Medical Specialties Commons^™

Inhibition Of Uba6 By Inosine Augments Tumour Immunogenicity And Responses, Lei Zhang, Li Jiang, Liang Yu, Qin Li, Xiangjun Tian, Jingquan He, Ling Zeng, Yuqin Yang, Chaoran Wang, Yuhan Wei, Xiaoyue Jiang, Jing Li, Xiaolu Ge, Qisheng Gu, Jikun Li, Di Wu, Anthony J Sadler, Di Yu, Dakang Xu, Yue Gao, Xiangliang Yuan, Baokun He

Faculty, Staff and Student Publications

Anti-cancer immunity and response to immune therapy is influenced by the metabolic states of the tumours. Immune checkpoint blockade therapy (ICB) is known to involve metabolic adaptation, however, the mechanism is not fully known. Here we show, by metabolic profiling of plasma samples from melanoma-bearing mice undergoing anti-PD1 and anti-CTLA4 combination therapy, that higher levels of purine metabolites, including inosine, mark ICB sensitivity. Metabolic profiles of ICB-treated human cancers confirm the association between inosine levels and ICB sensitivity. In mouse models, inosine supplementation sensitizes tumours to ICB, even if they are intrinsically ICB resistant, by enhancing T cell-mediated cytotoxicity and …

Clinical Activity Of Checkpoint Inhibitors In Angiosarcoma: A Retrospective Cohort Study, Vinod Ravi, Aparna Subramaniam, Jing Zheng, Behrang Amini, Van A Trinh, Jocelyn Joseph, Robert G Mennel, Andrew J Bishop, Erich M Sturgis, Ryan P Goepfert, Sudha Yalamanchili, Gilberto Botello, Bettzy Stephen, Sarina A Piha-Paul, Anisha B Patel, Alexander J Lazar, Anthony P Conley, Robert S Benjamin, Shreyaskumar R Patel, Phillip A Futreal, Neeta Somaiah, Aung Naing

Faculty, Staff and Student Publications

Background: Systemic treatments for angiosarcoma remains an area of unmet clinical need. The authors conducted this retrospective study to assess the clinical activity of checkpoint inhibitors in patients with angiosarcoma. The primary objective was to assess the objective response rate, and the secondary objective was to assess the progression-free and overall survival durations and disease control rate.

Methods: Patient data were obtained using The University of Texas MD Anderson Cancer Center Tumor Registry database. The final study population was refined to only include patients who had undergone pembrolizumab monotherapy. The objective response rate was evaluated using RECIST/irRECIST version 1.1. Progression-free …

Identification Of Risk Genes For Alzheimer’S Disease By Gene Embedding, Yashwanth Lagisetty, Thomas Bourquard, Ismael Al-Ramahi, Carl Grant Mangleburg, Samantha Mota, Shirin Soleimani, Joshua M Shulman, Juan Botas, Kwanghyuk Lee, Olivier Lichtarge

Duncan NRI Faculty and Staff Publications

Most disease-gene association methods do not account for gene-gene interactions, even though these play a crucial role in complex, polygenic diseases like Alzheimer’s disease (AD). To discover new genes whose interactions may contribute to pathology, we introduce GeneEMBED. This approach compares the functional perturbations induced in gene interaction network neighborhoods by coding variants from disease versus healthy subjects. In two independent AD cohorts of 5,169 exomes and 969 genomes, GeneEMBED identified novel candidates. These genes were differentially expressed in post mortem AD brains and modulated neurological phenotypes in mice. Four that were differentially overexpressed and modified neurodegeneration in vivo are …

Delineating Covid-19 Immunological Features Using Single-Cell Rna Sequencing, Wendao Liu, Johnathan Jia, Yulin Dai, Wenhao Chen, Guangsheng Pei, Qiheng Yan, Zhongming Zhao

Faculty, Staff and Student Publications

Understanding the molecular mechanisms of coronavirus disease 2019 (COVID-19) pathogenesis and immune response is vital for developing therapies. Single-cell RNA sequencing has been applied to delineate the cellular heterogeneity of the host response toward COVID-19 in multiple tissues and organs. Here, we review the applications and findings from over 80 original COVID-19 single-cell RNA sequencing studies as well as many secondary analysis studies. We describe that single-cell RNA sequencing reveals multiple features of COVID-19 patients with different severity, including cell populations with proportional alteration, COVID-19-induced genes and pathways, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in single cells, and adaptation …

Bet Inhibition Induces Vulnerability To Mcl1 Targeting Through Upregulation Of Fatty Acid Synthesis Pathway In Breast Cancer, Gonghong Yan, Augustin Luna, Heping Wang, Behnaz Bozorgui, Xubin Li, Maga Sanchez, Zeynep Dereli, Nermin Kahraman, Goknur Kara, Xiaohua Chen, Caishang Zheng, Daniel Mcgrail, Nidhi Sahni, Yiling Lu, Ozgun Babur, Murat Cokol, Bora Lim, Bulent Ozpolat, Chris Sander, Gordon B Mills, Anil Korkut

Faculty, Staff and Student Publications

Therapeutic options for treatment of basal-like breast cancers remain limited. Here, we demonstrate that bromodomain and extra-terminal (BET) inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancer cells. Consequently, co-targeting MCL1 and BET is highly synergistic in breast cancer models. The mechanism of adaptive response to BET inhibition involves the upregulation of lipid synthesis enzymes including the rate-limiting stearoyl-coenzyme A (CoA) desaturase. Changes in lipid synthesis pathway are associated with increases in cell motility and membrane fluidity as well as re-localization and activation of HER2/EGFR. In turn, the HER2/EGFR signaling results in the accumulation …

Openkbp-Opt: An International And Reproducible Evaluation Of 76 Knowledge-Based Planning Pipelines, Aaron Babier, Rafid Mahmood, Binghao Zhang, Victor G L Alves, Ana Maria Barragán-Montero, Joel Beaudry, Carlos E Cardenas, Yankui Chang, Zijie Chen, Jaehee Chun, Kelly Diaz, Harold David Eraso, Erik Faustmann, Sibaji Gaj, Skylar Gay, Mary Gronberg, Bingqi Guo, Junjun He, Gerd Heilemann, Sanchit Hira, Yuliang Huang, Fuxin Ji, Dashan Jiang, Jean Carlo Jimenez Giraldo, Hoyeon Lee, Jun Lian, Shuolin Liu, Keng-Chi Liu, José Marrugo, Kentaro Miki, Kunio Nakamura, Tucker Netherton, Dan Nguyen, Hamidreza Nourzadeh, Alexander F I Osman, Zhao Peng, José Darío Quinto Muñoz, Christian Ramsl, Dong Joo Rhee, Juan David Rodriguez, Hongming Shan, Jeffrey V Siebers, Mumtaz H Soomro, Kay Sun, Andrés Usuga Hoyos, Carlos Valderrama, Rob Verbeek, Enpei Wang, Siri Willems, Qi Wu, Xuanang Xu, Sen Yang, Lulin Yuan, Simeng Zhu, Lukas Zimmermann, Kevin L Moore, Thomas G Purdie, Andrea L Mcniven, Timothy C Y Chan

Faculty, Staff and Student Publications

Objective.To establish an open framework for developing plan optimization models for knowledge-based planning (KBP).

Approach.Our framework includes radiotherapy treatment data (i.e. reference plans) for 100 patients with head-and-neck cancer who were treated with intensity-modulated radiotherapy. That data also includes high-quality dose predictions from 19 KBP models that were developed by different research groups using out-of-sample data during the OpenKBP Grand Challenge. The dose predictions were input to four fluence-based dose mimicking models to form 76 unique KBP pipelines that generated 7600 plans (76 pipelines × 100 patients). The predictions and KBP-generated plans were compared to the reference …

Modelling Aggressive Prostate Cancers Of Young Men In Immune-Competent Mice, Driven By Isogenic Trp53 Alterations And Pten Loss, Javier Octavio Mejía-Hernández, Simon P Keam, Reem Saleh, Fenella Muntz, Stephen B Fox, David Byrne, Arielle Kogan, Lokman Pang, Jennifer Huynh, Cassandra Litchfield, Franco Caramia, Guillermina Lozano, Hua He, James M You, Shahneen Sandhu, Scott G Williams, Ygal Haupt, Sue Haupt

Faculty, Staff and Student Publications

Understanding prostate cancer onset and progression in order to rationally treat this disease has been critically limited by a dire lack of relevant pre-clinical animal models. We have generated a set of genetically engineered mice that mimic human prostate cancer, initiated from the gland epithelia. We chose driver gene mutations that are specifically relevant to cancers of young men, where aggressive disease poses accentuated survival risks. An outstanding advantage of our models are their intact repertoires of immune cells. These mice provide invaluable insight into the importance of immune responses in prostate cancer and offer scope for studying treatments, including …

Why Study Mechanisms Of Brain Stimulation Therapies? To Modulate The Right Neurons, In The Right Way, At The Right Time, Matthew J Mcginley, Steven T Lee

Duncan NRI Faculty and Staff Publications

Clinical applications of vagus nerve stimulation (VNS) are burgeoning, but mechanistic work lags behind. In this issue of Neuron, Bowles and colleagues show that VNS timed with positive reinforcement improves motor learning and cortical function by a cholinergic mechanism.

Clonal Hematopoiesis Is Associated With Increased Risk Of Severe Neurotoxicity In Axicabtagene Ciloleucel Therapy Of Large B-Cell Lymphoma, Neeraj Y Saini, David M Swoboda, Uri Greenbaum, Junsheng Ma, Romil D Patel, Kartik Devashish, Kaberi Das, Mark R Tanner, Paolo Strati, Ranjit Nair, Luis Fayad, Sairah Ahmed, Hun Ju Lee, Swaminathan P Iyer, Raphael Steiner, Nitin Jain, Loretta Nastoupil, Sanam Loghavi, Guilin Tang, Roland L Bassett, Preetesh Jain, Michael Wang, Jason R Westin, Michael R Green, David A Sallman, Eric Padron, Marco L Davila, Frederick L Locke, Richard E Champlin, Guillermo Garcia-Manero, Elizabeth J Shpall, Partow Kebriaei, Christopher R Flowers, Michael D Jain, Feng Wang, Andrew P Futreal, Nancy Gillis, Sattva S Neelapu, Koichi Takahashi

Faculty, Staff and Student Publications

To explore the role of clonal hematopoiesis (CH) in chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pretreatment samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was higher in CH-positive patients than CH-negative patients (45.2% vs. 25.0%, P = 0.038). Higher toxicities with CH were primarily associated with DNMT3A, TET2, and ASXL1 genes (DTA mutations). Grade …

Follicular Lymphoma Microenvironment Characteristics Associated With Tumor Cell Mutations And Mhc Class Ii Expression, Guangchun Han, Qing Deng, Mario L Marques-Piubelli, Enyu Dai, Minghao Dang, Man Chun John Ma, Xubin Li, Haopeng Yang, Jared Henderson, Olga Kudryashova, Mark Meerson, Sergey Isaev, Nikita Kotlov, Krystle J Nomie, Alexander Bagaev, Edwin R Parra, Luisa M Solis Soto, Simrit Parmar, Fredrick B Hagemeister, Sairah Ahmed, Swaminathan P Iyer, Felipe Samaniego, Raphael Steiner, Luis Fayad, Hun Lee, Nathan H Fowler, Christopher R Flowers, Paolo Strati, Jason R Westin, Sattva S Neelapu, Loretta J Nastoupil, Francisco Vega, Linghua Wang, Michael R Green

Faculty, Staff and Student Publications

Follicular lymphoma (FL) is a B-cell malignancy with a complex tumor microenvironment that is rich in nonmalignant immune cells. We applied single-cell RNA sequencing to characterize the diverse tumor and immune cell populations of FL and identified major phenotypic subsets of FL T cells, including a cytotoxic CD4 T-cell population. We characterized four major FL subtypes with differential representation or relative depletion of distinct T-cell subsets. By integrating exome sequencing, we observed that somatic mutations are associated with, but not definitive for, reduced MHC expression on FL cells. In turn, expression of MHCII genes by FL cells was associated with …

Ablating Lgr5-Expressing Prostatic Stromal Cells Activates The Erk-Mediated Mechanosensory Signaling And Disrupts Prostate Tissue Homeostasis, Xing Wei, Li Zhang, Yiqun Zhang, Cody Cooper, Chris Brewer, Chia-Feng Tsai, Yi-Ting Wang, Micah Glaz, Hunter B Wessells, Jianwen Que, Mark A Titus, Vincenzino Cirulli, Adam Glaser, Tao Liu, Nicholas P Reder, Chad J Creighton, Li Xin

Faculty, Staff and Student Publications

Functional implication of stromal heterogeneity in the prostate remains incompletely understood. Using lineage tracing and light-sheet imaging, we show that some fibroblast cells at the mouse proximal prostatic ducts and prostatic urethra highly express Lgr5. Genetic ablation of these anatomically restricted stromal cells, but not nonselective ablation of prostatic stromal cells, rapidly induces prostate epithelial turnover and dedifferentiation that are reversed following spontaneous restoration of the Lgr5

Developing High-Affinity Decoy Receptors To Treat Multiple Myeloma And Diffuse Large B Cell Lymphoma, Yu Rebecca Miao, Kaushik Thakkar, Can Cenik, Dadi Jiang, Kazue Mizuno, Chenjun Jia, Caiyun Grace Li, Hongjuan Zhao, Anh Diep, Yu Xu, Xin Eric Zhang, Teddy Tat Chi Yang, Michaela Liedtke, Parveen Abidi, Wing-Sze Leung, Albert C Koong, Amato J Giaccia

Faculty, Staff and Student Publications

Disease relapse and treatment-induced immunotoxicity pose significant clinical challenges for patients with hematological cancers. Here, we reveal distinctive requirements for neutralizing TNF receptor ligands APRIL and BAFF and their receptor activity in MM and DLBCL, impacting protein translation and production in MM cells and modulating the translation efficiency of the ATM interactor (ATMIN/ACSIZ). Therapeutically, we investigated the use of BCMA decoy receptor (sBCMA-Fc) as an inhibitor of APRIL and BAFF. While wild-type sBCMA-Fc effectively blocked APRIL signaling in MM, it lacked activity in DLBCL due to its weak BAFF binding. To expand the therapeutic utility of sBCMA-Fc, we engineered an …

The Third Joint Meeting On Lung Cancer Of The Fhu Oncoage (University Côte D'Azur, Nice, France) And The University Of Texas Md Anderson Cancer Center (Houston, Tx, Usa) Understanding New Therapeutic Options And Promising Predictive Biomarkers For Lung Cancer Patients, Paul Hofman, George A Calin, Sandurai A Mani, Christophe Bontoux, Marius Ilié, Ignacio I Wistuba

Faculty, Staff and Student Publications

We are proud and happy to present this Special Issue, a follow-up to the third joint meeting on lung cancer of the FHU OncoAge (University Côte d’Azur, Nice, France) and the University of Texas MD Anderson Cancer Center (Houston, TX, USA), which was held virtually on 4 October 2021. This meeting was devoted to better understanding new mechanisms of lung carcinogenesis and novel therapeutic options for lung cancer patients. Moreover, some promising biomarkers for non-small cell lung carcinoma (NSCLC) were also discussed.

The Tfeb-Tgif1 Axis Regulates Emt In Mouse Epicardial Cells, Elena Astanina, Gabriella Doronzo, Davide Corà, Francesco Neri, Salvatore Oliviero, Tullio Genova, Federico Mussano, Emanuele Middonti, Edoardo Vallariello, Chiara Cencioni, Donatella Valdembri, Guido Serini, Federica Limana, Eleonora Foglio, Andrea Ballabio, Federico Bussolino

Duncan NRI Faculty and Staff Publications

Epithelial-mesenchymal transition (EMT) is a complex and pivotal process involved in organogenesis and is related to several pathological processes, including cancer and fibrosis. During heart development, EMT mediates the conversion of epicardial cells into vascular smooth muscle cells and cardiac interstitial fibroblasts. Here, we show that the oncogenic transcription factor EB (TFEB) is a key regulator of EMT in epicardial cells and that its genetic overexpression in mouse epicardium is lethal due to heart defects linked to impaired EMT. TFEB specifically orchestrates the EMT-promoting function of transforming growth factor (TGF) β, and this effect results from activated transcription of thymine-guanine-interacting …

Chd1 Promotes Sensitivity To Aurora Kinase Inhibitors By Suppressing Interaction Of Aurka With Its Coactivator Tpx2, Haoyan Li, Yin Wang, Kevin Lin, Varadha Balaji Venkadakrishnan, Martin Bakht, Wei Shi, Chenling Meng, Jie Zhang, Kaitlyn Tremble, Xin Liang, Jian H Song, Xu Feng, Vivien Van, Pingna Deng, Jared K Burks, Ana Aparicio, Khandan Keyomarsi, Junjie Chen, Yue Lu, Himisha Beltran, Di Zhao

Faculty, Staff and Student Publications

UNLABELLED: Clinical studies have shown that subsets of patients with cancer achieve a significant benefit from Aurora kinase inhibitors, suggesting an urgent need to identify biomarkers for predicting drug response. Chromodomain helicase DNA binding protein 1 (CHD1) is involved in chromatin remodeling, DNA repair, and transcriptional plasticity. Prior studies have demonstrated that CHD1 has distinct expression patterns in cancers with different molecular features, but its impact on drug responsiveness remains understudied. Here, we show that CHD1 promotes the susceptibility of prostate cancer cells to inhibitors targeting Aurora kinases, while depletion of CHD1 impairs their efficacy in vitro and in vivo. …

Association Study Between Polymorphisms In Dna Methylation-Related Genes And Testicular Germ Cell Tumor Risk, Chiara Grasso, Maja Popovic, Elena Isaevska, Fulvio Lazzarato, Valentina Fiano, Daniela Zugna, John Pluta, Benita Weathers, Kurt D'Andrea, Kristian Almstrup, Lynn Anson-Cartwright, D Timothy Bishop, Stephen J Chanock, Chu Chen, Victoria K Cortessis, Marlene D Dalgaard, Siamak Daneshmand, Alberto Ferlin, Carlo Foresta, Megan N Frone, Marija Gamulin, Jourik A Gietema, Mark H Greene, Tom Grotmol, Robert J Hamilton, Trine B Haugen, Russ Hauser, Robert Karlsson, Lambertus A Kiemeney, Davor Lessel, Patrizia Lista, Ragnhild A Lothe, Chey Loveday, Coby Meijer, Kevin T Nead, Jérémie Nsengimana, Rolf I Skotheim, Clare Turnbull, David J Vaughn, Fredrik Wiklund, Tongzhang Zheng, Andrea Zitella, Stephen M Schwartz, Katherine A Mcglynn, Peter A Kanetsky, Katherine L Nathanson, Lorenzo Richiardi

Faculty, Staff and Student Publications

Background: Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation.

Methods: In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the …

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 …

Smyd3 Impedes Small Cell Lung Cancer Sensitivity To Alkylation Damage Through Rnf113a Methylation-Phosphorylation Cross-Talk, Valentina Lukinović, Simone Hausmann, Gael S Roth, Clement Oyeniran, Tanveer Ahmad, Ning Tsao, Joshua R Brickner, Alexandre G Casanova, Florent Chuffart, Ana Morales Benitez, Jessica Vayr, Rebecca Rodell, Marianne Tardif, Pascal W T C Jansen, Yohann Couté, Michiel Vermeulen, Pierre Hainaut, Pawel K Mazur, Nima Mosammaparast, Nicolas Reynoird

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with dismal survival, limited therapeutic options, and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation levels. This cross-talk between posttranslational modifications acts as a key switch in promoting and maintaining RNF113A E3 ligase activity, essential for its role in alkylation damage response. In turn, SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. Our study sheds light on a novel role of …

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 …

Genetic Loci And Prioritization Of Genes For Kidney Function Decline Derived From A Meta-Analysis Of 62 Longitudinal Genome-Wide Association Studies, Mathias Gorski, Humaira Rasheed, Alexander Teumer, Laurent F Thomas, Sarah E Graham, Gardar Sveinbjornsson, Thomas W Winkler, Felix Günther, Klaus J Stark, Jin-Fang Chai, Bamidele O Tayo, Matthias Wuttke, Yong Li, Adrienne Tin, Tarunveer S Ahluwalia, Johan Ärnlöv, Bjørn Olav Åsvold, Stephan J L Bakker, Bernhard Banas, Nisha Bansal, Mary L Biggs, Ginevra Biino, Michael Böhnke, Eric Boerwinkle, Erwin P Bottinger, Hermann Brenner, Ben Brumpton, Robert J Carroll, Layal Chaker, John Chalmers, Miao-Li Chee, Miao-Ling Chee, Ching-Yu Cheng, Audrey Y Chu, Marina Ciullo, Massimiliano Cocca, James P Cook, Josef Coresh, Daniele Cusi, Martin H De Borst, Frauke Degenhardt, Kai-Uwe Eckardt, Karlhans Endlich, Michele K Evans, Mary F Feitosa, Andre Franke, Sandra Freitag-Wolf, Christian Fuchsberger, Piyush Gampawar, Ron T Gansevoort, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Christian Gieger, Daniel F Gudbjartsson, Stein Hallan, Pavel Hamet, Asahi Hishida, Kevin Ho, Edith Hofer, Bernd Holleczek, Hilma Holm, Anselm Hoppmann, Katrin Horn, Nina Hutri-Kähönen, Kristian Hveem, Shih-Jen Hwang, M Arfan Ikram, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Irma Karabegović, Chiea-Chuen Khor, Wolfgang Koenig, Holly Kramer, Bernhard K Krämer, Brigitte Kühnel, Johanna Kuusisto, Markku Laakso, Leslie A Lange, Terho Lehtimäki, Man Li, Wolfgang Lieb, Lifelines Cohort Study, Lars Lind, Cecilia M Lindgren, Ruth J F Loos, Mary Ann Lukas, Leo-Pekka Lyytikäinen, Anubha Mahajan, Pamela R Matias-Garcia, Christa Meisinger, Thomas Meitinger, Olle Melander, Yuri Milaneschi, Pashupati P Mishra, Nina Mononen, Andrew P Morris, Josyf C Mychaleckyj, Girish N Nadkarni, Mariko Naito, Masahiro Nakatochi, Mike A Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M Nolte, Teresa Nutile, Michelle L O'Donoghue, Jeffrey O'Connell, Isleifur Olafsson, Marju Orho-Melander, Afshin Parsa, Sarah A Pendergrass, Brenda W J H Penninx, Mario Pirastu, Michael H Preuss, Bruce M Psaty, Laura M Raffield, Olli T Raitakari, Myriam Rheinberger, Kenneth M Rice, Federica Rizzi, Alexander R Rosenkranz, Peter Rossing, Jerome I Rotter, Daniela Ruggiero, Kathleen A Ryan, Charumathi Sabanayagam, Erika Salvi, Helena Schmidt, Reinhold Schmidt, Markus Scholz, Ben Schöttker, Christina-Alexandra Schulz, Sanaz Sedaghat, Christian M Shaffer, Karsten B Sieber, Xueling Sim, Mario Sims, Harold Snieder, Kira J Stanzick, Unnur Thorsteinsdottir, Hannah Stocker, Konstantin Strauch, Heather M Stringham, Patrick Sulem, Silke Szymczak, Kent D Taylor, Chris H L Thio, Johanne Tremblay, Simona Vaccargiu, Pim Van Der Harst, Peter J Van Der Most, Niek Verweij, Uwe Völker, Kenji Wakai, Melanie Waldenberger, Lars Wallentin, Stefan Wallner, Judy Wang, Dawn M Waterworth, Harvey D White, Cristen J Willer, Tien-Yin Wong, Mark Woodward, Qiong Yang, Laura M Yerges-Armstrong, Martina Zimmermann, Alan B Zonderman, Tobias Bergler, Kari Stefansson, Carsten A Böger, Cristian Pattaro, Anna Köttgen, Florian Kronenberg, Iris M Heid

Faculty, Staff and Student Publications

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine …

Quality Of Life, Illness Perceptions, And Parental Lived Experiences In Tango2-Related Metabolic Encephalopathy And Arrhythmias, Chaya N Murali, Seema R Lalani, Mahshid S Azamian, Christina Y Miyake, Hadley Stevens Smith

Faculty, Staff and Students Publications

TANGO2 disorder is a rare genetic disease with multi-system effects that causes episodic crises. Quality of life and psychosocial effects of this rare disease have not previously been studied. To examine health-related quality of life (HRQoL), illness perceptions, and lived experience, we surveyed 16 children and 31 parents of children with TANGO2 disorder identified via a disease-specific social media group and research foundation email distribution list. We assessed HRQoL by parent proxy-report and child self-report using the Pediatric Quality of Life Inventory (PedsQL™). Parental perceptions of their child's condition were assessed using the revised illness perceptions questionnaire adapted for TANGO2 …

Precision Diabetes: Lessons Learned From Maturity-Onset Diabetes Of The Young (Mody), Mustafa Tosur, Louis H Philipson

Faculty, Staff and Students Publications

Maturity-onset of diabetes of the young (MODY) are monogenic forms of diabetes characterized by early onset diabetes with autosomal dominant inheritance. Since its first description about six decades ago, there have been significant advancements in our understanding of MODY from clinical presentations to molecular diagnostics and therapeutic responses. The prevalence of MODY is estimated as at least 1.1-6.5% of the pediatric diabetes population with a high degree of geographic variability that might arise from several factors in the criteria used to ascertain cases. GCK-MODY, HNF1A-MODY, and HNF4A-MODY account for >90% of MODY cases. While some MODY forms do not require …

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 …

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 …

‘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 …

Removal Of Kcnq2 From Parvalbumin-Expressing Interneurons Improves Anti-Seizure Efficacy Of Retigabine, Junzhan Jing, Corrinne Dunbar, Alina Sonesra, Ana Chavez, Suhyeorn Park, Ryan Yang, Heun Soh, Maxwell Lee, Anastasios V Tzingounis, Edward C Cooper, Xiaolong Jiang, Atul Maheshwari

Duncan NRI Faculty and Staff Publications

Anti-seizure drug (ASD) targets are widely expressed in both excitatory and inhibitory neurons. It remains unknown if the action of an ASD upon inhibitory neurons could counteract its beneficial effects on excitatory neurons (or vice versa), thereby reducing the efficacy of the ASD. Here, we examine whether the efficacy of the ASD retigabine (RTG) is altered after removal of the Kv7 potassium channel subunit KCNQ2, one of its drug targets, from parvalbumin-expressing interneurons (PV-INs). Parvalbumin-Cre (PV-Cre) mice were crossed with Kcnq2-floxed (Kcnq2fl/fl) mice to conditionally delete Kcnq2 from PV-INs. In these conditional knockout mice (cKO, PV-Kcnq2 …

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 …

Impact Of Medicaid Expansion Under The Affordable Care Act On Receipt Of Surgery For Breast Cancer, Leisha C Elmore, Meng Li, Heather Lin, Yu Shen, Simona F Shaitelman, Gildy Babiera, Nina Tamirisa, Isabelle Bedrosian

Faculty, Staff and Student Publications

To determine whether Medicaid expansion under the 2010 Affordable Care Act affected rates of breast cancer surgery.

Background: Data regarding the impact of Medicaid expansion on access to surgical treatment of breast cancer are limited.

Methods: Patients in the National Cancer Database diagnosed with non-metastatic breast cancer between January 1, 2010 and December 31, 2017 and residing in a state that expanded Medicaid in January 2014 or in a state that opted out of expansion were included. A quasi-experimental, difference-in-differences (DID) approach was used to assess rate of omission of surgical treatment.

Results: Of 624,237 patients diagnosed with invasive breast …