Genetic Phenomena Commons^™

Novel Dominant And Recessive Variants In Human Robo1 Cause Distinct Neurodevelopmental Defects Through Different Mechanisms, Yan Huang, Mengqi Ma, Xiao Mao, Davut Pehlivan, Oguz Kanca, Feride Un-Candan, Li Shu, Gulsen Akay, Tadahiro Mitani, Shenzhao Lu, Sukru Candan, Hua Wang, Bo Xiao, James R Lupski, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

The Roundabout (Robo) receptors, located on growth cones of neurons, induce axon repulsion in response to the extracellular ligand Slit. The Robo family of proteins controls midline crossing of commissural neurons during development in flies. Mono- and bi-allelic variants in human ROBO1 (HGNC: 10249) have been associated with incomplete penetrance and variable expressivity for a breath of phenotypes, including neurodevelopmental defects such as strabismus, pituitary defects, intellectual impairment, as well as defects in heart and kidney. Here, we report two novel ROBO1 variants associated with very distinct phenotypes. A homozygous missense p.S1522L variant in three affected siblings with nystagmus; and …

Two Interaction Surfaces Between Xpa And Rpa Organize The Preincision Complex In Nucleotide Excision Repair, Mihyun Kim, Hyun-Suk Kim, Areetha D'Souza, Kaitlyn Gallagher, Eunwoo Jeong, Agnieszka Topolska-Wós, Kateryna Ogorodnik Le Meur, Chi-Lin Tsai, Miaw-Sheue Tsai, Minyong Kee, John A Tainer, Jung-Eun Yeo, Walter J Chazin, Orlando D Schärer

Faculty, Staff and Student Publications

The xeroderma pigmentosum protein A (XPA) and replication protein A (RPA) proteins fulfill essential roles in the assembly of the preincision complex in the nucleotide excision repair (NER) pathway. We have previously characterized the two interaction sites, one between the XPA N-terminal (XPA-N) disordered domain and the RPA32 C-terminal domain (RPA32C), and the other with the XPA DNA binding domain (DBD) and the RPA70AB DBDs. Here, we show that XPA mutations that inhibit the physical interaction in either site reduce NER activity in biochemical and cellular systems. Combining mutations in the two sites leads to an additive inhibition of NER, …

Grk3 Is A Poor Prognosticator And Serves As A Therapeutic Target In Advanced Gastric Adenocarcinoma, Yuan Li, Yibo Fan, Jinbang Xu, Longfei Huo, Ailing W Scott, Jiankang Jin, Boxuan Yang, Shan Shao, Lang Ma, Ying Wang, Xiaodan Yao, Melissa Pool Pizzi, Matheus Sewastjanow Da Silva, Guoliang Zhang, Lijuan Zhuo, Eun Jeong Cho, Kevin N Dalby, Namita D Shanbhag, Zhenning Wang, Wenliang Li, Shumei Song, Jaffer A Ajani

Faculty, Staff and Student Publications

Background: G protein-coupled receptor (GPCR) is the most targeted protein family by the FDA-approved drugs. GPCR-kinase 3 (GRK3) is critical for GPCR signaling. Our genomic analysis showed that GRK3 expression correlated with poor prognosis of gastric adenocarcinoma (GAC) patients. However, GRK3's functions and clinical utility in GAC progression and metastases are unknown.

Methods: We studied GRK3 expression in normal, primary, and metastatic GAC tissues. We identified a novel GRK3 inhibitor, LD2, through a chemical-library screen. Through genetic and pharmacologic modulations of GRK3, a series of functional and molecular studies were performed in vitro and in vivo. Impact of GRK3 on …

Lysyl Hydroxylase 2 Mediated Collagen Post-Translational Modifications And Functional Outcomes, Masahiko Terajima, Yuki Taga, Tomoyuki Nakamura, Hou-Fu Guo, Yukako Kayashima, Nobuyo Maeda-Smithies, Kshitij Parag-Sharma, Jeong Seon Kim, Antonio L Amelio, Kazunori Mizuno, Jonathan M Kurie, Mitsuo Yamauchi

Faculty, Staff and Student Publications

Lysyl hydroxylase 2 (LH2) is a member of LH family that catalyzes the hydroxylation of lysine (Lys) residues on collagen, and this particular isozyme has been implicated in various diseases. While its function as a telopeptidyl LH is generally accepted, several fundamental questions remain unanswered: 1. Does LH2 catalyze the hydroxylation of all telopeptidyl Lys residues of collagen? 2. Is LH2 involved in the helical Lys hydroxylation? 3. What are the functional consequences when LH2 is completely absent? To answer these questions, we generated LH2-null MC3T3 cells (LH2KO), and extensively characterized the type I collagen phenotypes in comparison with controls. …

