Digital Commons Network^™

Myelodysplastic/Myeloproliferative Neoplasms-Unclassifiable With Isolated Isochromosome 17q Represents A Distinct Clinico-Biologic Subset: A Multi-Institutional Collaborative Study From The Bone Marrow Pathology Group, Rashmi Kanagal-Shamanna, Attilio Orazi, Robert P Hasserjian, Daniel A Arber, Kaaren Reichard, Eric D Hsi, Adam Bagg, Heesun Joyce Rogers, Julia Geyer, Faezeh Darbaniyan, Kim-Anh Do, Kyle M Devins, Olga Pozdnyakova, Tracy I George, Paola Dal Cin, Patricia T Greipp, Mark J Routbort, Keyur Patel, Guillermo Garcia-Manero, Srdan Verstovsek, L Jeffrey Medeiros, Sa A Wang, Carlos Bueso-Ramos

Faculty, Staff and Student Publications

Classification of myeloid neoplasms with isolated isochromosome i(17q) [17p deletion with inherent monoallelic TP53 loss plus 17q duplication] is controversial. Most cases fall within the WHO unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U) category. The uniformly dismal outcomes warrant better understanding of this entity. We undertook a multi-institutional retrospective study of 92 adult MDS/MPN-U cases from eight institutions. Twenty-nine (32%) patients had isolated i(17q) [MDS/MPN-i(17q)]. Compared to MDS/MPN without i(17q), MDS/MPN-i(17q) patients were significantly younger, had lower platelet and absolute neutrophil counts, and higher frequency of splenomegaly and circulating blasts. MDS/MPN-i(17q) cases showed frequent bilobed neutrophils (75% vs. 23%; P = 0.03), hypolobated …

Β-Adrenergic Signaling In Skin Cancer, Jennifer Batalla-Covello, Shahrukh Ali, Tongxin Xie, Moran Amit

Faculty, Staff and Student Publications

Activation of the sympathetic nervous system releases catecholamines that can interact with β-adrenergic receptors on tumor cells. Preclinical models have shown that the signaling processes initiated by activation of β-adrenergic receptors increase tumorigenesis, stimulate cell proliferation, and inhibit apoptosis. Indeed, preclinical studies have also shown that β-adrenergic blockade can decrease tumor burden. Researchers have been studying the effects of β-adrenergic receptor blockers on tumor cells and how they may slow the progression of melanoma, basal cell carcinoma, and squamous cell carcinoma. Moreover, clinical data have shown improved prognosis in patients with skin cancer who take β-blockers. This review discusses the …

Inhibiting Type I Arginine Methyltransferase Activity Promotes T Cell-Mediated Antitumor Immune Responses, Andrew Fedoriw, Leilei Shi, Shane O'Brien, Kimberly N Smitheman, Yunfei Wang, Jiakai Hou, Christian Sherk, Satyajit Rajapurkar, Jenny Laraio, Leila J Williams, Chunyu Xu, Guangchun Han, Qin Feng, Mark T Bedford, Linghua Wang, Olena Barbash, Ryan G Kruger, Patrick Hwu, Helai P Mohammad, Weiyi Peng

Faculty, Staff and Student Publications

Protein arginine methyltransferases (PRMT) are a widely expressed class of enzymes responsible for catalyzing arginine methylation on numerous protein substrates. Among them, type I PRMTs are responsible for generating asymmetric dimethylarginine. By controlling multiple basic cellular processes, such as DNA damage responses, transcriptional regulation, and mRNA splicing, type I PRMTs contribute to cancer initiation and progression. A type I PRMT inhibitor, GSK3368715, has been developed and has entered clinical trials for solid and hematologic malignancies. Although type I PRMTs have been reported to play roles in modulating immune cell function, the immunologic role of tumor-intrinsic pathways controlled by type I …

Comparative Molecular Genomic Analyses Of A Spontaneous Rhesus Macaque Model Of Mismatch Repair-Deficient Colorectal Cancer, Nejla Ozirmak Lermi, Stanton B Gray, Charles M Bowen, Laura Reyes-Uribe, Beth K Dray, Nan Deng, R Alan Harris, Muthuswamy Raveendran, Fernando Benavides, Carolyn L Hodo, Melissa W Taggart, Karen Colbert Maresso, Krishna M Sinha, Jeffrey Rogers, Eduardo Vilar

Faculty, Staff and Student Publications

Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029C

Effect Of Perfluorocarbon Composition On Activation Of Phase-Changing Ultrasound Contrast Agents, Trevor M Mitcham, Dmitry Nevozhay, Yunyun Chen, Linh D Nguyen, Gianmarco F Pinton, Stephen Y Lai, Konstantin V Sokolov, Richard R Bouchard

Faculty, Staff and Student Publications

BACKGROUND: While microbubble contrast agents (MCAs) are commonly used in ultrasound (US), they are inherently limited to vascular targets due to their size. Alternatively, phase-changing nanodroplet contrast agents (PNCAs) can be delivered as nanoscale agents (i.e., small enough to extravasate), but when exposed to a US field of sufficient mechanical index (MI), they convert to MCAs, which can be visualized with high contrast using nonlinear US.

