Biomedical Informatics Commons^™

Landscape Of Notch1 Mutations And Co-Occurring Biomarker Alterations In Chronic Lymphocytic Leukemia, Fatima Zahra Jelloul, Richard Yang, Sofia Garces, Rashmi Kanagal-Shamanna, Chi Y Ok, Sanam Loghavi, Mark J Routbort, Zhuang Zuo, C Cameron Yin, Kristen Floyd, Roland L Bassett, William Wierda, Nitin Jain, Philip Thompson, Rajyalakshmi Luthra, L Jeffrey Medeiros, Keyur P Patel

Faculty, Staff and Student Publications

NOTCH1 is one of the most frequently mutated genes in chronic lymphocytic leukemia and has emerged as a marker of poor prognosis. In addition to coding NOTCH1 mutations involving exon 34, non-coding NOTCH1 mutations involving the 3' UTR have been described in a limited number of chronic lymphocytic leukemia (CLL) patients and were associated with adverse outcomes. In this study, 1574 CLL patients were assessed using targeted sequencing with a 29 gene panel and the results were correlated with prognostic characteristics. NOTCH1 mutations were detected in 252 (16%) patients, including both coding (220/252, 14%), non-coding (24/252, 1.5%) and a mixture …

Free Cholesterol Bioavailability And Atherosclerosis, Rei J Abe, Jun-Ichi Abe, Minh T H Nguyen, Elizabeth A Olmsted-Davis, Abrar Mamun, Priyanka Banerjee, John P Cooke, Longhou Fang, Henry Pownall, Nhat-Tu Le

Faculty, Staff and Student Publications

Purpose of review: As both a cholesterol acceptor and carrier in the reverse cholesterol transport (RCT) pathway, high-density lipoprotein (HDL) is putatively atheroprotective. However, current pharmacological therapies to increase plasma HDL cholesterol (HDL-c) concentration have paradoxically failed to prevent or reduce atherosclerosis and cardiovascular disease (CVD). Given that free cholesterol (FC) transfer between surfaces of lipoproteins and cells is reversible, excess plasma FC can be transferred to the cells of peripheral tissue sites resulting in atherosclerosis. Here, we summarize potential mechanisms contributing to this paradox and highlight the role of excess free cholesterol (FC) bioavailability in atherosclerosis vs. atheroprotection.

Recent …

Blood-Brain Barrier Dysfunction In Bipolar Disorder: Molecular Mechanisms And Clinical Implications, Ning O Zhao, Natasha Topolski, Massimo Tusconi, Erika M Salarda, Christopher W Busby, Camila N N C Lima, Anilkumar Pillai, Joao Quevedo, Tatiana Barichello, Gabriel R Fries

Faculty, Staff and Student Publications

Bipolar disorder (BD) is a severe psychiatric disorder affecting approximately 1-3% of the population and characterized by a chronic and recurrent course of debilitating symptoms. An increasing focus has been directed to discover and explain the function of Blood-Brain Barrier (BBB) integrity and its association with a number of psychiatric disorders; however, there has been limited research in the role of BBB integrity in BD. Multiple pathways may play crucial roles in modulating BBB integrity in BD, such as inflammation, insulin resistance, and alterations of neuronal plasticity. In turn, BBB impairment is hypothesized to have a significant clinical impact in …

Differential Ets1 Binding To T:G Mismatches Within A Cpg Dinucleotide Contributes To C-To-T Somatic Mutation Rate Of The Idh2 Hotspot At Codon Arg140, Jie Yang, Esha Gupta, John R Horton, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

Cytosine to thymine (C>T) somatic mutation is highly enriched in certain types of cancer, and most commonly occurs via deamination of a 5-methylcytosine (5mC) to thymine, in the context of a CpG dinucleotide. In theory, deamination should occur at equal rates to both 5mC nucleotides on opposite strands. In most cases, the resulting T:G or G:T mismatch can be repaired by thymine DNA glycosylase activities. However, while some hotspot-associated CpG mutations have approximately equal numbers of mutations that resulted either from C>T or G>A in a CpG dinucleotide, many showed strand bias, being skewed toward C>T …

