Genetic Phenomena Commons^™

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 …

Mutations Of The Dna Repair Gene Pnkp In A Patient With Microcephaly, Seizures, And Developmental Delay (Mcsz) Presenting With A High-Grade Brain Tumor, Bingcheng Jiang, Cameron Murray, Bonnie L Cole, J N Mark Glover, Gordon K Chan, Jean Deschenes, Rajam S Mani, Sudip Subedi, John D Nerva, Anthony C Wang, Christina M Lockwood, Heather C Mefford, Sarah E S Leary, Jeffery G Ojemann, Michael Weinfeld, Chibawanye I Ene

Faculty, Staff and Student Publications

Polynucleotide Kinase-Phosphatase (PNKP) is a bifunctional enzyme that possesses both DNA 3'-phosphatase and DNA 5'-kinase activities, which are required for processing termini of single- and double-strand breaks generated by reactive oxygen species (ROS), ionizing radiation and topoisomerase I poisons. Even though PNKP is central to DNA repair, there have been no reports linking PNKP mutations in a Microcephaly, Seizures, and Developmental Delay (MSCZ) patient to cancer. Here, we characterized the biochemical significance of 2 germ-line point mutations in the PNKP gene of a 3-year old male with MSCZ who presented with a high-grade brain tumor (glioblastoma multiforme) within the cerebellum. …

Blinatumomab Maintenance After Allogeneic Hematopoietic Cell Transplantation For B-Lineage Acute Lymphoblastic Leukemia, Mahmoud R Gaballa, Pinaki Banerjee, Denái R Milton, Xianli Jiang, Christina Ganesh, Sajad Khazal, Vandana Nandivada, Sanjida Islam, Mecit Kaplan, May Daher, Rafet Basar, Amin Alousi, Rohtesh Mehta, Gheath Alatrash, Issa Khouri, Betul Oran, David Marin, Uday Popat, Amanda Olson, Priti Tewari, Nitin Jain, Elias Jabbour, Farhad Ravandi, Hagop Kantarjian, Ken Chen, Richard Champlin, Elizabeth Shpall, Katayoun Rezvani, Partow Kebriaei

Faculty, Staff and Student Publications

Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2 study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the …

Micrornas In Leukemias: A Clinically Annotated Compendium, Aleksander Turk, George A Calin, Tanja Kunej

Faculty, Staff and Student Publications

Leukemias are a group of malignancies of the blood and bone marrow. Multiple types of leukemia are known, however reliable treatments have not been developed for most leukemia types. Furthermore, even relatively reliable treatments can result in relapses. MicroRNAs (miRNAs) are a class of short, noncoding RNAs responsible for epigenetic regulation of gene expression and have been proposed as a source of potential novel therapeutic targets for leukemias. In order to identify central miRNAs for leukemia, we conducted data synthesis using two databases: miRTarBase and DISNOR. A total of 137 unique miRNAs associated with 16 types of leukemia were retrieved …

Drosophila Functional Screening Of De Novo Variants In Autism Uncovers Damaging Variants And Facilitates Discovery Of Rare Neurodevelopmental Diseases, Paul C Marcogliese, Samantha L Deal, Jonathan Andrews, J Michael Harnish, V Hemanjani Bhavana, Hillary K Graves, Sharayu Jangam, Xi Luo, Ning Liu, Danqing Bei, Yu-Hsin Chao, Brooke Hull, Pei-Tseng Lee, Hongling Pan, Pradnya Bhadane, Mei-Chu Huang, Colleen M Longley, Hsiao-Tuan Chao, Hyung-Lok Chung, Nele A Haelterman, Oguz Kanca, Sathiya N Manivannan, Linda Z Rossetti, Ryan J German, Amanda Gerard, Eva Maria Christina Schwaibold, Sarah Fehr, Renzo Guerrini, Annalisa Vetro, Eleina England, Chaya N Murali, Tahsin Stefan Barakat, Marieke F Van Dooren, Martina Wilke, Marjon Van Slegtenhorst, Gaetan Lesca, Isabelle Sabatier, Nicolas Chatron, Catherine A Brownstein, Jill A Madden, Pankaj B Agrawal, Boris Keren, Thomas Courtin, Laurence Perrin, Melanie Brugger, Timo Roser, Steffen Leiz, Frederic Tran Mau-Them, Julian Delanne, Elena Sukarova-Angelovska, Slavica Trajkova, Erik Rosenhahn, Vincent Strehlow, Konrad Platzer, Roberto Keller, Lisa Pavinato, Alfredo Brusco, Jill A Rosenfeld, Ronit Marom, Michael F Wangler, Shinya Yamamoto