PURPOSE: To investigate the effect of perfluorocarbon (PFC) core composition and presence of cholesterol in particle coatings on stability and image contrast generated from acoustic activation of PNCAs using high-frequency US suitable for clinical …

Notch-Induced Mdsc Recruitment After Ohsv Virotherapy In Cns Cancer Models Modulates Antitumor Immunotherapy, Yoshihiro Otani, Ji Young Yoo, Cole T Lewis, Samantha Chao, Jessica Swanner, Toshihiko Shimizu, Jin Muk Kang, Sara A Murphy, Kimberly Rivera-Caraballo, Bangxing Hong, Joseph C Glorioso, Hiroshi Nakashima, Sean E Lawler, Yeshavanth Banasavadi-Siddegowda, John D Heiss, Yuanqing Yan, Guangsheng Pei, Michael A Caligiuri, Zhongming Zhao, E Antonio Chiocca, Jianhua Yu, Balveen Kaur

Faculty, Staff and Student Publications

PURPOSE: Oncolytic herpes simplex virus-1 (oHSV) infection of brain tumors activates NOTCH, however the consequences of NOTCH on oHSV-induced immunotherapy is largely unknown. Here we evaluated the impact of NOTCH blockade on virus-induced immunotherapy.

EXPERIMENTAL DESIGN: RNA sequencing (RNA-seq), TCGA data analysis, flow cytometry, Luminex- and ELISA-based assays, brain tumor animal models, and serum analysis of patients with recurrent glioblastoma (GBM) treated with oHSV was used to evaluate the effect of NOTCH signaling on virus-induced immunotherapy.

RESULTS: TCGA data analysis of patients with grade IV glioma and oHSV treatment of experimental brain tumors in mice showed that NOTCH signaling significantly …

Trends In Acromioplasty Utilization During Arthroscopic Rotator Cuff Repair: An Epidemiological Study Of 139,586 Patients, Taylor J Willenbring, Marijke J Devos, Ryan J Warth, James M Gregory

Faculty, Staff and Student Publications

INTRODUCTION: Acromioplasty remains very common during rotator cuff repair (RCR) despite limited evidence of clinical efficacy. This study observed the incidence of acromioplasty from 2010 to 2018 in Texas using a publicly available database.

METHODS: A total of 139,586 records were analyzed from the Texas Healthcare Information Collection database ranging from 2010 to 2018. These cases were divided into those with and without acromioplasty (N = 107,427 and N = 32,159, respectively). Acromioplasty use was standardized as the number of acromioplasties per RCR (acromioplasty rate). Two subgroup analyses were conducted: surgical institution type and payor status.

RESULTS: In 2010, acromioplasty …

Characteristics And Predictors Of Intensive Care Unit Admission In Pediatric Blunt Abdominal Trauma, Steven C Mehl, Megan E Cunningham, Christian J Streck, Rowland Pettit, Eunice Y Huang, Matthew T Santore, Kuojen Tsao, Richard A Falcone, Melvin S Dassinger, Jeffrey H Haynes, Robert T Russell, Bindi J Naik-Mathuria, Shawn D St Peter, David Mooney, Jeffrey Upperman, Martin L Blakely, Adam M Vogel

Faculty, Staff and Student Publications

BACKGROUND: Pediatric trauma patients sustaining blunt abdominal trauma (BAT) with intra-abdominal injury (IAI) are frequently admitted to the intensive care unit (ICU). This study was performed to identify predictors for ICU admission following BAT.

METHODS: Prospective study of children (< 16 years) who presented to 14 Level-One Pediatric Trauma Centers following BAT over a 1-year period. Patients were categorized as ICU or non-ICU patients. Data collected included vitals, physical exam findings, laboratory results, imaging, and traumatic injuries. A multivariable hierarchical logistic regression model was used to identify predictors of ICU admission. Predictive ability of the model was assessed via tenfold cross-validated area under the receiver operating characteristic curves (cvAUC).

RESULTS: Included were 2,182 children with 21% (n = 463) admitted to the ICU. On univariate analysis, ICU patients were associated with abnormal age-adjusted shock index, increased injury severity scores (ISS), lower Glasgow coma scores (GCS), traumatic brain injury (TBI), and severe solid organ injury (SOI). With multivariable logistic regression, factors associated with ICU admission were severe trauma (ISS > 15), …

Survey Of Pediatric Critical Care Fellows On Postresuscitation Debriefing, Nicholas A Rossi, Mia Benavidez, Harold S Pine, Shiva Daram, Wasyl Szeremeta

Faculty, Staff and Student Publications

Choanal atresia is a rare congenital airway malformation that presents a unique surgical challenge for pediatric otolaryngologists. Here we report two classic cases of choanal atresia and examine the surgical approaches to this entity. The first case was a four-day-old female with a history of CHARGE syndrome and bilateral mixed membranous and bony choanal atresia confirmed by a CT scan. After undergoing transnasal endoscopic repair, choanal stents were placed for four weeks, and the patient was seen three months postoperatively and found to be doing well with no respiratory concerns. The second case involved a healthy three-year-old female presenting with …