Barriers And Facilitators Of Implementing Automated Radiotherapy Planning: A Multisite Survey Of Low- And Middle-Income Country Radiation Oncology Providers, Gwendolyn J Mcginnis, Matthew S Ning, Beth M Beadle, Nanette Joubert, William Shaw, Christoph Trauernich, Hannah Simonds, Surbhi Grover, Carlos E Cardenas, Laurence E Court, Grace L Smith

Faculty, Staff and Student Publications

Purpose: Global access to radiotherapy (RT) is inequitable, with obstacles to implementing modern technologies in low- and middle- income countries (LMICs). The Radiation Planning Assistant (RPA) is a web-based automated RT planning software package intended to increase accessibility of high-quality RT planning. We surveyed LMIC RT providers to identify barriers and facilitators of future RPA deployment and uptake.

Methods: RT providers underwent a pilot RPA teaching session in sub-Saharan Africa (Botswana, South Africa, and Tanzania) and Central America (Guatemala). Thirty providers (30 of 33, 90.9% response rate) participated in a postsession survey.

Results: Respondents included physicians (n = 10, 33%), …

Activity Of Decitabine As Maintenance Therapy In Core Binding Factor Acute Myeloid Leukemia, Jayastu Senapati, Mahran Shoukier, Guillermo Garcia-Manero, Xuemei Wang, Keyur Patel, Tapan Kadia, Farhad Ravandi, Naveen Pemmaraju, Maro Ohanian, Naval Daver, Courtney Dinardo, Yesid Alvarado, Jeffrey Aldrich, Gautam Borthakur

Faculty, Staff and Student Publications

Background: Posttherapy measurable residual disease (MRD) positivity in core binding factor acute myeloid leukemia (CBF-AML) is associated with shorter relapse-free survival (RFS). Elimination of MRD measured via quantitative reverse transcription polymerase chain reaction (qRTPCR) for disease specific transcripts can potentially lead to better outcomes in CBF-AML.

Methods: We prospectively monitored the MRD using qRTPCR and flow cytometry on bone marrow samples in patients with newly diagnosed CBF-AML who received decitabine (DAC) maintenance therapy after fludarabine/cytarabine/G-CSF (FLAG)-based induction/consolidation regimen. Negative qRTPCR (CMR) was defined as fusion transcript <0.01%.

Results: Thirty-one patients with CBF-AML including 14 with t(8;21) and 17 with inv(16) received …

Association Of Flame-Retardant Clothing With Mycosis Fungoides: A Retrospective Analysis, Katherine E Park, Vignesh Ramachandran, Jessica Tran, Tejas P Joshi, Naveen Garg, Madeleine Duvic

Faculty, Staff and Student Publications

Introduction: Mycosis fungoides (MF), the most prevalent form of cutaneous T-cell lymphoma (CTCL), has been associated with a variety of environmental and occupational exposures. Flame-retardant clothing (FRC), in contrast to flame-resistant clothing, is chemically treated and may constitute a previously unrecognized occupational hazard.

Objectives: To report an association between FRC and MF.

Methods: After encountering several young male patients whose onset of MF coincided with the occupational use of FRC and occupation as fire fighters, we did a retrospective search. Additional biopsy proven MF patients with use of FRC were identified by the EPIC electronic medical record using the search …

Home Cooking Quality Assessment Tool Validation Using Community Science And Crowdsourcing Approaches, Margaret Raber, Nalini Ranjit, Larkin L Strong, Karen Basen-Engquist

Faculty, Staff and Student Publications

Objective: To refine a measure of home cooking quality (defined as the usage level of practices with the potential to influence the nutrient content of prepared foods) and conduct a construct validation of the revised tool, the Healthy Cooking Questionnaire 2 (HCQ2).

Design: Two validation approaches are described: (1) a community science approach used to refine and validate Healthy Cooking Questionnaire (HCQ) constructs, and (2) responses to the revised HCQ (HCQ2) in a sample of Amazon Mechanical Turk (MTurk) workers to determine questionnaire comprehension.