Duncan NRI Faculty and Staff Publications

Individuals with autism spectrum disorder (ASD) exhibit an increased burden of de novo mutations (DNMs) in a broadening range of genes. While these studies have implicated hundreds of genes in ASD pathogenesis, which DNMs cause functional consequences in vivo remains unclear. We functionally test the effects of ASD missense DNMs using Drosophila through "humanization" rescue and overexpression-based strategies. We examine 79 ASD variants in 74 genes identified in the Simons Simplex Collection and find 38% of them to cause functional alterations. Moreover, we identify GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in 13 previously undiagnosed …

Blood-Based Biomarker Panel For Personalized Lung Cancer Risk Assessment, Johannes F Fahrmann, Tracey Marsh, Ehsan Irajizad, Nikul Patel, Eunice Murage, Jody Vykoukal, Jennifer B Dennison, Kim-Anh Do, Edwin Ostrin, Margaret R Spitz, Stephen Lam, Sanjay Shete, Rafael Meza, Martin C Tammemägi, Ziding Feng, Samir M Hanash

Faculty, Staff and Student Publications

Purpose: To investigate whether a panel of circulating protein biomarkers would improve risk assessment for lung cancer screening in combination with a risk model on the basis of participant characteristics.

Methods: A blinded validation study was performed using prostate lung colorectal ovarian (PLCO) Cancer Screening Trial data and biospecimens to evaluate the performance of a four-marker protein panel (4MP) consisting of the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment in combination with a lung cancer risk prediction model (PLCOm2012) compared with current US Preventive Services Task Force (USPSTF) screening criteria. The 4MP was …

Measurable Residual Disease Response And Prognosis In Treatment-Naïve Acute Myeloid Leukemia With Venetoclax And Azacitidine, Keith W Pratz, Brian A Jonas, Vinod Pullarkat, Christian Recher, Andre C Schuh, Michael J Thirman, Jacqueline S Garcia, Courtney D Dinardo, Vladimir Vorobyev, Nicola S Fracchiolla, Su-Peng Yeh, Jun Ho Jang, Muhit Ozcan, Kazuhito Yamamoto, Arpad Illes, Ying Zhou, Monique Dail, Brenda Chyla, Jalaja Potluri, Hartmut Döhner

Faculty, Staff and Student Publications

PURPOSE: There is limited evidence on the clinical utility of monitoring measurable residual disease (MRD) in patients with acute myeloid leukemia treated with lower-intensity therapy. Herein, we explored the outcomes of patients treated with venetoclax and azacitidine who achieved composite complete remission (CRc; complete remission + complete remission with incomplete hematologic recovery) and MRD < 10

METHODS: The patients included in this report were treated with venetoclax and azacitidine. Bone marrow aspirate samples for multiparametric flow cytometry assessments were collected for central analysis at baseline, end of cycle 1, and every three cycles thereafter. MRD-negative response was defined as < 1 residual blast per 1,000 leukocytes (< 10

RESULTS: One hundred …

Identification Of The Global Mir-130a Targetome Reveals A Role For Tbl1xr1 In Hematopoietic Stem Cell Self-Renewal And T(8; 21) Aml, Gabriela Krivdova, Veronique Voisin, Erwin M Schoof, Sajid A Marhon, Alex Murison, Jessica L Mcleod, Martino M Gabra, Andy G X Zeng, Stefan Aigner, Brian A Yee, Alexander A Shishkin, Eric L Van Nostrand, Karin G Hermans, Aaron C Trotman-Grant, Nathan Mbong, James A Kennedy, Olga I Gan, Elvin Wagenblast, Daniel D De Carvalho, Leonardo Salmena, Mark D Minden, Gary D Bader, Gene W Yeo, John E Dick, Eric R Lechman