New Insights Into The Genetic Etiology Of Alzheimer's Disease And Related Dementias, Céline Bellenguez, Fahri Küçükali, Iris E Jansen, Luca Kleineidam, Sonia Moreno-Grau, Najaf Amin, Adam C Naj, Rafael Campos-Martin, Benjamin Grenier-Boley, Victor Andrade, Peter A Holmans, Anne Boland, Vincent Damotte, Sven J Van Der Lee, Marcos R Costa, Teemu Kuulasmaa, Qiong Yang, Itziar De Rojas, Joshua C Bis, Amber Yaqub, Ivana Prokic, Julien Chapuis, Shahzad Ahmad, Vilmantas Giedraitis, Dag Aarsland, Pablo Garcia-Gonzalez, Carla Abdelnour, Emilio Alarcón-Martín, Daniel Alcolea, Montserrat Alegret, Ignacio Alvarez, Victoria Álvarez, Nicola J Armstrong, Anthoula Tsolaki, Carmen Antúnez, Ildebrando Appollonio, Marina Arcaro, Silvana Archetti, Alfonso Arias Pastor, Beatrice Arosio, Lavinia Athanasiu, Henri Bailly, Nerisa Banaj, Miquel Baquero, Sandra Barral, Alexa Beiser, Ana Belén Pastor, Jennifer E Below, Penelope Benchek, Luisa Benussi, Claudine Berr, Céline Besse, Valentina Bessi, Giuliano Binetti, Alessandra Bizarro, Rafael Blesa, Mercè Boada, Eric Boerwinkle, Barbara Borroni, Silvia Boschi, Paola Bossù, Geir Bråthen, Jan Bressler, Catherine Bresner, Henry Brodaty, Keeley J Brookes, Luis Ignacio Brusco, Dolores Buiza-Rueda, Katharina Bûrger, Vanessa Burholt, William S Bush, Miguel Calero, Laura B Cantwell, Geneviève Chene, Jaeyoon Chung, Michael L Cuccaro, Ángel Carracedo, Roberta Cecchetti, Laura Cervera-Carles, Camille Charbonnier, Hung-Hsin Chen, Caterina Chillotti, Simona Ciccone, Jurgen A H R Claassen, Christopher Clark, Elisa Conti, Anaïs Corma-Gómez, Emanuele Costantini, Carlo Custodero, Delphine Daian, Maria Carolina Dalmasso, Antonio Daniele, Efthimios Dardiotis, Jean-François Dartigues, Peter Paul De Deyn, Katia De Paiva Lopes, Lot D De Witte, Stéphanie Debette, Jürgen Deckert, Teodoro Del Ser, Nicola Denning, Anita Destefano, Martin Dichgans, Janine Diehl-Schmid, Mónica Diez-Fairen, Paolo Dionigi Rossi, Srdjan Djurovic, Emmanuelle Duron, Emrah Düzel, Carole Dufouil, Gudny Eiriksdottir, Sebastiaan Engelborghs, Valentina Escott-Price, Ana Espinosa, Michael Ewers, Kelley M Faber, Tagliavini Fabrizio, Sune Fallgaard Nielsen, David W Fardo, Lucia Farotti, Chiara Fenoglio, Marta Fernández-Fuertes, Raffaele Ferrari, Catarina B Ferreira, Evelyn Ferri, Bertrand Fin, Peter Fischer, Tormod Fladby, Klaus Fließbach, Bernard Fongang, Myriam Fornage, Juan Fortea, Tatiana M Foroud, Silvia Fostinelli, Nick C Fox, Emlio Franco-Macías, María J Bullido, Ana Frank-García, Lutz Froelich, Brian Fulton-Howard, Daniela Galimberti, Jose Maria García-Alberca, Pablo García-González, Sebastian Garcia-Madrona, Guillermo Garcia-Ribas, Roberta Ghidoni, Ina Giegling, Giaccone Giorgio, Alison M Goate, Oliver Goldhardt, Duber Gomez-Fonseca, Antonio González-Pérez, Caroline Graff, Giulia Grande, Emma Green, Timo Grimmer, Edna Grünblatt, Michelle Grunin, Vilmundur Gudnason, Tamar Guetta-Baranes, Annakaisa Haapasalo, Georgios Hadjigeorgiou, Jonathan L Haines, Kara L Hamilton-Nelson, Harald Hampel, Olivier Hanon, John Hardy, Annette M Hartmann, Lucrezia Hausner, Janet Harwood, Stefanie Heilmann-Heimbach, Seppo Helisalmi, Michael T Heneka, Isabel Hernández, Martin J Herrmann, Per Hoffmann, Clive Holmes, Henne Holstege, Raquel Huerto Vilas, Marc Hulsman, Jack Humphrey, Geert Jan Biessels, Xueqiu Jian, Charlotte Johansson, Gyungah R Jun, Yuriko Kastumata, John Kauwe, Patrick G Kehoe, Lena Kilander, Anne Kinhult Ståhlbom, Miia Kivipelto, Anne Koivisto, Johannes Kornhuber, Mary H Kosmidis, Walter A Kukull, Pavel P