Setting: The Community Scientist Program at the University of Texas MD Anderson Cancer Center facilitated discussion …

Ovarian Cancer Reporting Lexicon For Computed Tomography (Ct) And Magnetic Resonance (Mr) Imaging Developed By The Sar Uterine And Ovarian Cancer Disease-Focused Panel And The Esur Female Pelvic Imaging Working Group, Atul B Shinagare, Elizabeth A Sadowski, Hyesun Park, Olga R Brook, Rosemarie Forstner, Sumer K Wallace, Jeanne M Horowitz, Neil Horowitz, Marcia Javitt, Priyanka Jha, Aki Kido, Yulia Lakhman, Susanna I Lee, Lucia Manganaro, Katherine E Maturen, Stephanie Nougaret, Liina Poder, Gaiane M Rauch, Caroline Reinhold, Evis Sala, Isabelle Thomassin-Naggara, Herbert Alberto Vargas, Aradhana Venkatesan, Olivera Nikolic, Andrea G Rockall

Faculty, Staff and Student Publications

Objectives: Imaging evaluation is an essential part of treatment planning for patients with ovarian cancer. Variation in the terminology used for describing ovarian cancer on computed tomography (CT) and magnetic resonance (MR) imaging can lead to ambiguity and inconsistency in clinical radiology reports. The aim of this collaborative project between Society of Abdominal Radiology (SAR) Uterine and Ovarian Cancer (UOC) Disease-focused Panel (DFP) and the European Society of Uroradiology (ESUR) Female Pelvic Imaging (FPI) Working Group was to develop an ovarian cancer reporting lexicon for CT and MR imaging.

Methods: Twenty-one members of the SAR UOC DFP and ESUR FPI …

The Microrna-183/96/182 Cluster Inhibits Lung Cancer Progression And Metastasis By Inducing An Interleukin-2-Mediated Antitumor Cd8+ Cytotoxic T-Cell Response, Samrat T Kundu, B Leticia Rodriguez, Laura A Gibson, Amanda N Warner, Mabel G Perez, Rakhee Bajaj, Jared J Fradette, Caleb A Class, Luisa M Solis, Frank R Rojas Alvarez, Ignacio I Wistuba, Lixia Diao, Fengju Chen, Mohit Sachdeva, Jing Wang, David G Kirsch, Chad J Creighton, Don L Gibbons

Faculty, Staff and Student Publications

Here, Kundu et al. investigated the role of the microRNA-183/96/182 cluster (m96cl) in lung cancer and used a novel conditional m96cl mouse to establish that loss of m96cl accelerated the growth of K-Ras mutant autochthonous lung adenocarcinomas. Overall, the authors identified a novel mechanistic role of the m96cl in the suppression of lung cancer growth and metastasis by inducing an IL2-mediated systemic CD8+ CTL immune response.

Dance Of The Golgi: Understanding Golgi Dynamics In Cancer Metastasis, Rakhee Bajaj, Amanda N Warner, Jared F Fradette, Don L Gibbons

Faculty, Staff and Student Publications

The Golgi apparatus is at the center of protein processing and trafficking in normal cells. Under pathological conditions, such as in cancer, aberrant Golgi dynamics alter the tumor microenvironment and the immune landscape, which enhances the invasive and metastatic potential of cancer cells. Among these changes in the Golgi in cancer include altered Golgi orientation and morphology that contribute to atypical Golgi function in protein trafficking, post-translational modification, and exocytosis. Golgi-associated gene mutations are ubiquitous across most cancers and are responsible for modifying Golgi function to become pro-metastatic. The pharmacological targeting of the Golgi or its associated genes has been …

Targeting Cd123 In Blastic Plasmacytoid Dendritic Cell Neoplasm Using Allogeneic Anti-Cd123 Car T Cells, Tianyu Cai, Agnès Gouble, Kathryn L Black, Anna Skwarska, Ammar S Naqvi, Deanne Taylor, Ming Zhao, Qi Yuan, Mayumi Sugita, Qi Zhang, Roman Galetto, Stéphanie Filipe, Antonio Cavazos, Lina Han, Vinitha Kuruvilla, Helen Ma, Connie Weng, Chang-Gong Liu, Xiuping Liu, Sergej Konoplev, Jun Gu, Guilin Tang, Xiaoping Su, Gheath Al-Atrash, Stefan Ciurea, Sattva S Neelapu, Andrew A Lane, Hagop Kantarjian, Monica L Guzman, Naveen Pemmaraju, Julianne Smith, Andrei Thomas-Tikhonenko, Marina Konopleva