Faculty, Staff and Students Publications

Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSCs) point to shared core stemness properties. However, discordance between mRNA and protein signatures highlights an important role for post-transcriptional regulation by microRNAs (miRNAs) in governing this critical nexus. Here, we identify miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impairs B lymphoid differentiation and expands long-term HSCs. Integration of protein mass spectrometry and chimeric AGO2 crosslinking and immunoprecipitation (CLIP) identifies TBL1XR1 as a primary miR-130a target, whose loss of function phenocopies miR-130a overexpression. Moreover, we report that miR-130a is highly expressed …

Chromosomal Imbalances Detected Via Rna-Sequencing In 28 Cancers, Zuhal Ozcan, Francis A San Lucas, Justin W Wong, Kyle Chang, Konrad H Stopsack, Jerry Fowler, Yasminka A Jakubek, Paul Scheet

Faculty, Staff and Student Publications

Motivation: RNA-sequencing (RNA-seq) of tumor tissue is typically only used to measure gene expression. Here, we present a statistical approach that leverages existing RNA-seq data to also detect somatic copy number alterations (SCNAs), a pervasive phenomenon in human cancers, without a need to sequence the corresponding DNA.

Results: We present an analysis of 4942 participant samples from 28 cancers in The Cancer Genome Atlas (TCGA), demonstrating robust detection of SCNAs from RNA-seq. Using genotype imputation and haplotype information, our RNA-based method had a median sensitivity of 85% to detect SCNAs defined by DNA analysis, at high specificity (∼95%). As an …

A Multidisciplinary Approach And Consensus Statement To Establish Standards Of Care For Angelman Syndrome, Jessica Duis, Mark Nespeca, Jane Summers, Lynne Bird, Karen G C B Bindels-De Heus, M J Valstar, Marie-Claire Y De Wit, C Navis, Maartje Ten Hooven-Radstaake, Bianca M Van Iperen-Kolk, Susan Ernst, Melina Dendrinos, Terry Katz, Gloria Diaz-Medina, Akshat Katyayan, Srishti Nangia, Ronald Thibert, Daniel Glaze, Christopher Keary, Karine Pelc, Nicole Simon, Anjali Sadhwani, Helen Heussler, Anne Wheeler, Caroline Woeber, Margaret Deramus, Amy Thomas, Emily Kertcher, Lauren Devalk, Kristen Kalemeris, Kara Arps, Carol Baym, Nicole Harris, John P Gorham, Brenda L Bohnsack, Reid C Chambers, Sarah Harris, Henry G Chambers, Katherine Okoniewski, Elizabeth R Jalazo, Allyson Berent, Carlos A Bacino, Charles Williams, Anne Anderson

Duncan NRI Faculty and Staff Publications

Background: Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence-based literature. We present a consensus statement and comprehensive literature review that proposes a …

Clinical Exome Sequencing Data Reveal High Diagnostic Yields For Congenital Diaphragmatic Hernia Plus (Cdh+) And New Phenotypic Expansions Involving Cdh, Tiana M Scott, Ian M Campbell, Andres Hernandez-Garcia, Seema R Lalani, Pengfei Liu, Chad A Shaw, Jill A Rosenfeld, Daryl A Scott

Duncan NRI Faculty and Staff Publications

Background: Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted.

Methods: We analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions.

Results: Among the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other …

Targeting Mitochondrial Respiration And The Bcl2 Family In High-Grade Myc-Associated B-Cell Lymphoma, Giulio Donati, Micol Ravà, Marco Filipuzzi, Paola Nicoli, Laura Cassina, Alessandro Verrecchia, Mirko Doni, Simona Rodighiero, Federica Parodi, Alessandra Boletta, Christopher P Vellano, Joseph R Marszalek, Giulio F Draetta, Bruno Amati

Faculty, Staff and Student Publications

Multiple molecular features, such as activation of specific oncogenes (e.g., MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL), although their relationships and implications for targeted therapy remain to be fully unraveled. We report that MYC activity is closely correlated with-and most likely a driver of-gene signatures related to oxidative phosphorylation (OxPhos) in DLBCL, pointing to OxPhos enzymes, in particular mitochondrial electron transport chain (ETC) complexes, as possible therapeutic targets in high-grade MYC-associated lymphomas. In our experiments, indeed, MYC sensitized B cells to the ETC complex I inhibitor …