Kuksa, Brian W Kunkle, Amanda B Kuzma, Carmen Lage, Erika J Laukka, Lenore Launer, Alessandra Lauria, Chien-Yueh Lee, Jenni Lehtisalo, Ondrej Lerch, Alberto Lleó, William Longstreth, Oscar Lopez, Adolfo Lopez De Munain, Seth Love, Malin Löwemark, Lauren Luckcuck, Kathryn L Lunetta, Yiyi Ma, Juan Macías, Catherine A Macleod, Wolfgang Maier, Francesca Mangialasche, Marco Spallazzi, Marta Marquié, Rachel Marshall, Eden R Martin, Angel Martín Montes, Carmen Martínez Rodríguez, Carlo Masullo, Richard Mayeux, Simon Mead, Patrizia Mecocci, Miguel Medina, Alun Meggy, Shima Mehrabian, Silvia Mendoza, Manuel Menéndez-González, Pablo Mir, Susanne Moebus, Merel Mol, Laura Molina-Porcel, Laura Montrreal, Laura Morelli, Fermin Moreno, Kevin Morgan, Thomas Mosley, Markus M Nöthen, Carolina Muchnik, Shubhabrata Mukherjee, Benedetta Nacmias, Tiia Ngandu, Gael Nicolas, Børge G Nordestgaard, Robert Olaso, Adelina Orellana, Michela Orsini, Gemma Ortega, Alessandro Padovani, Caffarra Paolo, Goran Papenberg, Lucilla Parnetti, Florence Pasquier, Pau Pastor, Gina Peloso, Alba Pérez-Cordón, Jordi Pérez-Tur, Pierre Pericard, Oliver Peters, Yolande A L Pijnenburg, Juan A Pineda, Gerard Piñol-Ripoll, Claudia Pisanu, Thomas Polak, Julius Popp, Danielle Posthuma, Josef Priller, Raquel Puerta, Olivier Quenez, Inés Quintela, Jesper Qvist Thomassen, Alberto Rábano, Innocenzo Rainero, Farid Rajabli, Inez Ramakers, Luis M Real, Marcel J T Reinders, Christiane Reitz, Dolly Reyes-Dumeyer, Perry Ridge, Steffi Riedel-Heller, Peter Riederer, Natalia Roberto, Eloy Rodriguez-Rodriguez, Arvid Rongve, Irene Rosas Allende, Maitée Rosende-Roca, Jose Luis Royo, Elisa Rubino, Dan Rujescu, María Eugenia Sáez, Paraskevi Sakka, Ingvild Saltvedt, Ángela Sanabria, María Bernal Sánchez-Arjona, Florentino Sanchez-Garcia, Pascual Sánchez Juan, Raquel Sánchez-Valle, Sigrid B Sando, Chloé Sarnowski, Claudia L Satizabal, Michela Scamosci, Nikolaos Scarmeas, Elio Scarpini, Philip Scheltens, Norbert Scherbaum, Martin Scherer, Matthias Schmid, Anja Schneider, Jonathan M Schott, Geir Selbæk, Davide Seripa, Manuel Serrano, Jin Sha, Alexey A Shadrin, Olivia Skrobot, Susan Slifer, Gijsje J L Snijders, Hilkka Soininen, Vincenzo Solfrizzi, Alina Solomon, Yeunjoo Song, Sandro Sorbi, Oscar Sotolongo-Grau, Gianfranco Spalletta, Annika Spottke, Alessio Squassina, Eystein Stordal, Juan Pablo Tartan, Lluís Tárraga, Niccolo Tesí, Anbupalam Thalamuthu, Tegos Thomas, Giuseppe Tosto, Latchezar Traykov, Lucio Tremolizzo, Anne Tybjærg-Hansen, Andre Uitterlinden, Abbe Ullgren, Ingun Ulstein, Sergi Valero, Otto Valladares, Christine Van Broeckhoven, Jeffery Vance, Badri N Vardarajan, Aad Van Der Lugt, Jasper Van Dongen, Jeroen Van Rooij, John Van Swieten, Rik Vandenberghe, Frans Verhey, Jean-Sébastien Vidal, Jonathan Vogelgsang, Martin Vyhnalek, Michael Wagner, David Wallon, Li-San Wang, Ruiqi Wang, Leonie Weinhold, Jens Wiltfang, Gill Windle, Bob Woods, Mary Yannakoulia, Habil Zare, Yi Zhao, Xiaoling Zhang, Congcong Zhu, Miren Zulaica, Lindsay A Farrer, Bruce M Psaty, Mohsen Ghanbari, Towfique Raj, Perminder Sachdev, Karen Mather, Frank Jessen, M Arfan Ikram, Alexandre De Mendonça, Jakub Hort, Magda Tsolaki, Margaret A Pericak-Vance, Philippe Amouyel, Julie Williams, Ruth Frikke-Schmidt, Jordi Clarimon, Jean-François Deleuze, Giacomina Rossi, Sudha Seshadri, Ole A Andreassen, Martin Ingelsson, Mikko Hiltunen, Kristel Sleegers, Gerard D Schellenberg, Cornelia M Van Duijn, Rebecca Sims, Wiesje M Van Der Flier, Agustín Ruiz, Alfredo Ramirez, Jean-Charles Lambert