Faculty, Staff and Student Publications

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcomes with conventional therapy. Nearly 100% of BPDCNs overexpress interleukin 3 receptor subunit alpha (CD123). Given that CD123 is differentially expressed on the surface of BPDCN cells, it has emerged as an attractive therapeutic target. UCART123 is an investigational product consisting of allogeneic T cells expressing an anti-CD123 chimeric antigen receptor (CAR), edited with TALEN

Comparison Of Five Supervised Feature Selection Algorithms Leading To Top Features And Gene Signatures From Multi-Omics Data In Cancer, Tapas Bhadra, Saurav Mallik, Neaj Hasan, Zhongming Zhao

Faculty, Staff and Student Publications

BACKGROUND: As many complex omics data have been generated during the last two decades, dimensionality reduction problem has been a challenging issue in better mining such data. The omics data typically consists of many features. Accordingly, many feature selection algorithms have been developed. The performance of those feature selection methods often varies by specific data, making the discovery and interpretation of results challenging.

METHODS AND RESULTS: In this study, we performed a comprehensive comparative study of five widely used supervised feature selection methods (mRMR, INMIFS, DFS, SVM-RFE-CBR and VWMRmR) for multi-omics datasets. Specifically, we used five representative datasets: gene expression …

Venetoclax Combinations Delay The Time To Deterioration Of Hrqol In Unfit Patients With Acute Myeloid Leukemia, Keith W Pratz, Panayiotis Panayiotidis, Christian Recher, Xudong Wei, Brian A Jonas, Pau Montesinos, Vladimir Ivanov, Andre C Schuh, Courtney D Dinardo, Jan Novak, Vlatko Pejsa, Don Stevens, Su-Peng Yeh, Inho Kim, Mehmet Turgut, Nicola Fracchiolla, Kazuhito Yamamoto, Yishai Ofran, Andrew H Wei, Cat N Bui, Katy Benjamin, Rajesh Kamalakar, Jalaja Potluri, Wellington Mendes, Jacob Devine, Walter Fiedler

Faculty, Staff and Student Publications

Phase 3 trials Viale-A and Viale-C evaluated health-related quality of life (HRQoL) in patients with AML unfit for intensive chemotherapy who received venetoclax (VEN) + (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C) or placebo (PBO) + AZA or LDAC. Patient-reported outcomes included: EORTC QLQ-C30 global health status (GHS/QoL) and physical functioning (PF), PROMIS Cancer Fatigue Short Form 7a (Fatigue), and EQ-5D-5L health status visual analog scale (HS-VAS). Time to deterioration (TTD), defined as worsening from baseline in meaningful change thresholds (MCT) of ≥10, 5, or 7 points for GHS/QoL or PF, fatigue, and HS-VAS, respectively, was assessed; differences between groups …

Hereditary Retinoblastoma Ipsc Model Reveals Aberrant Spliceosome Function Driving Bone Malignancies, Jian Tu, Zijun Huo, Yao Yu, Dandan Zhu, An Xu, Mo-Fan Huang, Ruifeng Hu, Ruoyu Wang, Julian A Gingold, Yi-Hung Chen, Kuang-Lei Tsai, Nicolas R Forcioli-Conti, Sarah X L Huang, Thomas R Webb, Jie Su, Danielle A Bazer, Peilin Jia, Jason T Yustein, Lisa L Wang, Mien-Chie Hung, Zhongming Zhao, Chad D Huff, Jingnan Shen, Ruiying Zhao, Dung-Fang Lee

Faculty, Staff and Student Publications

The RB1 gene is frequently mutated in human cancers but its role in tumorigenesis remains incompletely defined. Using an induced pluripotent stem cell (iPSC) model of hereditary retinoblastoma (RB), we report that the spliceosome is an up-regulated target responding to oncogenic stress in RB1-mutant cells. By investigating transcriptomes and genome occupancies in RB iPSC–derived osteoblasts (OBs), we discover that both E2F3a, which mediates spliceosomal gene expression, and pRB, which antagonizes E2F3a, coregulate more than one-third of spliceosomal genes by cobinding to their promoters or enhancers. Pharmacological inhibition of the spliceosome in RB1-mutant cells leads to global intron retention, decreased cell …