Monitoring Malignant T-Cell Clones By Direct Tcr Expression Assay In Patients With Leukemic Cutaneous T-Cell Lymphoma During Extracorporeal Photopheresis, Xiao Ni, Sourindra Maiti, Alissa Redko, Pedram Bijani, Madeleine Duvic

Faculty, Staff and Student Publications

Background/purpose: Accurate assessment of malignant T-cell clones in patients with leukemic cutaneous T-cell lymphoma (L-CTCL) is crucial for diagnosis, treatment, and monitoring disease. Although multiple approaches to quantitate malignant T-cell clones have been reported, a cost-effective assay with broad coverage is not available. We report a NanoString-nCounter-Technology-based direct TCR expression assay (DTEA) that was previously developed to quantify both TCR-Vα and TCR-Vβ usages after adoptive immunotherapy. This study was performed to test the effectiveness of DTEA in assessing malignant T-cell clones in L-CTCL patients.

Methods: Total RNAs extracted from peripheral blood mononuclear cells of patients before starting extracorporeal photopheresis (ECP) …

Dose Accumulation Of Daily Adaptive Plans To Decide Optimal Plan Adaptation Strategy For Head-And-Neck Patients Treated With Mr-Linac, Shin Yun Lim, Alan Tran, Anh Ngoc Kieu Tran, Angela Sobremonte, Clifton D Fuller, Lori Simmons, Jinzhong Yang

Faculty, Staff and Student Publications

Advances in magnetic resonance linear accelerators (MR-Linacs) allow for superior visualization of soft tissue to guide online adaptive replanning for precise radiotherapy delivery. Elekta Unity MR-Linacs (Elekta AB, Stockholm, Sweden) provides 2 plan adaptation approaches, adapt-to-position (ATP), plan reoptimization based on the reference CT with the iso-shift measured from daily MR scans, and adapt-to-shape (ATS), full plan reoptimization based on the re-contoured daily MR scans. Our study aims to close the gap in knowledge regarding the use of the ATP technique in the treatment of head and neck (HN) cancers through the analysis of accumulated dose of daily ATP plans …

Accounting For Egfr Mutations In Epidemiologic Analyses Of Non-Small Cell Lung Cancers: Examples Based On The International Lung Cancer Consortium Data, Sabine Schmid, Mei Jiang, M Catherine Brown, Aline Fares, Miguel Garcia, Joelle Soriano, Mei Dong, Sera Thomas, Takashi Kohno, Leticia Ferro Leal, Nancy Diao, Juntao Xie, Zhichao Wang, David Zaridze, Ivana Holcatova, Jolanta Lissowska, Beata Świątkowska, Dana Mates, Milan Savic, Angela S Wenzlaff, Curtis C Harris, Neil E Caporaso, Hongxia Ma, Guillermo Fernandez-Tardon, Matthew J Barnett, Gary Goodman, Michael P A Davies, Mónica Pérez-Ríos, Fiona Taylor, Eric J Duell, Ben Schoettker, Hermann Brenner, Angeline Andrew, Angela Cox, Alberto Ruano-Ravina, John K Field, Loic Le Marchand, Ying Wang, Chu Chen, Adonina Tardon, Sanjay Shete, Matthew B Schabath, Hongbing Shen, Maria Teresa Landi, Brid M Ryan, Ann G Schwartz, Lihong Qi, Lori C Sakoda, Paul Brennan, Ping Yang, Jie Zhang, David C Christiani, Rui Manuel Reis, Kouya Shiraishi, Rayjean J Hung, Wei Xu, Geoffrey Liu

Faculty, Staff and Student Publications

Background: Somatic EGFR mutations define a subset of non-small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches.

Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did …

Subtype-Specific And Co-Occurring Genetic Alterations In B-Cell Non-Hodgkin Lymphoma, Man Chun John Ma, Saber Tadros, Alyssa Bouska, Tayla Heavican, Haopeng Yang, Qing Deng, Dalia Moore, Ariz Akhter, Keenan Hartert, Neeraj Jain, Jordan Showell, Sreejoyee Ghosh, Lesley Street, Marta Davidson, Christopher Carey, Joshua Tobin, Deepak Perumal, Julie M Vose, Matthew A Lunning, Aliyah R Sohani, Benjamin J Chen, Shannon Buckley, Loretta J Nastoupil, R Eric Davis, Jason R Westin, Nathan H Fowler, Samir Parekh, Maher Gandhi, Sattva Neelapu, Douglas Stewart, Kapil Bhalla, Javeed Iqbal, Timothy Greiner, Scott J Rodig, Adnan Mansoor, Michael R Green

Faculty, Staff and Student Publications

B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, …

Current State And Future Directions Of Genomic Medicine In Aortic Dissection: A Path To Prevention And Personalized Care, Alana C Cecchi, Madeline Drake, Chrisanne Campos, Jake Howitt, Jonathan Medina, Scott M Damrauer, Sherene Shalhub, Dianna M Milewicz, Aortic Dissection Collaborative

Faculty, Staff and Student Publications

Aortic dissection confers high mortality and morbidity rates despite advances in treatment, impacts quality of life, and contributes immense burden to the healthcare system globally. Efforts to prevent aortic dissection through screening and management of modifiable risk factors and early detection of aneurysms should incorporate genomic information, as it is integral to stratifying risk. However, effective integration of genomic-guided risk assessment into clinical practice will require addressing implementation barriers that currently permeate our healthcare systems. The Aortic Dissection Collaborative was established to define aortic dissection research priorities through patient engagement. Using a collaborative patient-centered feedback model, our Genomic Medicine Working …

Long-Term Survival Following Definitive Radiation Therapy For Recurrence Or Oligometastases In Gynecological Malignancies: A Landmark Analysis, Kelsey L Corrigan, Alison Yoder, Brian De, Lilie Lin, Anuja Jhingran, Melissa M Joyner, Patricia J Eifel, Lauren E Colbert, Karen H Lu, Ann H Klopp

Faculty, Staff and Student Publications

Objective: Radiation therapy (RT) may improve outcomes for patients with oligometastatic cancer. We sought to determine if there are long-term survivors treated with definitive RT for recurrent or oligometastatic gynecological cancer (ROMGC), and to evaluate the clinical and disease characteristics of these patients.

Methods: We performed a landmark analysis in 48 patients with ROMGC who survived for ≥5 years following definitive RT of their metastasis. Patient characteristics were extracted from the medical record. DFS was modeled using the Kaplan-Meier method.

Results: This cohort included 20 patients (42%) with ovarian cancer, 16 (33%) with endometrial cancer, 11 (23%) with cervical cancer, …

Peripheral And Central Kynurenine Pathway Abnormalities In Major Depression, Elisabeth R Paul, Lilly Schwieler, Sophie Erhardt, Sandra Boda, Ada Trepci, Robin Kämpe, Anna Asratian, Lovisa Holm, Adam Yngve, Robert Dantzer, Markus Heilig, J Paul Hamilton, Martin Samuelsson

Faculty, Staff and Student Publications

Considerable data relate major depressive disorder (MDD) with aberrant immune system functioning. Pro-inflammatory cytokines facilitate metabolism of tryptophan along the kynurenine pathway (KP) putatively resulting in reduced neuroprotective and increased neurotoxic KP metabolites in MDD, in addition to modulating metabolic and immune function. This central nervous system hypothesis has, however, only been tested in the periphery. Here, we measured KP-metabolite levels in both plasma and cerebrospinal fluid (CSF) of depressed patients (n = 63/36 respectively) and healthy controls (n = 48/33). Further, we assessed the relation between KP abnormalities and brain-structure volumes, as well as body mass index (BMI), an …

Characterization Of Patient-Derived Bone Marrow Human Mesenchymal Stem Cells As Oncolytic Virus Carriers For The Treatment Of Glioblastoma, Yuzaburo Shimizu, Joy Gumin, Feng Gao, Anwar Hossain, Elizabeth J Shpall, Akihide Kondo, Brittany C Parker Kerrigan, Jing Yang, Daniel Ledbetter, Juan Fueyo, Candelaria Gomez-Manzano, Frederick F Lang