Faculty, Staff and Student Publications

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly …

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. …

Wwox Binding To The Murine Brca1-Brct Domain Regulates Timing Of Brip1 And Ctip Phospho-Protein Interactions With This Domain At Dna Double-Strand Breaks, And Repair Pathway Choice, Dongju Park, Mehdi Gharghabi, Colleen R Reczek, Rebecca Plow, Charles Yungvirt, C Marcelo Aldaz, Kay Huebner

Faculty, Staff and Student Publications

Wwox-deficient human cells show elevated homologous recombination, leading to resistance to killing by double-strand break-inducing agents. Human Wwox binds to the Brca1 981-PPLF-984 Wwox-binding motif, likely blocking the pChk2 phosphorylation site at Brca1-S988. This phosphorylation site is conserved across mammalian species; the PPLF motif is conserved in primates but not in rodents. We now show that murine Wwox does not bind Brca1 near the conserved mouse Brca1 phospho-S971 site, leaving it open for Chk2 phosphorylation and Brca1 activation. Instead, murine Wwox binds to Brca1 through its BRCT domain, where pAbraxas, pBrip1, and pCtIP, of the A, B, and C binding …

Precision Dosimetry In Yttrium-90 Radioembolization Through Ct Imaging Of Radiopaque Microspheres In A Rabbit Liver Model, E Courtney Henry, Matthew Strugari, George Mawko, Kimberly Brewer, David Liu, Andrew C Gordon, Jeffrey N Bryan, Charles Maitz, James J Karnia, Robert Abraham, S Cheenu Kappadath, Alasdair Syme

Faculty, Staff and Student Publications

Purpose: To perform precision dosimetry in yttrium-90 radioembolization through CT imaging of radiopaque microspheres in a rabbit liver model and to compare extracted dose metrics to those produced from conventional PET-based dosimetry.

Materials and methods: A CT calibration phantom was designed containing posts with nominal microsphere concentrations of 0.5 mg/mL, 5.0 mg/mL, and 25.0 mg/mL. The mean Hounsfield unit was extracted from the post volumes to generate a calibration curve to relate Hounsfield units to microsphere concentration. A nominal bolus of 40 mg of microspheres was administered to the livers of eight rabbits, followed by PET/CT imaging. A CT-based activity …

Fusionai, A Dna-Sequence-Based Deep Learning Protocol Reduces The False Positives Of Human Fusion Gene Prediction, Pora Kim, Hua Tan, Jiajia Liu, Himansu Kumar, Xiaobo Zhou

Faculty, Staff and Student Publications

Even though there were many tool developments of fusion gene prediction from NGS data, too many false positives are still an issue. Wise use of the genomic features around the fusion gene breakpoints will be helpful to identify reliable fusion genes efficiently. For this aim, we developed FusionAI, a deep learning pipeline predicting human fusion gene breakpoints from DNA sequence. FusionAI is freely available via https://compbio.uth.edu/FusionGDB2/FusionAI. For complete details on the use and execution of this protocol, please refer to Kim et al. (2021b).

Proteomic Profiling Based Classification Of Cll Provides Prognostication For Modern Therapy And Identifies Novel Therapeutic Targets, Ti'ara L Griffen, Fieke W Hoff, Yihua Qiu, James W Lillard, Alessandra Ferrajoli, Philip Thompson, Endurance Toro, Kevin Ruiz, Jan Burger, William Wierda, Steven M Kornblau

Faculty, Staff and Student Publications

Protein expression for 384 total and post-translationally modified proteins was assessed in 871 CLL and MSBL patients and was integrated with clinical data to identify strategies for improving diagnostics and therapy, making this the largest CLL proteomics study to date. Proteomics identified six recurrent signatures that were highly prognostic of survival and time to first or second treatment at three levels: individual proteins, when grouped into 40 functionally related groups (PFGs), and systemically in signatures (SGs). A novel SG characterized by hairy cell leukemia like proteomics but poor therapy response was discovered. SG membership superseded other prognostic factors (Rai Staging, …

A Novel Proton-Integrating Radiography System Design Using A Monolithic Scintillator Detector: Experimental Studies, Chinmay D Darne, Daniel G Robertson, Fahed Alsanea, Charles-Antoine Collins-Fekete, Sam Beddar