Convection Enhanced Delivery Of The Oncolytic Adenovirus Delta24-Rgd In Patients With Recurrent Gbm: A Phase I Clinical Trial Including Correlative Studies, Erik H P Van Putten, Anne Kleijn, Victor W Van Beusechem, David Noske, Cor H J Lamers, Anna L De Goede, Sander Idema, Daphna Hoefnagel, Jenneke J Kloezeman, Juan Fueyo, Frederick F Lang, Charlotte E Teunissen, René M Vernhout, Cathy Bakker, Winald Gerritsen, David T Curiel, Arnold Vulto, Martine L M Lamfers, Clemens M F Dirven

Faculty, Staff and Student Publications

Purpose: Testing safety of Delta24-RGD (DNX-2401), an oncolytic adenovirus, locally delivered by convection enhanced delivery (CED) in tumor and surrounding brain of patients with recurrent glioblastoma.

Patients and methods: Dose-escalation phase I study with 3+3 cohorts, dosing 107 to 1 × 1011 viral particles (vp) in 20 patients. Besides clinical parameters, adverse events, and radiologic findings, blood, cerebrospinal fluid (CSF), brain interstitial fluid, and excreta were sampled over time and analyzed for presence of immune response, viral replication, distribution, and shedding.

Results: Of 20 enrolled patients, 19 received the oncolytic adenovirus Delta24-RGD, which was found to be safe and feasible. …

Cytospin-A Regulates Colorectal Cancer Cell Division And Migration By Modulating Stability Of Microtubules And Actin Filaments, Fan Fan, Jason Roszik, Ling Xia, Susmita Ghosh, Rui Wang, Xiangcang Ye, David Hawke, Lee M Ellis, Rajat Bhattacharya

Faculty, Staff and Student Publications

Simple Summary

In this study, we report the effects of depleting cytospin-A (CYTSA), also known as the sperm antigen with calponin homology and coiled-coil domain (SPECC1L) protein, on the proliferation and migration of colorectal cancer (CRC) cells. Mutations in this protein have been previously linked to different developmental disorders. In our studies, depletion of CYTSA in various CRC cells led to significant decreases in proliferation, increases in cell death, and increased formation of multinucleated cells. Knocking down CYTSA also led to severe inhibition of CRC cell migration and invasion. These effects could be related to a significant decrease in the …

Targeting Non-Coding Rnas To Overcome Cancer Therapy Resistance, Baoqing Chen, Mihnea P Dragomir, Chen Yang, Qiaoqiao Li, David Horst, George A Calin

Faculty, Staff and Student Publications

It is now well known that non-coding RNAs (ncRNAs), rather than protein-coding transcripts, are the preponderant RNA transcripts. NcRNAs, particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are widely appreciated as pervasive regulators of multiple cancer hallmarks such as proliferation, apoptosis, invasion, metastasis, and genomic instability. Despite recent discoveries in cancer therapy, resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy continue to be a major setback. Recent studies have shown that ncRNAs also play a major role in resistance to different cancer therapies by rewiring essential signaling pathways. In this review, we present the intricate mechanisms through …

Autologous Stem Cell Transplantation For Large B-Cell Lymphoma With Secondary Central Nervous System Involvement, Serkan Akin, Chitra Hosing, Issa Khouri, Sairah Ahmed, Amin Alousi, Nathan Fowler, Jacinth Joseph, Jonathan Truxillo, Jeremy L Ramdial, Farzaneh Maadani, Gabriela Rondon, May Daher, Jin S Im, Raphael Steiner, Jason Westin, Swaminathan P Iyer, Bouthaina Dabaja, Paolo Anderlini, Uday R Popat, Muzaffar H Qazilbash, Christopher R Flowers, Elizabeth Shpall, Richard E Champlin, Yago Nieto, Samer A Srour

