skills training using videos and guided walkthroughs, (3) quizzes with feedback, and (4) hands-on learning exercises. In addition, novice reviewers were coached weekly during consensus review discussions. TeamExpert was composed of 2 experienced reviewers, …

Impact Of Somatic Mutations On Survival Outcomes In Patients With Anaplastic Thyroid Carcinoma, Jennifer Rui Wang, Matthew Montierth, Li Xu, Maitrayee Goswami, Xiao Zhao, Gilbert Cote, Wenyi Wang, Priyanka Iyer, Ramona Dadu, Naifa L Busaidy, Stephen Y Lai, Neil D Gross, Renata Ferrarotto, Charles Lu, Gary Brandon Gunn, Michelle D Williams, Mark Routbort, Mark E Zafereo, Maria E Cabanillas

Faculty, Staff and Student Publications

PURPOSE: Anaplastic thyroid carcinoma (ATC) uniformly present with aggressive disease, but the mutational landscape of tumors varies. We aimed to determine whether tumor mutations affect survival outcomes in ATC.

MATERIALS AND METHODS: Patients who underwent mutation sequencing using targeted gene panels between 2005 and 2019 at a tertiary referral center were included. Associations between mutation status and survival outcomes were assessed using Cox proportional hazards models.

RESULTS: A total of 202 patients were included, where 122 died of ATC (60%). The median follow-up was 31 months (interquartile range, 18-45 months). The most common mutations were in

CONCLUSION: Mutation analysis provides …

Mediating And Maintaining Methylation While Minimizing Mutation: Recent Advances On Mammalian Dna Methyltransferases, Xiaodong Cheng, Robert M Blumenthal

Faculty, Staff and Student Publications

Mammalian genomes are methylated on carbon-5 of many cytosines, mostly in CpG dinucleotides. Methylation patterns are maintained during mitosis via DNMT1, and regulatory factors involved in processes that include histone modifications. Methylation in a sequence longer than CpG can influence the binding of sequence-specific transcription factors, thus affecting gene expression. 5-Methylcytosine deamination results in C-to-T transition. While some mutations are beneficial, most are not; so boosting C-to-T transitions can be dangerous. Given the role of DNMT3A in establishing de novo DNA methylation during development, it is this CpG methylation and deamination that provide the major mutagenic impetus in the DNMT3A …

Assessing The Practicality Of Using A Single Knowledge-Based Planning Model For Multiple Linac Vendors, Raphael J Douglas, Adenike Olanrewaju, Lifei Zhang, Beth M Beadle, Laurence E Court

Faculty, Staff and Student Publications

Purpose: Knowledge-based planning (KBP) has been shown to be an effective tool in quality control for intensity-modulated radiation therapy treatment planning and generating high-quality plans. Previous studies have evaluated its ability to create consistent plans across institutions and between planners within the same institution as well as its use as teaching tool for inexperienced planners. This study evaluates whether planning quality is consistent when using a KBP model to plan across different treatment machines.

Materials and methods: This study used a RapidPlan model (Varian Medical Systems) provided by the vendor, to which we added additional planning objectives, maximum dose limits, …

Love And Fear: A Special Issue, C Sue Carter, Robert Dantzer

Faculty, Staff and Student Publications

Love and fear were forged by the same fundamental evolutionary processes that permitted life on Earth. Both love and fear are deeply interwoven with the adaptive management of stress and disease. Love and fear share common roots and both can play a role in reproduction, survival, perceived safety and wellbeing. This special issue of Comprehensive Psychoneuroendocrinology focuses specifically on the causes and consequences of love from the interactive perspectives of evolution, neurobiology and culture.

Clinical Activity Of Mitogen-Activated Protein Kinase-Targeted Therapies In Patients With Non-V600 Braf-Mutant Tumors, Matthew Dankner, Yifan Wang, Rouhi Fazelzad, Benny Johnson, Caroline A Nebhan, Ibiayi Dagogo-Jack, Nathaniel J Myall, Georg Richtig, Jillian W P Bracht, Marco Gerlinger, Eiji Shinozaki, Takayuki Yoshino, Daisuke Kotani, Jason R Fangusaro, Oliver Gautschi, Julien Mazieres, Jeffrey A Sosman, Scott Kopetz, Vivek Subbiah, Michael A Davies, Anna L Groover, Ryan J Sullivan, Keith T Flaherty, Douglas B Johnson, Andrea Benedetti, David W Cescon, Anna Spreafico, George Zogopoulos, April A N Rose

Faculty, Staff and Student Publications

Purpose: Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established.