Faculty, Staff and Student Publications

Research on proton-based imaging systems aims to improve treatment planning, internal anatomy visualization, and patient alignment for proton radiotherapy. The purpose of this study was to demonstrate a new proton radiography system design consisting of a monolithic plastic scintillator volume and two optical cameras for use with scanning proton pencil beams. Unlike the thin scintillating plates currently used for proton radiography, the plastic scintillator volume (20 × 20 × 20 cm

Elucidating Mechanisms Of Genetic Cross-Disease Associations At The Procr Vascular Disease Locus, David Stacey, Lingyan Chen, Paulina J Stanczyk, Joanna M M Howson, Amy M Mason, Stephen Burgess, Stephen Macdonald, Jonathan Langdown, Harriett Mckinney, Kate Downes, Neda Farahi, James E Peters, Saonli Basu, James S Pankow, Weihong Tang, Nathan Pankratz, Maria Sabater-Lleal, Paul S De Vries, Nicholas L Smith, Amy D Gelinas, Daniel J Schneider, Nebojsa Janjic, Nilesh J Samani, Shu Ye, Charlotte Summers, Edwin R Chilvers, John Danesh, Dirk S Paul

Faculty, Staff and Student Publications

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, …

Analysis Of The Circrna And T-Ucr Populations Identifies Convergent Pathways In Mouse And Human Models Of Rett Syndrome, Edilene Siqueira, Aida Obiols-Guardia, Olga C Jorge-Torres, Cristina Oliveira-Mateos, Marta Soler, Deepthi Ramesh-Kumar, Fernando Setién, Daniëlle Van Rossum, Ainhoa Pascual-Alonso, Clara Xiol, Cristina Ivan, Masayoshi Shimizu, Judith Armstrong, George A Calin, R Jeroen Pasterkamp, Manel Esteller, Sonia Guil

Faculty, Staff and Student Publications

Noncoding RNAs play regulatory roles in physiopathology, but their involvement in neurodevelopmental diseases is poorly understood. Rett syndrome is a severe, progressive neurodevelopmental disorder linked to loss-of-function mutations of the MeCP2 gene for which no cure is yet available. Analysis of the noncoding RNA profile corresponding to the brain-abundant circular RNA (circRNA) and transcribed-ultraconserved region (T-UCR) populations in a mouse model of the disease reveals widespread dysregulation and enrichment in glutamatergic excitatory signaling and microtubule cytoskeleton pathways of the corresponding host genes. Proteomic analysis of hippocampal samples from affected individuals confirms abnormal levels of several cytoskeleton-related proteins together with key …

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 …

Identification Of A Novel Microdeletion Causative Of Nance-Horan Syndrome, Mariana Lopez Martinolich, Hope Northrup, Pedro Mancias, Paul Hillman, Kavya Rao, Kate Mowrey

Faculty, Staff and Student Publications

BACKGROUND: Nance-Horan syndrome (NHS) is a rare X-linked genetic disorder characterized by ophthalmologic and dental anomalies as well as dysmorphic facies. The clinical phenotype in males includes congenital cataracts, vision loss, microcornea, nystagmus, microphthalmia, glaucoma, screwdriver blade-shaped incisors, supernumerary maxillary incisors, diastema, delays, intellectual disability, and dysmorphic facies. With the evolution of array-CGH technology, a total of five kindreds with NHS have been reported in the medical literature with microdeletions encompassing the NHS gene rather than sequencing variants.

METHODS: The patient is a 19-year-old male born to non-consanguineous parents with a past medical history of bilateral congenital cataracts, nystagmus, poor …

Use Of The Deep Learning Approach To Measure Alveolar Bone Level, Chun-Teh Lee, Tanjida Kabir, Jiman Nelson, Sally Sheng, Hsiu-Wan Meng, Thomas E Van Dyke, Muhammad F Walji, Xiaoqian Jiang, Shayan Shams

Faculty, Staff and Student Publications

AIM: The goal was to use a deep convolutional neural network to measure the radiographic alveolar bone level to aid periodontal diagnosis.

MATERIALS AND METHODS: A deep learning (DL) model was developed by integrating three segmentation networks (bone area, tooth, cemento-enamel junction) and image analysis to measure the radiographic bone level and assign radiographic bone loss (RBL) stages. The percentage of RBL was calculated to determine the stage of RBL for each tooth. A provisional periodontal diagnosis was assigned using the 2018 periodontitis classification. RBL percentage, staging, and presumptive diagnosis were compared with the measurements and diagnoses made by the …

Reporting Outcomes Of Pediatric Intensive Care Unit Patients To Referring Physicians Via An Electronic Health Record-Based Feedback System, Christina L Cifra, Cody R Tigges, Sarah L Miller, Nathaniel Curl, Christopher D Monson, Kimberly C Dukes, Heather S Reisinger, Priyadarshini R Pennathur, Dean F Sittig, Hardeep Singh

Faculty, Staff and Student Publications

BACKGROUND: Many critically ill children are initially evaluated in front-line settings by clinicians with variable pediatric training before they are transferred to a pediatric intensive care unit (PICU). Because clinicians learn from past performance, communicating outcomes of patients back to front-line clinicians who provide pediatric emergency care could be valuable; however, referring clinicians do not consistently receive this important feedback.