Faculty, Staff and Student Publications

Objective: Delta-24-RGD is an oncolytic adenovirus that is capable of replicating in and killing human glioma cells. Although intratumoral delivery of Delta-24-RGD can be effective, systemic delivery would improve its clinical application. Bone marrow-derived human mesenchymal stem cells (BM-hMSCs) obtained from healthy donors have been investigated as virus carriers. However, it is unclear whether BM-hMSCs can be derived from glioma patients previously treated with marrow-toxic chemotherapy or whether such BM-hMSCs can deliver oncolytic viruses effectively. Herein, the authors undertook a prospective clinical trial to determine the feasibility of obtaining BM-hMSCs from patients with recurrent malignant glioma who were previously exposed …

Local Treatment Of A Pediatric Osteosarcoma Model With A 4-1bbl Armed Oncolytic Adenovirus Results In An Antitumor Effect And Leads To Immune Memory, Naiara Martinez-Velez, Virginia Laspidea, Marta Zalacain, Sara Labiano, Marc García-Moure, Montse Puigdelloses, Lucía Marrodan, Marisol Gonzalez-Huarriz, Guillermo Herrador, Daniel De La Nava, Iker Ausejo-Mauleon, Juan Fueyo, Candelaria Gomez-Manzano, Ana Patiño-García, Marta M Alonso

Faculty, Staff and Student Publications

Osteosarcoma is an aggressive bone tumor occurring primarily in pediatric patients. Despite years of intensive research, the outcomes of patients with metastatic disease or those who do not respond to therapy have remained poor and have not changed in the last 30 years. Oncolytic virotherapy is becoming a reality to treat local and metastatic tumors while maintaining a favorable safety profile. Delta-24-ACT is a replicative oncolytic adenovirus engineered to selectively target cancer cells and to potentiate immune responses through expression of the immune costimulatory ligand 4-1BB. This work aimed to assess the antisarcoma effect of Delta-24-ACT. MTS and replication assays …

Safety And Activity Of Pembrolizumab In Combination With Rituximab In Relapsed Or Refractory Follicular Lymphoma, Loretta J Nastoupil, Collin K Chin, Jason R Westin, Nathan H Fowler, Felipe Samaniego, Xiaoyun Cheng, Man Chun John Ma, Zhiqiang Wang, Fuliang Chu, Ly Dsouza, Chizobam Obi, Jennifer Mims, Lei Feng, Shouhao Zhou, Michael Green, Richard Eric Davis, Sattva S Neelapu

Faculty, Staff and Student Publications

PD-1 blockade enhances the function of antitumor T cells and antibody-dependent, cell-mediated cytotoxicity (ADCC) of NK cells. In a single-center, open-label, phase 2 trial, we tested the combination of pembrolizumab, an anti-PD-1 monoclonal antibody, and rituximab, an anti-CD20 monoclonal antibody that induces ADCC, in 30 patients with follicular lymphoma (FL) with rituximab-sensitive disease who had relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 16 cycles, and rituximab was given at 375 mg/m2 IV weekly for 4 weeks in cycle 1 only. The most common grade 3/4 adverse events (AEs) were …

Spatial Transcriptomics Of Dorsal Root Ganglia Identifies Molecular Signatures Of Human Nociceptors, Diana Tavares-Ferreira, Stephanie Shiers, Pradipta R Ray, Andi Wangzhou, Vivekanand Jeevakumar, Ishwarya Sankaranarayanan, Anna M Cervantes, Jeffrey C Reese, Alexander Chamessian, Bryan A Copits, Patrick M Dougherty, Robert W Gereau, Michael D Burton, Gregory Dussor, Theodore J Price

Faculty, Staff and Student Publications

Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG …

Feasibility Of Administering Human Pancreatic Cancer Chemotherapy In A Spontaneous Pancreatic Cancer Mouse Model, Abagail M Delahoussaye, Joseph Abi Jaoude, Morgan Green, Tara N Fujimoto, Jessica Molkentine, Carolina J Garcia Garcia, Jason P Gay, Ningping Feng, Joseph Marszalek, Natalie Fowlkes, Cullen M Taniguchi

Faculty, Staff and Student Publications

Background: Both modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel chemotherapy regimens have been shown to improve clinical outcomes in patients with pancreatic cancer, and are often used interchangeably as the standard of care. Preclinical studies often do not use these regimens, since administering these multiagent approaches can be difficult. In this study, we assessed the feasibility of administering these two chemotherapy regimens in spontaneous pancreatic tumors using KPC mice with the ultimate goal of advancing preclinical studies.