Faculty, Staff and Student Publications

Secondary central nervous system large B-cell lymphoma (SCNSL) is rare, with a generally poor prognosis. There is limited data about the role of autologous stem cell transplantation (ASCT) in these high-risk patients. We explored in this study treatment outcomes and prognostic factors for patients with SCNSL who underwent ASCT. We included all consecutive patients who underwent ASCT at our institution. Primary endpoints were progression-free survival (PFS) and overall survival (OS). One-hundred two patients were identified. Median age at transplant was 56 (range, 21-71) years. With a median follow-up of 56 (range, 1-256) months, the median PFS and OS were 40 …

Distinct Molecular And Immune Hallmarks Of Inflammatory Arthritis Induced By Immune Checkpoint Inhibitors For Cancer Therapy, Sang T Kim, Yanshuo Chu, Mercy Misoi, Maria E Suarez-Almazor, Jean H Tayar, Huifang Lu, Maryam Buni, Jordan Kramer, Emma Rodriguez, Zulekha Hussain, Sattva S Neelapu, Jennifer Wang, Amishi Y Shah, Nizar M Tannir, Matthew T Campbell, Don L Gibbons, Tina Cascone, Charles Lu, George R Blumenschein, Mehmet Altan, Bora Lim, Vincente Valero, Monica E Loghin, Janet Tu, Shannon N Westin, Aung Naing, Guillermo Garcia-Manero, Noha Abdel-Wahab, Hussein A Tawbi, Patrick Hwu, Isabella C Glitza Oliva, Michael A Davies, Sapna P Patel, Jun Zou, Andrew Futreal, Adi Diab, Linghua Wang, Roza Nurieva

Faculty, Staff and Student Publications

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8

Ndrg1 In Aggressive Breast Cancer Progression And Brain Metastasis, Emilly S Villodre, Xiaoding Hu, Bedrich L Eckhardt, Richard Larson, Lei Huo, Ester C Yoon, Yun Gong, Juhee Song, Shuying Liu, Naoto T Ueno, Savitri Krishnamurthy, Stefan Pusch, Debu Tripathy, Wendy A Woodward, Bisrat G Debeb

Faculty, Staff and Student Publications

BACKGROUND: N-Myc downstream regulated gene 1 (NDRG1) suppresses metastasis in many human malignancies, including breast cancer, yet has been associated with worse survival in patients with inflammatory breast cancer. The role of NDRG1 in the pathobiology of aggressive breast cancers remains elusive.

METHODS: To study the role of NDRG1 in tumor growth and brain metastasis in vivo, we transplanted cells into cleared mammary fat pads or injected them in tail veins of SCID/Beige mice (n = 7-10 per group). NDRG1 protein expression in patient breast tumors (n = 216) was assessed by immunohistochemical staining. Kaplan-Meier method with 2-sided log-rank test …

Bismuth Nanoparticle And Polyhydroxybutyrate Coatings Enhance The Radiopacity Of Absorbable Inferior Vena Cava Filters For Fluoroscopy-Guided Placement And Longitudinal Computed Tomography Monitoring In Pigs, Jossana A Damasco, Steven Y Huang, Joy Vanessa D Perez, John Andrew T Manongdo, Katherine A Dixon, Malea L Williams, Megan C Jacobsen, Roland Barbosa, Gino Martin Canlas, Gouthami Chintalapani, Adam D Melancon, Rick R Layman, Natalie W Fowlkes, Elizabeth M Whitley, Marites P Melancon

Faculty, Staff and Student Publications

Inferior vena cava filters (IVCFs) constructed with poly-

Exploiting 4–1bb Immune Checkpoint To Enhance The Efficacy Of Oncolytic Virotherapy For Diffuse Intrinsic Pontine Gliomas, Virginia Laspidea, Montserrat Puigdelloses, Sara Labiano, Lucía Marrodán, Marc Garcia-Moure, Marta Zalacain, Marisol Gonzalez-Huarriz, Naiara Martínez-Vélez, Iker Ausejo-Mauleon, Daniel De La Nava, Guillermo Herrador-Cañete, Javier Marco-Sanz, Elisabeth Guruceaga, Carlos E De Andrea, María Villalba, Oren Becher, Massimo Squatrito, Verónica Matía, Jaime Gállego Pérez-Larraya, Ana Patiño-García, Sumit Gupta, Candelaria Gomez-Manzano, Juan Fueyo, Marta M Alonso