OBJECTIVES: Our aim was to determine the feasibility, usability, and clinical relevance of a semiautomated electronic health record (EHR)-supported system developed at a single institution to deliver timely and relevant PICU patient outcome feedback to referring emergency department (ED) physicians. …

Assessing The Contribution Of Rare Variants To Complex Trait Heritability From Whole-Genome Sequence Data, Pierrick Wainschtein, Deepti Jain, Zhili Zheng, Topmed Anthropometry Working Group, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, L Adrienne Cupples, Aladdin H Shadyab, Barbara Mcknight, Benjamin M Shoemaker, Braxton D Mitchell, Bruce M Psaty, Charles Kooperberg, Ching-Ti Liu, Christine M Albert, Dan Roden, Daniel I Chasman, Dawood Darbar, Donald M Lloyd-Jones, Donna K Arnett, Elizabeth A Regan, Eric Boerwinkle, Jerome I Rotter, Jeffrey R O'Connell, Lisa R Yanek, Mariza De Andrade, Matthew A Allison, Merry-Lynn N Mcdonald, Mina K Chung, Myriam Fornage, Nathalie Chami, Nicholas L Smith, Patrick T Ellinor, Ramachandran S Vasan, Rasika A Mathias, Ruth J F Loos, Stephen S Rich, Steven A Lubitz, Susan R Heckbert, Susan Redline, Xiuqing Guo, Y -D Ida Chen, Cecelia A Laurie, Ryan D Hernandez, Stephen T Mcgarvey, Michael E Goddard, Cathy C Laurie, Kari E North, Leslie A Lange, Bruce S Weir, Loic Yengo, Jian Yang, Peter M Visscher

Faculty, Staff and Student Publications

Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error …

Type 2 Diabetes Partitioned Polygenic Scores Associate With Disease Outcomes In 454,193 Individuals Across 13 Cohorts, Daniel Dicorpo, Jessica Leclair, Joanne B Cole, Chloé Sarnowski, Fariba Ahmadizar, Lawrence F Bielak, Anneke Blokstra, Erwin P Bottinger, Layal Chaker, Yii-Der I Chen, Ye Chen, Paul S De Vries, Tariq Faquih, Mohsen Ghanbari, Valborg Gudmundsdottir, Xiuqing Guo, Natalie R Hasbani, Dorina Ibi, M Arfan Ikram, Maryam Kavousi, Hampton L Leonard, Aaron Leong, Josep M Mercader, Alanna C Morrison, Girish N Nadkarni, Mike A Nalls, Raymond Noordam, Michael Preuss, Jennifer A Smith, Stella Trompet, Petra Vissink, Jie Yao, Wei Zhao, Eric Boerwinkle, Mark O Goodarzi, Vilmundur Gudnason, J Wouter Jukema, Sharon L R Kardia, Ruth J F Loos, Ching-Ti Liu, Alisa K Manning, Dennis Mook-Kanamori, James S Pankow, H Susan J Picavet, Naveed Sattar, Eleanor M Simonsick, W M Monique Verschuren, Ko Willems Van Dijk, Jose C Florez, Jerome I Rotter, James B Meigs, Josée Dupuis, Miriam S Udler

Faculty, Staff and Student Publications

OBJECTIVE: Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters, termed β-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed.

RESEARCH DESIGN AND METHODS: Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) …

Elucidating The Clinical Spectrum And Molecular Basis Of Hyal2 Deficiency, James Fasham, Siying Lin, Promita Ghosh, Francesca Clementina Radio, Emily G Farrow, Isabelle Thiffault, Jennifer Kussman, Dihong Zhou, Rick Hemming, Kenneth Zahka, Barry A Chioza, Lettie E Rawlins, Olivia K Wenger, Adam C Gunning, Simone Pizzi, Roberta Onesimo, Giuseppe Zampino, Emily Barker, Natasha Osawa, Megan Christine Rodriguez, Teresa M Neuhann, Elaine H Zackai, Beth Keena, Jenina Capasso, Alex V Levin, Elizabeth Bhoj, Dong Li, Hakon Hakonarson, Ingrid M Wentzensen, Adam Jackson, Kate E Chandler, Zeynep H Coban-Akdemir, Jennifer E Posey, Siddharth Banka, James R Lupski, Sarah E Sheppard, Marco Tartaglia, Barbara Triggs-Raine, Andrew H Crosby, Emma L Baple

Faculty, Staff and Student Publications

PURPOSE: We previously defined biallelic HYAL2 variants causing a novel disorder in 2 families, involving orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, with Hyal2 knockout mice displaying similar phenotypes. In this study, we better define the phenotype and pathologic disease mechanism.

METHODS: Clinical and genomic investigations were undertaken alongside molecular studies, including immunoblotting and immunofluorescence analyses of variant/wild-type human HYAL2 expressed in mouse fibroblasts, and in silico modeling of putative pathogenic variants.