Methods: We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration-approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, …

Selinexor In Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial, Mrinal M Gounder, Albiruni Abdul Razak, Neeta Somaiah, Sant Chawla, Javier Martin-Broto, Giovanni Grignani, Scott M Schuetze, Bruno Vincenzi, Andrew J Wagner, Bartosz Chmielowski, Robin L Jones, Richard F Riedel, Silvia Stacchiotti, Elizabeth T Loggers, Kristen N Ganjoo, Axel Le Cesne, Antoine Italiano, Xavier Garcia Del Muro, Melissa Burgess, Sophie Piperno-Neumann, Christopher Ryan, Mary F Mulcahy, Charles Forscher, Nicolas Penel, Scott Okuno, Anthony Elias, Lee Hartner, Tony Philip, Thierry Alcindor, Bernd Kasper, Peter Reichardt, Lore Lapeire, Jean-Yves Blay, Christine Chevreau, Claudia Maria Valverde Morales, Gary K Schwartz, James L Chen, Hari Deshpande, Elizabeth J Davis, Garth Nicholas, Stefan Gröschel, Helen Hatcher, Florence Duffaud, Antonio Casado Herráez, Roberto Diaz Beveridge, Giuseppe Badalamenti, Mikael Eriksson, Christian Meyer, Margaret Von Mehren, Brian A Van Tine, Katharina Götze, Filomena Mazzeo, Alexander Yakobson, Aviad Zick, Alexander Lee, Anna Estival Gonzalez, Andrea Napolitano, Mark A Dickson, Dayana Michel, Changting Meng, Lingling Li, Jianjun Liu, Osnat Ben-Shahar, Dane R Van Domelen, Christopher J Walker, Hua Chang, Yosef Landesman, Jatin J Shah, Sharon Shacham, Michael G Kauffman, Steven Attia

Faculty, Staff and Student Publications

Purpose: Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents.

Methods: SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of …

Regulation And Function Of Id2 In Plasmacytoid Dendritic Cells, Rachel L Babcock, Yifan Zhou, Bhakti Patel, Taylor T Chrisikos, Laura M Kahn, Allison M Dyevoich, Yusra B Medik, Stephanie S Watowich

Faculty, Staff and Student Publications

Plasmacytoid dendritic cells (pDCs) are specialized type I interferon (IFN-I) producing cells that promote anti-viral immune responses and contribute to autoimmunity. Development of pDCs requires the transcriptional regulator E2-2 and is opposed by inhibitor of DNA binding 2 (Id2). Prior work indicates Id2 is induced in pDCs upon maturation and may affect pDC IFN-I production via suppression of E2-2, suggesting an important yet uncharacterized role in this lineage. We found TLR7 agonists stimulate Id2 mRNA and protein expression in pDCs. We further show that transcriptional activation of Id2 is dependent on the E2 ubiquitin-conjugating enzyme Ubc13, but independent of IFN-I …

Probing The Structure And Function Of Polymerase Θ Helicase-Like Domain, Scott Vanson, Yuzhen Li, Richard D Wood, Sylvie Doublié

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DNA Polymerase θ is the key actuator of the recently identified double-strand break repair pathway, theta-mediated end joining (TMEJ). It is the only known polymerase to have a 3-domain architecture containing an independently functional family A DNA polymerase tethered by a long central region to an N-terminal helicase-like domain (HLD). Full-length polymerase θ and the isolated HLD hydrolyze ATP in the presence of DNA, but no processive DNA duplex unwinding has been observed. Based on sequence and structure conservation, the HLD is classified as a member of helicase superfamily II and, more specifically, the Ski2-like family. The specific subdomain composition …

Dynamic Expression Of Schlafen 11 (Slfn11) In Circulating Tumour Cells As A Liquid Biomarker In Small Cell Lung Cancer, Bingnan Zhang, C Allison Stewart, Qi Wang, Robert J Cardnell, Pedro Rocha, Junya Fujimoto, Luisa M Solis Soto, Runsheng Wang, Veronica Novegil, Peter Ansell, Lei He, Luisa Fernandez, Adam Jendrisak, Cole Gilbertson, Joseph D Schonhoft, Jiyun Byun, Joshua Jones, Amanda K L Anderson, Ana Aparicio, Hai Tran, Marcelo V Negrao, Jianjun Zhang, Wei-Lien Wang, Ignacio I Wistuba, Jing Wang, Rick Wenstrup, Lauren A Byers, Carl M Gay

Faculty, Staff and Student Publications

Introduction: Small cell lung cancer (SCLC) is an aggressive malignancy with no established biomarkers. Schlafen 11(SLFN11), a DNA/RNA helicase that sensitises cancer cells to DNA-damaging agents, has emerged as a promising predictive biomarker for several drug classes including platinum and PARP inhibitors. Detection of SLFN11 in circulating tumour cells (CTCs) may provide a valuable alternative to tissue sampling.