Faculty, Staff and Student Publications

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors, and patient survival has not changed despite many therapeutic efforts, emphasizing the urgent need for effective treatments. Here, we evaluated the anti-DIPG effect of the oncolytic adenovirus Delta-24-ACT, which was engineered to express the costimulatory ligand 4-1BBL to potentiate the antitumor immune response of the virus. Delta-24-ACT induced the expression of functional 4-1BBL on the membranes of infected DIPG cells, which enhanced the costimulation of CD8+ T lymphocytes. In vivo, Delta-24-ACT treatment of murine DIPG orthotopic tumors significantly improved the survival of treated mice, leading to long-term survivors that developed …

Lymphocyte Depletion Rate As A Biomarker Of Radiation Dose To Circulating Lymphocytes During Fractionated Partial-Body Radiation Therapy, Susannah G Ellsworth, Anirudh Yalamanchali, Tim Lautenschlaeger, Stuart A Grossman, Clemens Grassberger, Steven H Lin, Radhe Mohan

Faculty, Staff and Student Publications

Purpose: Radiation causes exponential depletion of circulating lymphocyte populations; in turn, radiation-induced lymphopenia is associated with worse survival for many solid tumors, possibly owing to attenuated antitumor immune responses. Identifying reliable and reproducible methods of calculating the radiation dose to circulating immune cells may facilitate development of techniques to reduce the risk and severity of radiation-induced toxic effects to circulating lymphocytes.

Methods and materials: Patient-specific lymphocyte loss rates were derived from a clinical data set including 684 adult patients with solid tumors. Multivariable linear regression was used to model the relationship between the lymphocyte loss rate and physical parameters of …

Hsp90-Cdc37 Functions As A Chaperone For The Oncogenic Fgfr3-Tacc3 Fusion, Tao Li, Farideh Mehraein-Ghomi, M Elizabeth Forbes, Sanjeev V Namjoshi, E Ashley Ballard, Qianqian Song, Ping-Chieh Chou, Xuya Wang, Brittany C Parker Kerrigan, Frederick F Lang, Glenn Lesser, Waldemar Debinski, Xuejun Yang, Wei Zhang

Faculty, Staff and Student Publications

The FGFR3-TACC3 (F3-T3) fusion gene was discovered as an oncogenic molecule in glioblastoma and bladder cancers, and has subsequently been found in many cancer types. Notably, F3-T3 was found to be highly expressed in both untreated and matched recurrence glioblastoma under the concurrent radiotherapy and temozolomide (TMZ) treatment, suggesting that targeting F3-T3 is a valid strategy for treatment. Here, we show that the F3-T3 protein is a client of heat shock protein 90 (HSP90), forming a ternary complex with the cell division cycle 37 (CDC37). Deprivation of HSP90 or CDC37 disrupts the formation of the ternary complex, which destabilizes glycosylated …

Targeting The Nrf2/Ho-1 Antioxidant Pathway In Flt3-Itd-Positive Aml Enhances Therapy Efficacy, Sankaranarayan Kannan, Mary E Irwin, Shelley M Herbrich, Tiewei Cheng, Lanisha L Patterson, Marisa J L Aitken, Kapil Bhalla, M James You, Marina Konopleva, Patrick A Zweidler-Mckay, Joya Chandra

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is a molecularly heterogenous hematological malignancy, with one of the most common mutations being internal tandem duplication (ITD) of the juxtamembrane domain of the fms-like tyrosine kinase receptor-3 (FLT3). Despite the development of FLT3-directed tyrosine kinase inhibitors (TKI), relapse and resistance are problematic, requiring improved strategies. In both patient samples and cell lines, FLT3-ITD raises levels of reactive oxygen species (ROS) and elicits an antioxidant response which is linked to chemoresistance broadly in AML. NF-E2-related factor 2 (NRF2) is a transcription factor regulating the antioxidant response including heme oxygenase -1 (HO-1), a heat shock protein implicated …

Enzymatic Characterization Of Mrna Cap Adenosine-N6 Methyltransferase Pcif1 Activity On Uncapped Rnas, Dan Yu, Nan Dai, Eric J Wolf, Ivan R Corrêa, Jujun Zhou, Tao Wu, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

The phosphorylated RNA polymerase II CTD interacting factor 1 (PCIF1) is a methyltransferase that adds a methyl group to the N6-position of 2′O-methyladenosine (Am), generating N6, 2′O-dimethyladenosine (m6Am) when Am is the cap-proximal nucleotide. In addition, PCIF1 has ancillary methylation activities on internal adenosines (both A and Am), although with much lower catalytic efficiency relative to that of its preferred cap substrate. The PCIF1 preference for 2′O-methylated Am over unmodified A nucleosides is due mainly to increased binding affinity for Am. Importantly, it was recently reported that PCIF1 can methylate viral RNA. Although some viral RNA can be translated in …

Loss Of Rnf43 Accelerates Kras-Mediated Neoplasia And Remodels The Tumor Immune Microenvironment In Pancreatic Adenocarcinoma, Abdel Nasser Hosein, Gita Dangol, Takashi Okumura, Jason Roszik, Kimal Rajapakshe, Megan Siemann, Mohamed Zaid, Bidyut Ghosh, Maria Monberg, Paola A Guerrero, Aatur Singhi, Cara L Haymaker, Hans Clevers, Lotfi Abou-Elkacem, Sonja M Woermann, Anirban Maitra

Faculty, Staff and Student Publications

Background & aims: RNF43 is an E3 ubiquitin ligase that is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC) and precursor cystic neoplasms of the pancreas. The impact of RNF43 mutations on PDAC is poorly understood and autochthonous models have not been characterized sufficiently. In this study, we describe a genetically engineered mouse model (GEMM) of PDAC with conditional expression of oncogenic Kras and deletion of the catalytic domain of Rnf43 in exocrine cells.

Methods: We generated Ptf1a-Cre;LSL-KrasG12D;Rnf43flox/flox (KRC) and Ptf1a-Cre; LSL-KrasG12D (KC) mice and animal survival was assessed. KRC mice were sacrificed at 2 months, 4 months, and at moribund …

An Efficient Magnetic Resonance Image Data Quality Screening Dashboard, Evan D H Gates, Adrian Celaya, Dima Suki, Dawid Schellingerhout, David Fuentes

Faculty, Staff and Student Publications

Purpose: Complex data processing and curation for artificial intelligence applications rely on high-quality data sets for training and analysis. Manually reviewing images and their associated annotations is a very laborious task and existing quality control tools for data review are generally limited to raw images only. The purpose of this work was to develop an imaging informatics dashboard for the easy and fast review of processed magnetic resonance (MR) imaging data sets; we demonstrated its ability in a large-scale data review.

Methods: We developed a custom R Shiny dashboard that displays key static snapshots of each imaging study and its …

Zanubrutinib For Treatment-Naïve And Relapsed/Refractory Chronic Lymphocytic Leukaemia: Long-Term Follow-Up Of The Phase I/Ii Au-003 Study, Akash Mukherjee, Denái R Milton, Elias J Jabbour, Alison M Gulbis, Tapan Kadia, Nitin Jain, Celina Ledesma, Jan Burger, Alessandra Ferrajoli, William Wierda, L Jeffrey Medeiros, Hagop Kantarjian, Richard Champlin, Issa F Khouri

Faculty, Staff and Student Publications

We aimed to study the risks of graft-versus-host disease (GVHD), non-relapse mortality (NRM) and survival outcomes of allogeneic stem cell transplantation (alloSCT) in patients with chronic lymphocytic leukemia (n = 17), Richter's syndrome (n = 14), or lymphoma (n = 18) after small molecule inhibitors (SMIs). Patients had a median of 4 prior therapies, including ibrutinib (n = 46; 94%), venetoclax (n = 19; 39%), and idelalisib (n = 6; 12%). Twenty-one (43%) had >1 SMI. P53 mutation was detected in 58% of patients. The 3-year overall and progression-free survival rates were 68% and …