Regulation Of Drosophila Oviduct Muscle Contractility By Octopamine, Sonali A Deshpande, Ethan W Rohrbach, James D Asuncion, Jenna Harrigan, Aditya Eamani, Ellery H Schlingmann, Daniel J Suto, Pei-Tseng Lee, Felix E Schweizer, Hugo J Bellen, David E Krantz

Duncan NRI Faculty and Staff Publications

Octopamine is essential for egg-laying in

Phase 2 Of Extracellular Rna Communication Consortium Charts Next-Generation Approaches For Extracellular Rna Research, Bogdan Mateescu, Jennifer C Jones, Roger P Alexander, Eric Alsop, Ji Yeong An, Mohammad Asghari, Alex Boomgarden, Laura Bouchareychas, Alfonso Cayota, Hsueh-Chia Chang, Al Charest, Daniel T Chiu, Robert J Coffey, Saumya Das, Peter De Hoff, Andrew Demello, Crislyn D'Souza-Schorey, David Elashoff, Kiarash R Eliato, Jeffrey L Franklin, David J Galas, Mark B Gerstein, Ionita H Ghiran, David B Go, Stephen Gould, Tristan R Grogan, James N Higginbotham, Florian Hladik, Tony Jun Huang, Xiaoye Huo, Elizabeth Hutchins, Dennis K Jeppesen, Tijana Jovanovic-Talisman, Betty Y S Kim, Sung Kim, Kyoung-Mee Kim, Yong Kim, Robert R Kitchen, Vaughan Knouse, Emily L Laplante, Carlito B Lebrilla, L James Lee, Kathleen M Lennon, Guoping Li, Feng Li, Tieyi Li, Tao Liu, Zirui Liu, Adam L Maddox, Kyle Mccarthy, Bessie Meechoovet, Nalin Maniya, Yingchao Meng, Aleksandar Milosavljevic, Byoung-Hoon Min, Amber Morey, Martin Ng, John Nolan, Getulio P De Oliveira Junior, Michael E Paulaitis, Tuan Anh Phu, Robert L Raffai, Eduardo Reátegui, Matthew E Roth, David A Routenberg, Joel Rozowsky, Joseph Rufo, Satyajyoti Senapati, Sigal Shachar, Himani Sharma, Anil K Sood, Stavros Stavrakis, Alessandra Stürchler, Muneesh Tewari, Juan P Tosar, Alexander K Tucker-Schwartz, Andrey Turchinovich, Nedyalka Valkov, Kendall Van Keuren-Jensen, Kasey C Vickers, Lucia Vojtech, Wyatt N Vreeland, Ceming Wang, Kai Wang, Zeyu Wang, Joshua A Welsh, Kenneth W Witwer, David T W Wong, Jianping Xia, Ya-Hong Xie, Kaichun Yang, Mikołaj P Zaborowski, Chenguang Zhang, Qin Zhang, Angela M Zivkovic, Louise C Laurent

Faculty, Staff and Student Publications

The extracellular RNA communication consortium (ERCC) is an NIH-funded program aiming to promote the development of new technologies, resources, and knowledge about exRNAs and their carriers. After Phase 1 (2013-2018), Phase 2 of the program (ERCC2, 2019-2023) aims to fill critical gaps in knowledge and technology to enable rigorous and reproducible methods for separation and characterization of both bulk populations of exRNA carriers and single EVs. ERCC2 investigators are also developing new bioinformatic pipelines to promote data integration through the exRNA atlas database. ERCC2 has established several Working Groups (Resource Sharing, Reagent Development, Data Analysis and Coordination, Technology Development, nomenclature, …

A Multi-Institutional Prediction Model To Estimate The Risk Of Recurrence And Mortality After Mastectomy For T1-2n1 Breast Cancer, Sarah M C Sittenfeld, Emily C Zabor, Sarah N Hamilton, Henry M Kuerer, Mahmoud El-Tamer, George E Naoum, Pauline T Truong, Alan Nichol, Benjamin D Smith, Wendy A Woodward, Tracy-Ann Moo, Simon N Powell, Chirag S Shah, Alphonse G Taghian, Ibrahim Abu-Gheida, Rahul D Tendulkar

Faculty, Staff and Student Publications

Background: Post-mastectomy radiation therapy (PMRT) in women with pathologic stage T1-2N1M0 breast cancer is controversial.

Methods: Data from five North American institutions including women undergoing mastectomy without neoadjuvant therapy with pT1-2N1M0 breast cancer treated from 2006 to 2015 were pooled for analysis. Competing-risks regression was performed to identify factors associated with locoregional recurrence (LRR), distant metastasis (DM), overall recurrence (OR), and breast cancer mortality (BCM).