RESULTS: Ten newly identified individuals with this condition were investigated, and they were associated with 9 novel pathogenic variants. Clinical studies defined genotype-phenotype correlations and …

Post-Acquisition Hyperpolarized 29silicon Magnetic Resonance Image Processing For Visualization Of Colorectal Lesions Using A User-Friendly Graphical Interface, Caitlin V Mccowan, Duncan Salmon, Jingzhe Hu, Shivanand Pudakalakatti, Nicholas Whiting, Jennifer S Davis, Daniel D Carson, Niki M Zacharias, Pratip K Bhattacharya, Mary C Farach-Carson

Faculty, Staff and Student Publications

Medical imaging devices often use automated processing that creates and displays a self-normalized image. When improperly executed, normalization can misrepresent information or result in an inaccurate analysis. In the case of diagnostic imaging, a false positive in the absence of disease, or a negative finding when disease is present, can produce a detrimental experience for the patient and diminish their health prospects and prognosis. In many clinical settings, a medical technical specialist is trained to operate an imaging device without sufficient background information or understanding of the fundamental theory and processes involved in image creation and signal processing. Here, we …

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 …

Metabolic Stress Induces Gd2+ Cancer Stem Cell-Like Phenotype In Triple-Negative Breast Cancer, Appalaraju Jaggupilli, Stanley Ly, Khoa Nguyen, Vivek Anand, Bin Yuan, Fouad El-Dana, Yuanqing Yan, Zoe Arvanitis, Danthasinghe Waduge Badrajee Piyarathna, Nagireddy Putluri, Helen Piwnica-Worms, Henry Charles Manning, Michael Andreeff, V Lokesh Battula

Faculty, Staff and Student Publications

Background: Metabolic stress resulting from nutrient deficiency is one of the hallmarks of a growing tumour. Here, we tested the hypothesis that metabolic stress induces breast cancer stem-like cell (BCSC) phenotype in triple-negative breast cancer (TNBC).

Methods: Flow cytometry for GD2 expression, mass spectrometry and Ingenuity Pathway Analysis for metabolomics, bioinformatics, in vitro tumorigenesis and in vivo models were used.

Results: Serum/glucose deprivation not only increased stress markers but also enhanced GD2+ BCSC phenotype and function in TNBC cells. Global metabolomics profiling identified upregulation of glutathione biosynthesis in GD2high cells, suggesting a role of glutamine in the BCSC phenotype. Cueing …

Stem Cell Architecture Drives Myelodysplastic Syndrome Progression And Predicts Response To Venetoclax-Based Therapy, Irene Ganan-Gomez, Hui Yang, Feiyang Ma, Guillermo Montalban-Bravo, Natthakan Thongon, Valentina Marchica, Guillaume Richard-Carpentier, Kelly Chien, Ganiraju Manyam, Feng Wang, Ana Alfonso, Shuaitong Chen, Caleb Class, Rashmi Kanagal-Shamanna, Justin P Ingram, Yamini Ogoti, Ashley Rose, Sanam Loghavi, Pamela Lockyer, Benedetta Cambo, Muharrem Muftuoglu, Sarah Schneider, Vera Adema, Michael Mclellan, John Garza, Matteo Marchesini, Nicola Giuliani, Matteo Pellegrini, Jing Wang, Jason Walker, Ziyi Li, Koichi Takahashi, Joel D Leverson, Carlos Bueso-Ramos, Michael Andreeff, Karen Clise-Dwyer, Guillermo Garcia-Manero, Simona Colla

Faculty, Staff and Student Publications

Myelodysplastic syndromes (MDS) are heterogeneous neoplastic disorders of hematopoietic stem cells (HSCs). The current standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, almost 50% of MDS patients fail HMA therapy and progress to acute myeloid leukemia, facing a dismal prognosis due to lack of approved second-line treatment options. As cancer stem cells are the seeds of disease progression, we investigated the biological properties of the MDS HSCs that drive disease evolution, seeking to uncover vulnerabilities that could be therapeutically exploited. Through integrative molecular profiling of HSCs and progenitor cells in large patient cohorts, we found …

Chronic Estrus Disrupts Uterine Gland Development And Homeostasis, C Allison Stewart, M David Stewart, Ying Wang, Rachel D Mullen, Bonnie K Kircher, Rui Liang, Yu Liu, Richard R Behringer

Faculty, Staff and Student Publications

Female mice homozygous for an engineered Gnrhr E90K mutation have reduced gonadotropin-releasing hormone signaling, leading to infertility. Their ovaries have numerous antral follicles but no corpora lutea, indicating a block to ovulation. These mutants have high levels of circulating estradiol and low progesterone, indicating a state of persistent estrus. This mouse model provided a unique opportunity to examine the lack of cyclic levels of ovarian hormones on uterine gland biology. Although uterine gland development appeared similar to controls during prepubertal development, it was compromised during adolescence in the mutants. By age 20 weeks, uterine gland development was comparable to controls, …