Methods: KPC mice were created by breeding KrasLSL-G12D/+ to Trp53fl/fl;Ptf1αCre/+, resulting in KrasLSL-G12D/+;p53fl/+;Ptf1αCre/+ mice. At 14 weeks of age, mice were palpated for spontaneous tumor …

Fungal Mycobiome Drives Il-33 Secretion And Type 2 Immunity In Pancreatic Cancer, Aftab Alam, Eric Levanduski, Parker Denz, Helena Solleiro Villavicencio, Maulasri Bhatta, Lamees Alhorebi, Yali Zhang, Eduardo Cortes Gomez, Brian Morreale, Sharon Senchanthisai, Jun Li, Steven G Turowski, Sandra Sexton, Sheila Jani Sait, Prashant K Singh, Jianmin Wang, Anirban Maitra, Pawel Kalinski, Ronald A Depinho, Huamin Wang, Wenting Liao, Scott I Abrams, Brahm H Segal, Prasenjit Dey

Faculty, Staff and Student Publications

TH2 cells and innate lymphoid cells 2 (ILC2) can stimulate tumor growth by secreting pro-tumorigenic cytokines such as interleukin-4 (IL-4), IL-5, and IL-13. However, the mechanisms by which type 2 immune cells traffic to the tumor microenvironment are unknown. Here, we show that oncogenic KrasG12D increases IL-33 expression in pancreatic ductal adenocarcinoma (PDAC) cells, which recruits and activates TH2 and ILC2 cells. Correspondingly, cancer-cell-specific deletion of IL-33 reduces TH2 and ILC2 recruitment and promotes tumor regression. Unexpectedly, IL-33 secretion is dependent on the intratumoral fungal mycobiome. Genetic deletion of IL-33 or anti-fungal treatment decreases TH2 and ILC2 infiltration and increases …

Effective Therapy For Aml With Runx1 Mutation By Cotreatment With Inhibitors Of Protein Translation And Bcl2, Christopher P Mill, Warren Fiskus, Courtney D Dinardo, Christine Birdwell, John A Davis, Tapan M Kadia, Koichi Takahashi, Nicholas Short, Naval Daver, Maro Ohanian, Gautam Borthakur, Steven M Kornblau, Michael R Green, Yuan Qi, Xiaoping Su, Joseph D Khoury, Kapil N Bhalla

Faculty, Staff and Student Publications

The majority of RUNX1 mutations in acute myeloid leukemia (AML) are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared with AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1, and c-Myc. Compared with AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. Homoharringtonine treatment repressed …

Lipid-Loaded Tumor-Associated Macrophages Sustain Tumor Growth And Invasiveness In Prostate Cancer, Michela Masetti, Roberta Carriero, Federica Portale, Giulia Marelli, Nicolò Morina, Marta Pandini, Marta Iovino, Bianca Partini, Marco Erreni, Andrea Ponzetta, Elena Magrini, Piergiuseppe Colombo, Grazia Elefante, Federico Simone Colombo, Joke M M Den Haan, Clelia Peano, Javier Cibella, Alberto Termanini, Paolo Kunderfranco, Jolanda Brummelman, Matthew Wai Heng Chung, Massimo Lazzeri, Rodolfo Hurle, Paolo Casale, Enrico Lugli, Ronald A Depinho, Subhankar Mukhopadhyay, Siamon Gordon, Diletta Di Mitri

Faculty, Staff and Student Publications

Tumor-associated macrophages (TAMs) are correlated with the progression of prostatic adenocarcinoma (PCa). The mechanistic basis of this correlation and therapeutic strategies to target TAMs in PCa remain poorly defined. Here, single-cell RNA sequencing was used to profile the transcriptional landscape of TAMs in human PCa, leading to identification of a subset of macrophages characterized by dysregulation in transcriptional pathways associated with lipid metabolism. This subset of TAMs correlates positively with PCa progression and shorter disease-free survival and is characterized by an accumulation of lipids that is dependent on Marco. Mechanistically, cancer cell-derived IL-1β enhances Marco expression on macrophages, and reciprocally, …

Srgn-Triggered Aggressive And Immunosuppressive Phenotype In A Subset Of Ttf-1-Negative Lung Adenocarcinomas, Ichidai Tanaka, Delphine Dayde, Mei Chee Tai, Haruki Mori, Luisa M Solis, Satyendra C Tripathi, Johannes F Fahrmann, Nese Unver, Gargy Parhy, Rekha Jain, Edwin R Parra, Yoshiko Murakami, Clemente Aguilar-Bonavides, Barbara Mino, Muge Celiktas, Dilsher Dhillon, Julian Phillip Casabar, Masahiro Nakatochi, Francesco Stingo, Veera Baladandayuthapani, Hong Wang, Hiroyuki Katayama, Jennifer B Dennison, Philip L Lorenzi, Kim-Anh Do, Junya Fujimoto, Carmen Behrens, Edwin J Ostrin, Jaime Rodriguez-Canales, Tetsunari Hase, Takayuki Fukui, Taisuke Kajino, Seiichi Kato, Yasushi Yatabe, Waki Hosoda, Koji Kawaguchi, Kohei Yokoi, Toyofumi F Chen-Yoshikawa, Yoshinori Hasegawa, Adi F Gazdar, Ignacio I Wistuba, Samir Hanash, Ayumu Taguchi

Faculty, Staff and Student Publications

BACKGROUND: Approximately 20% of lung adenocarcinoma (LUAD) is negative for the lineage-specific oncogene Thyroid transcription factor 1 (TTF-1) and exhibits worse clinical outcome with a low frequency of actionable genomic alterations. To identify molecular features associated with TTF-1-negative LUAD, we compared the transcriptomic and proteomic profiles of LUAD cell lines. SRGN , a chondroitin sulfate proteoglycan Serglycin, was identified as a markedly overexpressed gene in TTF-1-negative LUAD. We therefore investigated the roles and regulation of SRGN in TTF-1-negative LUAD.

METHODS: Proteomic and metabolomic analyses of 41 LUAD cell lines were done using mass spectrometry. The function of SRGN was investigated …

Interplay Between Soluble Cd74 And Macrophage-Migration Inhibitory Factor Drives Tumor Growth And Influences Patient Survival In Melanoma, Yasunari Fukuda, Matias A Bustos, Sung-Nam Cho, Jason Roszik, Suyeon Ryu, Victor M Lopez, Jared K Burks, Jeffrey E Lee, Elizabeth A Grimm, Dave S B Hoon, Suhendan Ekmekcioglu

Faculty, Staff and Student Publications

Soluble forms of receptors play distinctive roles in modulating signal-transduction pathways. Soluble CD74 (sCD74) has been identified in sera of inflammatory diseases and implicated in their pathophysiology; however, few relevant data are available in the context of cancer. Here we assessed the composition and production mechanisms, as well as the clinical significance and biological properties, of sCD74 in melanoma. Serum sCD74 levels were significantly elevated in advanced melanoma patients compared with normal healthy donors, and the high ratio of sCD74 to macrophage-migration inhibitory factor (MIF) conferred significant predictive value for prolonged survival in these patients (p = 0.0035). Secretion of …

Construction And Validation Of Prognostic Nomogram For Metaplastic Breast Cancer, Yongfeng Li, Daobao Chen, Haojun Xuan, Mihnea P Dragomir, George A Calin, Xuli Meng, Meng Chen, Hongchuan Jin

Faculty, Staff and Student Publications

In this study we aimed to develop nomogram models for predicting the overall survival (OS) and cancer-specific survival (CSS) of patients with metaplastic breast cancer (MBC). Data of patients diagnosed with MBC from 1973 to 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox analyses were performed to identify independent prognostic factors for OS and CSS of MBC patients. The obtained prognostic variables were combined to construct nomogram models for predicting OS and CSS in patients with MBC. Model performance was evaluated using concordance index (C-index) and calibration plots. Data from 1125 patients …