Results: A total of 3532 patients were included for analysis with a median follow-up time among survivors of 6.8 years (interquartile range [IQR], 4.5-9.5 years). The 2154 (61%) patients who received PMRT had significantly more …

Improved Sars-Cov-2 Sequencing Surveillance Allows The Identification Of New Variants And Signatures In Infected Patients, Antonio Grimaldi, Francesco Panariello, Patrizia Annunziata, Teresa Giuliano, Michela Daniele, Biancamaria Pierri, Chiara Colantuono, Marcello Salvi, Valentina Bouché, Anna Manfredi, Maria Concetta Cuomo, Denise Di Concilio, Claudia Tiberio, Mariano Fiorenza, Giuseppe Portella, Ilaria Cimmino, Antonio Sorrentino, Giovanna Fusco, Maria Rosaria Granata, Pellegrino Cerino, Antonio Limone, Luigi Atripaldi, Andrea Ballabio, Davide Cacchiarelli

Duncan NRI Faculty and Staff Publications

Background: Genomic surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the only approach to rapidly monitor and tackle emerging variants of concern (VOC) of the COVID-19 pandemic. Such scrutiny is crucial to limit the spread of VOC that might escape the immune protection conferred by vaccination strategies or previous virus exposure. It is also becoming clear now that efficient genomic surveillance would require monitoring of the host gene expression to identify prognostic biomarkers of treatment efficacy and disease progression. Here we propose an integrative workflow to both generate thousands of SARS-CoV-2 genome sequences per week and analyze host …

Current Challenges In Image-Guided Magnetic Hyperthermia Therapy For Liver Cancer, Anirudh Sharma, Erik Cressman, Anilchandra Attaluri, Dara L Kraitchman, Robert Ivkov

Faculty, Staff and Student Publications

For patients diagnosed with advanced and unresectable hepatocellular carcinoma (HCC), liver transplantation remains the best option to extend life. Challenges with organ supply often preclude liver transplantation, making palliative non-surgical options the default front-line treatments for many patients. Even with imaging guidance, success following treatment remains inconsistent and below expectations, so new approaches are needed. Imaging-guided thermal therapy interventions have emerged as attractive procedures that offer individualized tumor targeting with the potential for the selective targeting of tumor nodules without impairing liver function. Furthermore, imaging-guided thermal therapy with added standard-of-care chemotherapies targeted to the liver tumor can directly reduce the …

A Comprehensive Search Of Non-Canonical Proteins In Non-Small Cell Lung Cancer And Their Impact On The Immune Response, Ehsan Irajizad, Johannes F Fahrmann, James P Long, Jody Vykoukal, Makoto Kobayashi, Michela Capello, Chuan-Yih Yu, Yining Cai, Fu Chung Hsiao, Nikul Patel, Soyoung Park, Qian Peng, Jennifer B Dennison, Taketo Kato, Mei Chee Tai, Ayumu Taguchi, Humam Kadara, Ignacio I Wistuba, Hiroyuki Katayama, Kim-Anh Do, Samir M Hanash, Edwin J Ostrin

Faculty, Staff and Student Publications

There is substantial interest in mining neoantigens for cancer applications. Non-canonical proteins resulting from frameshift mutations have been identified as neoantigens in cancer. We investigated the landscape of non-canonical proteins in non-small cell lung cancer (NSCLC) and their induced immune response in the form of autoantibodies. A database of cryptoproteins was computationally constructed and comprised all alternate open reading frames (altORFs) and ORFs identified in pseudogenes, noncoding RNAs, and untranslated regions of mRNAs that did not align with known canonical proteins. Proteomic profiles of seventeen lung adenocarcinoma (LUAD) cell lines were searched to evaluate the occurrence of cryptoproteins. To assess …

Oncogenic Collagen I Homotrimers From Cancer Cells Bind To Α3Β1 Integrin And Impact Tumor Microbiome And Immunity To Promote Pancreatic Cancer, Yang Chen, Sujuan Yang, Jena Tavormina, Desiree Tampe, Michael Zeisberg, Huamin Wang, Krishnan K Mahadevan, Chang-Jiun Wu, Hikaru Sugimoto, Chia-Chi Chang, Robert R Jenq, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

In contrast to normal type I collagen (Col1) heterotrimer (α1/α2/α1) produced by fibroblasts, pancreatic cancer cells specifically produce unique Col1 homotrimer (α1/α1/α1). Col1 homotrimer results from epigenetic suppression of the Col1a2 gene and promotes oncogenic signaling, cancer cell proliferation, tumor organoid formation, and growth via α3β1 integrin on cancer cells, associated with tumor microbiome enriched in anaerobic Bacteroidales in hypoxic and immunosuppressive tumors. Deletion of Col1 homotrimers increases overall survival of mice with pancreatic ductal adenocarcinoma (PDAC), associated with reprograming of the tumor microbiome with increased microaerophilic Campylobacterales, which can be reversed with broad-spectrum antibiotics. Deletion of Col1 homotrimers enhances …

Miracle Of Microrna-Driven Cancer Nanotherapeutics, Goknur Kara, Banu Arun, George A Calin, Bulent Ozpolat

Faculty, Staff and Student Publications

MicroRNAs (miRNAs) are non-protein-coding RNA molecules 20-25 nucleotides in length that can suppress the expression of genes involved in numerous physiological processes in cells. Accumulating evidence has shown that dysregulation of miRNA expression is related to the pathogenesis of various human diseases and cancers. Thus, stragegies involving either restoring the expression of tumor suppressor miRNAs or inhibiting overexpressed oncogenic miRNAs hold potential for targeted cancer therapies. However, delivery of miRNAs to tumor tissues is a challenging task. Recent advances in nanotechnology have enabled successful tumor-targeted delivery of miRNA therapeutics through newly designed nanoparticle-based carrier systems. As a result, miRNA therapeutics …

Identification Of The Nrf2 Transcriptional Network As A Therapeutic Target For Trigeminal Neuropathic Pain, Chirag Vasavda, Risheng Xu, Jason Liew, Ruchita Kothari, Ryan S Dhindsa, Evan R Semenza, Bindu D Paul, Dustin P Green, Mark F Sabbagh, Joseph Y Shin, Wuyang Yang, Adele M Snowman, Lauren K Albacarys, Abhay Moghekar, Carlos A Pardo-Villamizar, Mark Luciano, Judy Huang, Chetan Bettegowda, Shawn G Kwatra, Xinzhong Dong, Michael Lim, Solomon H Snyder

Duncan NRI Faculty and Staff Publications

Trigeminal neuralgia, historically dubbed the "suicide disease," is an exceedingly painful neurologic condition characterized by sudden episodes of intense facial pain. Unfortunately, the only U.S. Food and Drug Administration (FDA)-approved medication for trigeminal neuralgia carries substantial side effects, with many patients requiring surgery. Here, we identify the NRF2 transcriptional network as a potential therapeutic target. We report that cerebrospinal fluid from patients with trigeminal neuralgia accumulates reactive oxygen species, several of which directly activate the pain-transducing channel TRPA1. Similar to our patient cohort, a mouse model of trigeminal neuropathic pain also exhibits notable oxidative stress. We discover that stimulating the …

The Value Of In Vivo Reflectance Confocal Microscopy As An Assessment Tool In Chemotherapy-Induced Peripheral Neuropathy: A Pilot Study, Sabrina R Ramnarine, Patrick M Dougherty, Roman Rolke, Linda J Williams, Christi Alessi-Fox, Andrew J Coleman, Caterina Longo, Lesley A Colvin, Marie T Fallon

Faculty, Staff and Student Publications

Background: There is a lack of standardized objective and reliable assessment tools for chemotherapy-induced peripheral neuropathy (CIPN). In vivo reflectance confocal microscopy (RCM) imaging offers a non-invasive method to identify peripheral neuropathy markers, namely Meissner's corpuscles (MC). This study investigated the feasibility and value of RCM in CIPN.

Patients and methods: Reflectance confocal microscopy was performed on the fingertip to evaluate MC density in 45 healthy controls and 9 patients with cancer (prior, during, and post-chemotherapy). Quantification was completed by 2 reviewers (one blinded), with maximum MC count/3 × 3 mm image reported. Quantitative Sensory Testing (QST; thermal and mechanical …

Adaptation And Dosimetric Commissioning Of A Synchrotron-Based Proton Beamline For Flash Experiments, Ming Yang, Xiaochun Wang, Fada Guan, Uwe Titt, Kiminori Iga, Dadi Jiang, Takeshi Takaoka, Satoshi Tootake, Tadashi Katayose, Masumi Umezawa, Emil Schüler, Steven Frank, Steven H Lin, Narayan Sahoo, Albert C Koong, Radhe Mohan, X Ronald Zhu

Faculty, Staff and Student Publications

Objective. Irradiation with ultra-high dose rates (>40 Gy s^-1), also known as FLASH irradiation, has the potential to shift the paradigm of radiation therapy because of its reduced toxicity to normal tissues compared to that of conventional irradiations. The goal of this study was to (1) achieve FLASH irradiation conditions suitable for pre-clinicalin vitroandin vivobiology experiments using our synchrotron-based proton beamline and (2) commission the FLASH irradiation conditions achieved.

Approach. To achieve these suitable FLASH conditions, we made a series of adaptations to our proton beamline, including modifying the spill length …

Rare Genetic Variants Explain Missing Heritability In Smoking, Seon-Kyeong Jang, Luke Evans, Allison Fialkowski, Donna K. Arnett, Allison E. Ashley-Koch, Kathleen C. Barnes, Diane M. Becker, Joshua C. