Genetic Phenomena Commons^™

Targeting Ras Mutant Colorectal Cancer With Dual Inhibition Of Mek And Cdk4/6, Alexey V Sorokin, Preeti Kanikarla Marie, Lea Bitner, Muddassir Syed, Melanie Woods, Ganiraju Manyam, Lawrence N Kwong, Benny Johnson, Van K Morris, Philip Jones, David G Menter, Michael S Lee, Scott Kopetz

Faculty, Staff and Student Publications

UNLABELLED: KRAS and NRAS mutations occur in 45% of colorectal cancers, with combined MAPK pathway and CDK4/6 inhibition identified as a potential therapeutic strategy. In the current study, this combinatorial treatment approach was evaluated in a co-clinical trial in patient-derived xenografts (PDX), and safety was established in a clinical trial of binimetinib and palbociclib in patients with metastatic colorectal cancer with RAS mutations. Across 18 PDX models undergoing dual inhibition of MEK and CDK4/6, 60% of tumors regressed, meeting the co-clinical trial primary endpoint. Prolonged duration of response occurred predominantly in TP53 wild-type models. Clinical evaluation of binimetinib and palbociclib …

Serologic Versus Molecular Testing For Screening For Hepatitis C Virus Infection In Patients With Hematologic Malignancies, Harrys A Torres, Georgios Angelidakis, Ying Jiang, Minas Economides, Khalis Mustafayev, Marcel Yibirin, Robert Orlowski, Richard Champlin, Srdan Verstovsek, Issam Raad

Faculty, Staff and Student Publications

Testing for antibody against hepatitis C virus (anti-HCV) is a low-cost diagnostic method worldwide; however, an optimal screening test for HCV in patients with cancer has not been established. We sought to identify an appropriate screening test for HCV infection in patients with hematologic malignancies and/or hematopoietic cell transplants (HCT). Patients in our center were simultaneously screened using serological (anti-HCV) and molecular (HCV RNA) assays (February 2019-November 2019). In total, 214 patients were enrolled in this study. Three patients (1.4%) were positive for anti-HCV, and 2 (0.9%) were positive for HCV RNA. The overall percentage agreement was 99.5% (95% CI: …

Association Between Abnormal Lipid Profile And Inflammation And Progression Of Myelodysplastic Syndrome To Acute Leukemia, Wei Qiao, Elliana Young, Chun Feng, Suyu Liu, Jeff Jin, Laila Noor, Cristhiam M Rojas Hernandez, Gautam Borthakur, Olga Gorlova, Vahid Afshar-Kharghan

Faculty, Staff and Student Publications

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with a small risk of developing hematologic malignancies and a higher risk of cardiovascular diseases (CVD). We asked whether the reverse correlation exists and cardiometabolic risk factors have an impact on the progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). We investigated the association between abnormal lipid profiles and inflammation in MDS, which shares many genetic mutations with CHIP, and the risk of developing acute leukemia. We examined the medical records of 11071 MDS patients. Among them, 5422 had at least one lipid profile or C-reactive protein (CRP) measurement. In …

Lats1/2 Control Tgfb-Directed Epithelial-To-Mesenchymal Transition In The Murine Dorsal Cranial Neuroepithelium Through Yap Regulation, Idaliz M Martínez Traverso, Jeffrey D Steimle, Xiaolei Zhao, Jun Wang, James F Martin

Faculty, Staff and Student Publications

Hippo signaling, an evolutionarily conserved kinase cascade involved in organ size control, plays key roles in various tissue developmental processes, but its role in craniofacial development remains poorly understood. Using the transgenic Wnt1-Cre2 driver, we inactivated the Hippo signaling components Lats1 and Lats2 in the cranial neuroepithelium of mouse embryos and found that the double conditional knockout (DCKO) of Lats1/2 resulted in neural tube and craniofacial defects. Lats1/2 DCKO mutant embryos had microcephaly with delayed and defective neural tube closure. Furthermore, neuroepithelial cell shape and architecture were disrupted within the cranial neural tube in Lats1/2 DCKO mutants. RNA sequencing of …

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 …

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. …

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 …

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 …

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 …

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, …