Medical Genetics Commons^™

Does A Multiple Myeloma Polygenic Risk Score Predict Overall Survival Of Patients With Myeloma?, Angelica Macauda, Alyssa Clay-Gilmour, Thomas Hielscher, Michelle A T Hildebrandt, Marcin Kruszewski, Robert Z Orlowski, Shaji K Kumar, Elad Ziv, Enrico Orciuolo, Elizabeth E Brown, Asta Försti, Rosalie G Waller, Mitchell J Machiela, Stephen J Chanock, Nicola J Camp, Marcin Rymko, Małgorzata Raźny, Wendy Cozen, Judit Várkonyi, Chiara Piredda, Matteo Pelosini, Alem A Belachew, Edyta Subocz, Kari Hemminki, Malwina Rybicka-Ramos, Graham G Giles, Roger L Milne, Jonathan N Hofmann, Jan Maciej Zaucha, Annette Juul Vangsted, Hartmut Goldschmidt, S Vincent Rajkumar, Waldemar Tomczak, Juan Sainz, Aleksandra Butrym, Marzena Watek, Elżbieta Iskierka-Jazdzewska, Gabriele Buda, Dennis P Robinson, Artur Jurczyszyn, Marek Dudziński, Joaquin Martinez-Lopez, Jason P Sinnwell, Susan L Slager, Krzysztof Jamroziak, Rui Manuel Vieira Reis, Niels Weinhold, Parveen Bhatti, Luis G Carvajal-Carmona, Daria Zawirska, Aaron D Norman, Grzegorz Mazur, Sonja I Berndt, Daniele Campa, Celine M Vachon, Federico Canzian

Faculty, Staff and Student Publications

Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival.

Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association …

Exercise Promotes Pro-Apoptotic Ceramide Signaling In A Mouse Melanoma Model, Jonghae Lee, Hannah Savage, Shinji Maegawa, Riccardo Ballarò, Sumedha Pareek, Bella Samia Guerrouahen, Vidya Gopalakrishnan, Keri Schadler

Faculty, Staff and Student Publications

Ceramides are essential sphingolipids that mediate cell death and survival. Low ceramide content in melanoma is one mechanism of drug resistance. Thus, increasing the ceramide content in tumor cells is likely to increase their sensitivity to cytotoxic therapy. Aerobic exercise has been shown to modulate ceramide metabolism in healthy tissue, but the relationship between exercise and ceramide in tumors has not been evaluated. Here, we demonstrate that aerobic exercise causes tumor cell apoptosis and accumulation of pro-apoptotic ceramides in B16F10 but not BP melanoma models using mice. B16F10 tumor-bearing mice were treated with two weeks of moderate treadmill exercise, or …

Pramlintide: A Novel Therapeutic Approach For Osteosarcoma Through Metabolic Reprogramming, Yuanzheng Yang, Zhanglong Peng, Elsa R Flores, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Despite aggressive combination chemotherapy and surgery, outcomes for patients with osteosarcoma have remained stagnant for more than 25 years, and numerous clinical trials have identified no new therapies. p53 deletion or mutation is found in more than 80% of osteosarcoma tumors. In p53-deficient cancers with structurally altered p63 and p73, interfering with tumor cell metabolism using Pramlintide (an FDA-approved drug for type 2 diabetes) results in tumor regression. Pramlintide response is mediated through upregulation of islet amyloid polypeptide (IAPP). Here, we showed that osteosarcoma cells have altered p63, p73, and p53, and decreased IAPP expression but have the two main …

Evidence For An Association Between Coffin-Siris Syndrome And Congenital Diaphragmatic Hernia, Yoel Gofin, Xiaonan Zhao, Amanda Gerard, Fernando Scaglia, Michael F Wangler, Samantha A Schrier Vergano, Daryl A Scott

Duncan NRI Faculty and Staff Publications

Coffin-Siris syndrome (CSS) is an autosomal dominant neurodevelopmental syndrome that can present with a variety of structural birth defects. Pathogenic variants in 12 genes have been shown to cause CSS. Most of these genes encode proteins that are a part of the mammalian switch/sucrose non-fermentable (mSWI/SNF; BAF) complex. An association between genes that cause CSS and congenital diaphragmatic hernia (CDH) has been suggested based on case reports and the analysis of CSS and CDH cohorts. Here, we describe an unpublished individual with CSS and CDH, and we report additional clinical information on four published cases. Data from these individuals, and …

Kctd7 Deficiency Induces Myoclonic Seizures Associated With Purkinje Cell Death And Microvascular Defects, Justine H Liang, Jonathan Alevy, Viktor Akhanov, Ryan Seo, Cory A Massey, Danye Jiang, Joy Zhou, Roy V Sillitoe, Jeffrey L Noebels, Melanie A Samuel

Duncan NRI Faculty and Staff Publications

Mutations in the potassium channel tetramerization domain-containing 7 (KCTD7) gene are associated with a severe neurodegenerative phenotype characterized by childhood onset of progressive and intractable myoclonic seizures accompanied by developmental regression. KCTD7-driven disease is part of a large family of progressive myoclonic epilepsy syndromes displaying a broad spectrum of clinical severity. Animal models of KCTD7-related disease are lacking, and little is known regarding how KCTD7 protein defects lead to epilepsy and cognitive dysfunction. We characterized Kctd7 expression patterns in the mouse brain during development and show that it is selectively enriched in specific regions as the brain matures. We further …

‘Fly-Ing’ From Rare To Common Neurodegenerative Disease Mechanisms, Mengqi Ma, Matthew J Moulton, Shenzhao Lu, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Genome sequencing advances have enabled researchers and clinicians to probe vast numbers of human variants to distinguish pathogenic from benign variation. Model organisms have been critical in variant assessment and delineating molecular mechanisms of some of the diseases caused by these variants. The fruit fly, Drosophila melanogaster, has played a valuable role in this endeavor, taking advantage of its genetic technologies and established biological knowledge. In this review, we highlight the utility of the fly in studying the function of genes associated with rare neurological diseases that have led to a better understanding of common disease mechanisms. We emphasize …

Genome-Wide Association Analyses Of Physical Activity And Sedentary Behavior Provide Insights Into Underlying Mechanisms And Roles In Disease Prevention, Zhe Wang, Andrew Emmerich, Nicolas J Pillon, Tim Moore, Daiane Hemerich, Marilyn C Cornelis, Eugenia Mazzaferro, Siacia Broos, Tarunveer S Ahluwalia, Traci M Bartz, Amy R Bentley, Lawrence F Bielak, Mike Chong, Audrey Y Chu, Diane Berry, Rajkumar Dorajoo, Nicole D Dueker, Elisa Kasbohm, Bjarke Feenstra, Mary F Feitosa, Christian Gieger, Mariaelisa Graff, Leanne M Hall, Toomas Haller, Fernando P Hartwig, David A Hillis, Ville Huikari, Nancy Heard-Costa, Christina Holzapfel, Anne U Jackson, Åsa Johansson, Anja Moltke Jørgensen, Marika A Kaakinen, Robert Karlsson, Kathleen F Kerr, Boram Kim, Chantal M Koolhaas, Zoltan Kutalik, Vasiliki Lagou, Penelope A Lind, Mattias Lorentzon, Leo-Pekka Lyytikäinen, Massimo Mangino, Christoph Metzendorf, Kristine R Monroe, Alexander Pacolet, Louis Pérusse, Rene Pool, Rebecca C Richmond, Natalia V Rivera, Sebastien Robiou-Du-Pont, Katharina E Schraut, Christina-Alexandra Schulz, Heather M Stringham, Toshiko Tanaka, Alexander Teumer, Constance Turman, Peter J Van Der Most, Mathias Vanmunster, Frank J A Van Rooij, Jana V Van Vliet-Ostaptchouk, Xiaoshuai Zhang, Jing-Hua Zhao, Wei Zhao, Zhanna Balkhiyarova, Marie N Balslev-Harder, Sebastian E Baumeister, John Beilby, John Blangero, Dorret I Boomsma, Soren Brage, Peter S Braund, Jennifer A Brody, Marcel Bruinenberg, Ulf Ekelund, Ching-Ti Liu, John W Cole, Francis S Collins, L Adrienne Cupples, Tõnu Esko, Stefan Enroth, Jessica D Faul, Lindsay Fernandez-Rhodes, Alison E Fohner, Oscar H Franco, Tessel E Galesloot, Scott D Gordon, Niels Grarup, Catharina A Hartman, Gerardo Heiss, Jennie Hui, Thomas Illig, Russell Jago, Alan James, Peter K Joshi, Taeyeong Jung, Mika Kähönen, Tuomas O Kilpeläinen, Woon-Puay Koh, Ivana Kolcic, Peter P Kraft, Johanna Kuusisto, Lenore J Launer, Aihua Li, Allan Linneberg, Jian'an Luan, Pedro Marques Vidal, Sarah E Medland, Yuri Milaneschi, Arden Moscati, Bill Musk, Christopher P Nelson, Ilja M Nolte, Nancy L Pedersen, Annette Peters, Patricia A Peyser, Christine Power, Olli T Raitakari, Mägi Reedik, Alex P Reiner, Paul M Ridker, Igor Rudan, Kathy Ryan, Mark A Sarzynski, Laura J Scott, Robert A Scott, Stephen Sidney, Kristin Siggeirsdottir, Albert V Smith, Jennifer A Smith, Emily Sonestedt, Marin Strøm, E Shyong Tai, Koon K Teo, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Andre G Uitterlinden, Jagadish Vangipurapu, Natasja Van Schoor, Uwe Völker, Gonneke Willemsen, Kayleen Williams, Quenna Wong, Huichun Xu, Kristin L Young, Jian Min Yuan, M Carola Zillikens, Alan B Zonderman, Adam Ameur, Stefania Bandinelli, Joshua C Bis, Michael Boehnke, Claude Bouchard, Daniel I Chasman, George Davey Smith, Eco J C De Geus, Louise Deldicque, Marcus Dörr, Michele K Evans, Luigi Ferrucci, Myriam Fornage, Caroline Fox, Theodore Garland, Vilmundur Gudnason, Ulf Gyllensten, Torben Hansen, Caroline Hayward, Bernardo L Horta, Elina Hyppönen, Marjo-Riitta Jarvelin, W Craig Johnson, Sharon L R Kardia, Lambertus A Kiemeney, Markku Laakso, Claudia Langenberg, Terho Lehtimäki, Loic Le Marchand, Patrik K E Magnusson, Nicholas G Martin, Mads Melbye, Andres Metspalu, David Meyre, Kari E North, Claes Ohlsson, Albertine J Oldehinkel, Marju Orho-Melander, Guillaume Pare, Taesung Park, Oluf Pedersen, Brenda W J H Penninx, Tune H Pers, Ozren Polasek, Inga Prokopenko, Charles N Rotimi, Nilesh J Samani, Xueling Sim, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Nicholas J Timpson, Rob M Van Dam, Nathalie Van Der Velde, Cornelia M Van Duijn, Peter Vollenweider, Henry Völzke, Trudy Voortman, Gérard Waeber, Nicholas J Wareham, David R Weir, Heinz-Erich Wichmann, James F Wilson, Andrea L Hevener, Anna Krook, Juleen R Zierath, Martine A I Thomis, Ruth J F Loos, Marcel Den Hoed

Faculty, Staff and Student Publications

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle …

Genetic Analyses Of The Electrocardiographic Qt Interval And Its Components Identify Additional Loci And Pathways, William J Young, Najim Lahrouchi, Aaron Isaacs, Thuyvy Duong, Luisa Foco, Farah Ahmed, Jennifer A Brody, Reem Salman, Raymond Noordam, Jan-Walter Benjamins, Jeffrey Haessler, Leo-Pekka Lyytikäinen, Linda Repetto, Maria Pina Concas, Marten E Van Den Berg, Stefan Weiss, Antoine R Baldassari, Traci M Bartz, James P Cook, Daniel S Evans, Rebecca Freudling, Oliver Hines, Jonas L Isaksen, Honghuang Lin, Hao Mei, Arden Moscati, Martina Müller-Nurasyid, Casia Nursyifa, Yong Qian, Anne Richmond, Carolina Roselli, Kathleen A Ryan, Eduardo Tarazona-Santos, Sébastien Thériault, Stefan Van Duijvenboden, Helen R Warren, Jie Yao, Dania Raza, Stefanie Aeschbacher, Gustav Ahlberg, Alvaro Alonso, Laura Andreasen, Joshua C Bis, Eric Boerwinkle, Archie Campbell, Eulalia Catamo, Massimiliano Cocca, Michael J Cutler, Dawood Darbar, Alessandro De Grandi, Antonio De Luca, Jun Ding, Christina Ellervik, Patrick T Ellinor, Stephan B Felix, Philippe Froguel, Christian Fuchsberger, Martin Gögele, Claus Graff, Mariaelisa Graff, Xiuqing Guo, Torben Hansen, Susan R Heckbert, Paul L Huang, Heikki V Huikuri, Nina Hutri-Kähönen, M Arfan Ikram, Rebecca D Jackson, Juhani Junttila, Maryam Kavousi, Jan A Kors, Thiago P Leal, Rozenn N Lemaitre, Henry J Lin, Lars Lind, Allan Linneberg, Simin Liu, Peter W Macfarlane, Massimo Mangino, Thomas Meitinger, Massimo Mezzavilla, Pashupati P Mishra, Rebecca N Mitchell, Nina Mononen, May E Montasser, Alanna C Morrison, Matthias Nauck, Victor Nauffal, Pau Navarro, Kjell Nikus, Guillaume Pare, Kristen K Patton, Giulia Pelliccione, Alan Pittman, David J Porteous, Peter P Pramstaller, Michael H Preuss, Olli T Raitakari, Alexander P Reiner, Antonio Luiz P Ribeiro, Kenneth M Rice, Lorenz Risch, David Schlessinger, Ulrich Schotten, Claudia Schurmann, Xia Shen, M Benjamin Shoemaker, Gianfranco Sinagra, Moritz F Sinner, Elsayed Z Soliman, Monika Stoll, Konstantin Strauch, Kirill Tarasov, Kent D Taylor, Andrew Tinker, Stella Trompet, André Uitterlinden, Uwe Völker, Henry Völzke, Melanie Waldenberger, Lu-Chen Weng, Eric A Whitsel, James G Wilson, Christy L Avery, David Conen, Adolfo Correa, Francesco Cucca, Marcus Dörr, Sina A Gharib, Giorgia Girotto, Niels Grarup, Caroline Hayward, Yalda Jamshidi, Marjo-Riitta Järvelin, J Wouter Jukema, Stefan Kääb, Mika Kähönen, Jørgen K Kanters, Charles Kooperberg, Terho Lehtimäki, Maria Fernanda Lima-Costa, Yongmei Liu, Ruth J F Loos, Steven A Lubitz, Dennis O Mook-Kanamori, Andrew P Morris, Jeffrey R O'Connell, Morten Salling Olesen, Michele Orini, Sandosh Padmanabhan, Cristian Pattaro, Annette Peters, Bruce M Psaty, Jerome I Rotter, Bruno Stricker, Pim Van Der Harst, Cornelia M Van Duijn, Niek Verweij, James F Wilson, Dan E Arking, Julia Ramirez, Pier D Lambiase, Nona Sotoodehnia, Borbala Mifsud, Christopher Newton-Cheh, Patricia B Munroe

Faculty, Staff and Student Publications

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and …

Aapm Medical Physics Practice Guideline 5b: Commissioning And Qa Of Treatment Planning Dose Calculations-Megavoltage Photon And Electron Beams, Mark W Geurts, Dustin J Jacqmin, Lindsay E Jones, Stephen F Kry, Dimitris N Mihailidis, Jared D Ohrt, Timothy Ritter, Jennifer B Smilowitz, Nicholai E Wingreen

Faculty, Staff and Student Publications

The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education, and professional practice of medical physics. The AAPM has more than 8000 members and is the principal organization of medical physicists in the United States. The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the United States. Existing medical physics practice guidelines will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth …

High Prevalence Of Osteopathy In Chronic Pancreatitis: A Cross-Sectional Analysis From The Proceed Study, Phil A Hart, Dhiraj Yadav, Liang Li, Savi Appana, William Fisher, Evan Fogel, Chris E Forsmark, Walter G Park, Stephen Pandol, Mark D Topazian, Stephen K Van Den Eden, Santhi Swaroop Vege, David Bradley, Jose Serrano, Darwin L Conwell, Consortium For The Study Of Chronic Pancreatitis, Diabetes, And Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

osteopenia). However, existing literature is mostly limited to retrospective or administrative studies that have not clearly defined the prevalence and risk factors. Our aim was to identify patient- and disease-related associations with osteopathy in a prospective cohort study of CP.

Methods: We studied 282 subjects with definitive CP enrolled in the PROCEED study who had a baseline dual-energy X-ray absorptiometry (DXA) scan. Osteopenia and osteoporosis were defined using the lowest T-scores. Clinical data were collected using standardized case report forms. Comparisons were performed with a multivariate logistic regression model with forward selection to identify risk factors for osteopathy.

Results: The …

Spatially Restricted Drivers And Transitional Cell Populations Cooperate With The Microenvironment In Untreated And Chemo-Resistant Pancreatic Cancer, Daniel Cui Zhou, Reyka G Jayasinghe, Siqi Chen, John M Herndon, Michael D Iglesia, Pooja Navale, Michael C Wendl, Wagma Caravan, Kazuhito Sato, Erik Storrs, Chia-Kuei Mo, Jingxian Liu, Austin N Southard-Smith, Yige Wu, Nataly Naser Al Deen, John M Baer, Robert S Fulton, Matthew A Wyczalkowski, Ruiyang Liu, Catrina C Fronick, Lucinda A Fulton, Andrew Shinkle, Lisa Thammavong, Houxiang Zhu, Hua Sun, Liang-Bo Wang, Yize Li, Chong Zuo, Joshua F Mcmichael, Sherri R Davies, Elizabeth L Appelbaum, Keenan J Robbins, Sara E Chasnoff, Xiaolu Yang, Ashley N Reeb, Clara Oh, Mamatha Serasanambati, Preet Lal, Rajees Varghese, Jay R Mashl, Jennifer Ponce, Nadezhda V Terekhanova, Lijun Yao, Fang Wang, Lijun Chen, Michael Schnaubelt, Rita Jui-Hsien Lu, Julie K Schwarz, Sidharth V Puram, Albert H Kim, Sheng-Kwei Song, Kooresh I Shoghi, Ken S Lau, Tao Ju, Ken Chen, Deyali Chatterjee, William G Hawkins, Hui Zhang, Samuel Achilefu, Milan G Chheda, Stephen T Oh, William E Gillanders, Feng Chen, David G Denardo, Ryan C Fields, Li Ding

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells …

Hic2 Controls Developmental Hemoglobin Switching By Repressing Bcl11a Transcription, Peng Huang, Scott A Peslak, Ren Ren, Eugene Khandros, Kunhua Qin, Cheryl A Keller, Belinda Giardine, Henry W Bell, Xianjiang Lan, Malini Sharma, John R Horton, Osheiza Abdulmalik, Stella T Chou, Junwei Shi, Merlin Crossley, Ross C Hardison, Xiaodong Cheng, Gerd A Blobel

Faculty, Staff and Student Publications

The fetal-to-adult switch in hemoglobin production is a model of developmental gene control with relevance to the treatment of hemoglobinopathies. The expression of transcription factor BCL11A, which represses fetal β-type globin (HBG) genes in adult erythroid cells, is predominantly controlled at the transcriptional level but the underlying mechanism is unclear. We identify HIC2 as a repressor of BCL11A transcription. HIC2 and BCL11A are reciprocally expressed during development. Forced expression of HIC2 in adult erythroid cells inhibits BCL11A transcription and induces HBG expression. HIC2 binds to erythroid BCL11A enhancers to reduce chromatin accessibility and binding of transcription factor GATA1, …

Imaging Characteristics Of 4th Ventricle Subependymoma, Ali S Haider, Tarek Y El Ahmadieh, Maryam Haider, Kimmo J Hatanpaa, Marco C Pinho, Bruce E Mickey, Raymond Sawaya, Gregory N Fuller, Donald F Schomer, Maria Gule-Monroe

Faculty, Staff and Student Publications

Purpose: Subependymomas located within the 4th ventricle are rare, and the literature describing imaging characteristics is sparse. Here, we describe the clinical and radiological characteristics of 29 patients with 4th ventricle subependymoma.

Methods: This is a retrospective multi-center study performed after Institutional Review Board (IRB) approval. Patients diagnosed with suspected 4th ventricle subependymoma were identified. A review of clinical, radiology, and pathology reports along with magnetic resonance imaging (MRI) images was performed.

Results: Twenty-nine patients, including 6 females, were identified. Eighteen patients underwent surgery with histopathological confirmation of subependymoma. The median age at diagnosis was 52 years. Median tumor volume …

Auto-Detection And Segmentation Of Involved Lymph Nodes In Hpv-Associated Oropharyngeal Cancer Using A Convolutional Deep Learning Neural Network, Nicolette Taku, Kareem A Wahid, Lisanne V Van Dijk, Jaakko Sahlsten, Joel Jaskari, Kimmo Kaski, Clifton D Fuller, Mohamed A Naser

Faculty, Staff and Student Publications

PURPOSE: Segmentation of involved lymph nodes on head and neck computed tomography (HN-CT) scans is necessary for the radiotherapy planning of early-stage human papilloma virus (HPV) associated oropharynx cancers (OPC). We aimed to train a deep learning convolutional neural network (DL-CNN) to segment involved lymph nodes on HN-CT scans.

METHODS: Ground-truth segmentation of involved nodes was performed on pre-surgical HN-CT scans for 90 patients who underwent levels II-IV neck dissection for node-positive HPV-OPC (training/validation [n = 70] and testing [n = 20]). A 5-fold cross validation approach was used to train 5 DL-CNN sub-models based on a residual U-net architecture. …

Swallowing After Primary Tors And Unilateral Or Bilateral Radiation For Low- To Intermediate-Risk Tonsil Cancer, Carly E A Barbon, Christopher M K Yao, Christine B Peterson, Amy C Moreno, Ryan P Goepfert, Faye M Johnson, Gregory M Chronowski, Clifton D Fuller, Neil D Gross, Katherine A Hutcheson

Faculty, Staff and Student Publications

Objective: The primary course of treatment for patients with low- to intermediate-risk tonsil cancer has evolved with a shift toward primary transoral robotic surgery (TORS) or radiation therapy (RT). While favorable outcomes have been reported after deintensification via unilateral TORS or RT (uniRT), comparisons of functional outcomes between these treatments are lacking. We compared clinical outcomes (Dynamic Imaging Grade of Swallowing Toxicity [DIGEST] and feeding tube [FT]) and patient-reported swallowing outcomes (MD Anderson Dysphagia Inventory [MDADI]) based on primary treatment strategy: TORS, uniRT, or bilateral RT (biRT).

Study design: Secondary analysis of prospective cohort.

Setting: Single institution.

Methods: The study …

Schwann Cells Induce Phenotypic Changes In Oral Cancer Cells, Maria Daniela Santi, Morgan Zhang, Elizabeth Salvo, Kesava Asam, Chi T Viet, Tongxin Xie, Moran Amit, Bradley Aouizerat, Yi Ye

Faculty, Staff and Student Publications

Head and neck cancer (HNC) is the seventh most common cancer worldwide, the majority being oral squamous cell carcinoma. Despite advances in cancer diagnosis and treatment, the survival rate of patients with HNC remains stagnant. The cancer-nerve interaction has been recognized as an important driver of cancer progression. Schwann cells, a type of peripheral glia, have been implicated in promoting cancer cell growth, migration, dispersion, and invasion into the nerve in many cancers. Here, it is demonstrated that the presence of Schwann cells makes oral cancer cells more aggressive by promoting their proliferation, extracellular matrix breakdown, and altering cell metabolism. …

Oligometastatic Disease In The Liver: The Role Of Interventional Oncology, Ather Adnan, Rahul Anil Sheth, Alda Tam

Faculty, Staff and Student Publications

Oligometastatic disease represents a clinically discrete intermediate stage of cancer progression and is an expanding area of research. While surgical metastatectomy has been recognized for decades as an effective treatment option in select patients, options for metastasis-directed therapy have broadened in scope with advancements in the armamentarium of non- and minimally invasive modalities. Recent preclinical studies investigating the immunology surrounding liver metastases demonstrate treatment resistance to immunotherapy in affected patients and show how locoregional therapy has the ability to overcome this resistance. In this paper, we review advancements in our understanding of oligometastatic disease, metastasis-directed therapy, effect of liver metastasis …

An Empirical Model Of Proton Rbe Based On The Linear Correlation Between X-Ray And Proton Radiosensitivity, David B Flint, Chase E Ruff, Scott J Bright, Pablo Yepes, Qianxia Wang, Mandira Manandhar, Mariam Ben Kacem, Broderick X Turner, David K J Martinus, Simona F Shaitelman, Gabriel O Sawakuchi

Faculty, Staff and Student Publications

Background: Proton relative biological effectiveness (RBE) is known to depend on physical factors of the proton beam, such as its linear energy transfer (LET), as well as on cell-line specific biological factors, such as their ability to repair DNA damage. However, in a clinical setting, proton RBE is still considered to have a fixed value of 1.1 despite the existence of several empirical models that can predict proton RBE based on how a cell's survival curve (linear-quadratic model [LQM]) parameters α and β vary with the LET of the proton beam. Part of the hesitation to incorporate variable RBE models …

Lmo2 Expression Is Frequent In T-Lymphoblastic Leukemia And Correlates With Survival, Regardless Of T-Cell Stage, Kerri-Ann Latchmansingh, Xiaoqiong Wang, Ramiro E Verdun, Mario L Marques-Piubelli, Francisco Vega, M James You, Jennifer Chapman, Izidore S Lossos

Faculty, Staff and Student Publications

T- lymphoblastic leukemia/lymphoma (T-LL) is an aggressive malignancy of immature T-cells with poor overall survival (OS) and in need of new therapies. LIM-domain only 2 (LMO2) is a critical regulator of hematopoietic cell development that can be overexpressed in T-LL due to chromosomal abnormalities. Deregulated LMO2 expression contributes to T-LL development by inducing block of T-cell differentiation and continuous thymocyte self-renewal. However, LMO2 expression and its biologic significance in T-LL remain largely unknown. We analyzed LMO2 expression in 100 initial and follow-up biopsies of T-LL from 67 patients, including 31 (46%) early precursor T-cell (ETP)-ALL, 26 (39%) cortical and 10 …

Multidimensional Single-Cell Analysis Identifies A Role For Cd2-Cd58 Interactions In Clinical Antitumor T Cell Responses, Gabrielle Romain, Paolo Strati, Ali Rezvan, Mohsen Fathi, Irfan N Bandey, Jay R T Adolacion, Darren Heeke, Ivan Liadi, Mario L Marques-Piubelli, Luisa M Solis, Ankit Mahendra, Francisco Vega, Laurence Jn Cooper, Harjeet Singh, Mike Mattie, Adrian Bot, Sattva S Neelapu, Navin Varadarajan

Faculty, Staff and Student Publications

The in vivo persistence of adoptively transferred T cells is predictive of antitumor response. Identifying functional properties of infused T cells that lead to in vivo persistence and tumor eradication has remained elusive. We profiled CD19-specific chimeric antigen receptor (CAR) T cells as the infusion products used to treat large B cell lymphomas using high-throughput single-cell technologies based on time-lapse imaging microscopy in nanowell grids (TIMING), which integrates killing, cytokine secretion, and transcriptional profiling. Our results show that the directional migration of CD19-specific CAR T cells is correlated with multifunctionality. We showed that CD2 on T cells is associated with …

Targeting The Dna Damage Response Beyond Poly(Adp-Ribose) Polymerase Inhibitors: Novel Agents And Rational Combinations, Natalie Y L Ngoi, Shannon N Westin, Timothy A Yap

Faculty, Staff and Student Publications

Purpose of review: Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed treatment paradigms in multiple cancer types defined by homologous recombination deficiency (HRD) and have become the archetypal example of synthetic lethal targeting within the DNA damage response (DDR). Despite this success, primary and acquired resistance to PARP inhibition inevitability threaten the efficacy and durability of response to these drugs. Beyond PARP inhibitors, recent advances in large-scale functional genomic screens have led to the identification of a steadily growing list of genetic dependencies across the DDR landscape. This has led to a wide array of novel synthetic lethal targets and corresponding inhibitors, …

Fusobacterium Is Enriched In Oral Cancer And Promotes Induction Of Programmed Death-Ligand 1 (Pd-L1), Chieko Michikawa, Vancheswaran Gopalakrishnan, Amani M Harrandah, Tatiana V Karpinets, Rekha Rani Garg, Randy A Chu, Yuk Pheel Park, Sasanka S Chukkapallia, Nikhita Yadlapalli, Kelly C Erikson-Carter, Frederico Omar Gleber-Netto, Elias Sayour, Ann Progulske-Fox, Edward K L Chan, Xiaogang Wu, Jianhua Zhang, Christian Jobin, Jennifer A Wargo, Curtis R Pickering, Jeffrey N Myers, Natalie Silver

Faculty, Staff and Student Publications

Recently, increased number of studies have demonstrated a relationship between the oral microbiome and development of head and neck cancer, however, there are few studies to investigate the role of oral bacteria in the context of the tumor microenvironment in a single head and neck subsite. Here, paired tumor and adjacent normal tissues from thirty-seven oral tongue squamous cell carcinoma (SCC) patients were subjected to 16S rRNA gene sequencing and whole exome sequencing (WES), in addition to RNA sequencing for tumor samples. We observed that Fusobacterium was significantly enriched in oral tongue cancer and that Rothia and Streptococcus were enriched …

The Microbiome In Gastrointestinal Cancers, Michael G White, Jennifer A Wargo

Faculty, Staff and Student Publications

The human microbiome has been recognized as increasingly important to health and disease. This is especially prescient in the development of various cancers, their progression, and the microbiome's modulation of various anticancer therapeutics. Mechanisms behind these interactions have been increasingly well described through modulation of the host immune system as well as induction of genetic changes and local inactivation of cancer therapeutics. Here, we review these associations for a variety of gastrointestinal malignancies as well as contemporary strategies proposed to leverage these associations to improve cancer treatment outcomes.

Game Of Clones: Battles In The Field Of Carcinogenesis, Zahraa Rahal, Ansam Sinjab, Ignacio I Wistuba, Humam Kadara

Faculty, Staff and Student Publications

Recent advances in bulk sequencing approaches as well as genomic decoding at the single-cell level have revealed surprisingly high somatic mutational burdens in normal tissues, as well as increased our understanding of the landscape of "field cancerization", that is, molecular and immune alterations in mutagen-exposed normal-appearing tissues that recapitulated those present in tumors. Charting the somatic mutational landscapes in normal tissues can have strong implications on our understanding of how tumors arise from mutagenized epithelium. Making sense of those mutations to understand the progression along the pathologic continuum of normal epithelia, preneoplasias, up to malignant tissues will help pave way …

Integrated Imaging And Molecular Analysis To Decipher Tumor Microenvironment In The Era Of Immunotherapy, Jia Wu, Aaron T Mayer, Ruijiang Li

Faculty, Staff and Student Publications

Radiological imaging is an integral component of cancer care, including diagnosis, staging, and treatment response monitoring. It contains rich information about tumor phenotypes that are governed not only by cancer cellintrinsic biological processes but also by the tumor microenvironment, such as the composition and function of tumor-infiltrating immune cells. By analyzing the radiological scans using a quantitative radiomics approach, robust relations between specific imaging and molecular phenotypes can be established. Indeed, a number of studies have demonstrated the feasibility of radiogenomics for predicting intrinsic molecular subtypes and gene expression signatures in breast cancer based on MRI. In parallel, promising results …

Membrane-Anchored And Tumor-Targeted Il12 (Attil12)-Pbmc Therapy For Osteosarcoma, Qing Yang, Jiemiao Hu, Zhiliang Jia, Qi Wang, Jing Wang, Long Hoang Dao, Wendong Zhang, Sheng Zhang, Xueqing Xia, Richard Gorlick, Shulin Li

Faculty, Staff and Student Publications

Purpose: Chimeric antigen receptor (CAR) T-cell therapy has shown great promise for treating hematologic malignancies but requires a long duration of T-cell expansion, is associated with severe toxicity, and has limited efficacy for treating solid tumors. We designed experiments to address those challenges.

Experimental design: We generated a cell membrane-anchored and tumor-targeted IL12 (attIL12) to arm peripheral blood mononuclear cells (PBMC) instead of T cells to omit the expansion phase for required CAR T cells.

Results: This IL12-based attIL12-PBMC therapy showed significant antitumor efficacy in both heterogeneous osteosarcoma patient-derived xenograft tumors and metastatic osteosarcoma tumors with no observable toxic effects. …

Estrogen-Related Receptor Alpha Is An Ampk-Regulated Factor That Promotes Ischemic Muscle Revascularization And Recovery In Diet-Induced Obese Mice, Danesh H Sopariwala, Andrea S Rios, Mi Kyung Park, Min Sup Song, Ashok Kumar, Vihang A Narkar

Faculty, Staff and Student Publications

Obesity and type II diabetes are leading causes of peripheral arterial disease (PAD), which is characterized by vascular insufficiency and ischemic damage in the limb skeletal muscle. Glycemic control is not sufficient to prevent progression of PAD, and molecular targets that can promote muscle neo-angiogenesis in obesity and diabetes remain poorly defined. Here, we have investigated whether nuclear receptor estrogen-related receptor alpha (ERRα) can promote ischemic revascularization in the skeletal muscles of diet-induced obese (DIO) mice. Using muscle-specific ERRα transgenic mice, we found that ERRα overexpression promotes revascularization, marked by increased capillary staining and muscle perfusion in DIO mice after …

Pure Erythroid Leukemia Is Characterized By Biallelic Tp53 Inactivation And Abnormal P53 Expression Patterns In De Novo And Secondary Cases, Hong Fang, Sa A Wang, Joseph D Khoury, Siba El Hussein, Do Hwan Kim, Mehrnoosh Tashakori, Zhenya Tang, Shaoying Li, Zhihong Hu, Fatima Zahra Jelloul, Keyur P Patel, Timothy J Mcdonnell, Tapan Kadia, L Jeffrey Medeiros, Wei Wang

Faculty, Staff and Student Publications

No abstract provided.

Car Treg Cells: Prime Suspects In Therapeutic Resistance, Neeraj Saini, Sattva S Neelapu

Faculty, Staff and Student Publications

Using comprehensive single-cell profiling, two studies reveal the molecular phenotypes of CAR T cells associated with durable response in patients with lymphoma, and highlight the role of CAR regulatory T cells in mediating resistance.

Repurposing Epigenetic Inhibitors To Target The Clostridioides Difficile-Specific Dna Adenine Methyltransferase And Sporulation Regulator Cama, Jujun Zhou, John R Horton, Dan Yu, Ren Ren, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

Epigenetically targeted therapeutic development, particularly for SAM-dependent methylations of DNA, mRNA and histones has been proceeding rapidly for cancer treatments over the past few years. However, this approach has barely begun to be exploited for developing new antibiotics, despite an overwhelming global need to counter antimicrobial resistance. Here, we explore whether SAM analogues, some of which are in (pre)clinical studies as inhibitors of human epigenetic enzymes, can also inhibit Clostridioides difficile-specific DNA adenine methyltransferase (CamA), a sporulation regulator present in all C. difficile genomes sequenced to date, but found in almost no other bacteria. We found that SGC0946 (an …