Methods: SLFN11 expression was evaluated in tumour samples and characterised in circulating tumour cells (CTC) longitudinally to determine its potential role as a biomarker of response.

Results: Among 196 SCLC tumours, 51% expressed SLFN11 by IHC. In addition, 20/29 extra-thoracic high-grade neuroendocrine …

Ablation Of Long Noncoding Rna Malat1 Activates Antioxidant Pathway And Alleviates Sepsis In Mice, Jingshu Chen, Shu Tang, Sui Ke, James J Cai, Daniel Osorio, Andrei Golovko, Benjamin Morpurgo, Shaodong Guo, Yuxiang Sun, Melanie Winkle, George A Calin, Yanan Tian

Faculty, Staff and Student Publications

The metastasis-associated lung adenocarcinoma transcript1 (MALAT1) is a long noncoding RNA (lncRNA) and is known for its role in cancer development and prognosis. In this study, we report that MALAT1 plays an important role in regulating acute inflammatory responses in sepsis. In patient samples, MALAT1 expression was positively correlated with severity of sepsis. In cultured macrophages, LPS treatment significantly induced MALAT1 expression, while genetic ablation of MALAT1 greatly reduced proinflammatory cytokine levels. Furthermore, MALAT1-ablated mice had significantly increased survival rates in cecal ligation and puncture (CLP)-induced sepsis and LPS-induced endotoxemia. One novel and salient feature of MALAT1-ablated mice is greatly …

Sexual Orientation And Gender Identity Data Collection In Oncology Practice: Findings Of An Asco Survey, Charles S Kamen, Mandi L Pratt-Chapman, Stephen C Meersman, Gwendolyn P Quinn, Matthew B Schabath, Shail Maingi, Janette K Merrill, Elizabeth Garrett-Mayer, Melinda Kaltenbaugh, Caroline Schenkel, Shine Chang

Faculty, Staff and Student Publications

Purpose: Lack of collection of sexual orientation and gender identity (SOGI) data in oncology practices limits assessment of sexual and gender minority (SGM) cancer patients' experiences and restricts opportunities to improve health outcomes of SGM patients. Despite national calls for routine SOGI data collection, individual-level and institutional barriers hinder progress. This study aimed to identify these barriers in oncology.

Methods: An online survey of ASCO members and others assessed SOGI data collection in oncology practices, institutional characteristics related to SOGI data collection, respondents' attitudes about SOGI data and SGM patients, and respondent demographics. Logistic regression calculated adjusted odds ratios (ORs) …

Clinical Research In Ovarian Cancer: Consensus Recommendations From The Gynecologic Cancer Intergroup, Ignace Vergote, Antonio Gonzalez-Martin, Domenica Lorusso, Charlie Gourley, Mansoor Raza Mirza, Jean-Emmanuel Kurtz, Aikou Okamoto, Kathleen Moore, Frédéric Kridelka, Iain Mcneish, Alexander Reuss, Bénédicte Votan, Andreas Du Bois, Sven Mahner, Isabelle Ray-Coquard, Elise C Kohn, Jonathan S Berek, David S P Tan, Nicoletta Colombo, Rongyu Zang, Nicole Concin, Dearbhaile O'Donnell, Alejandro Rauh-Hain, C Simon Herrington, Christian Marth, Andres Poveda, Keiichi Fujiwara, Gavin C E Stuart, Amit M Oza, Michael A Bookman, Participants Of The 6th Gynecologic Cancer Intergroup (Gcig) Ovarian Cancer Consensus Conference On Clinical Research

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The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with …

Novel Mitochondria-Targeting Compounds Selectively Kill Human Leukemia Cells, Svetlana B Panina, Jingqi Pei, Natalia Baran, Elissa Tjahjono, Shraddha Patel, Gheath Alatrash, Sergej Konoplev, Leonid A Stolbov, Vladimir V Poroikov, Marina Konopleva, Natalia V Kirienko

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is a heterogeneous group of aggressive hematological malignancies commonly associated with treatment resistance, high risk of relapse, and mitochondrial dysregulation. We identified six mitochondria-affecting compounds (PS compounds) that exhibit selective cytotoxicity against AML cells in vitro. Structure-activity relationship studies identified six analogs from two original scaffolds that had over an order of magnitude difference between LD50 in AML and healthy peripheral blood mononuclear cells. Mechanistically, all hit compounds reduced ATP and selectively impaired both basal and ATP-linked oxygen consumption in leukemic cells. Compounds derived from PS127 significantly upregulated production of reactive oxygen species (ROS) in AML …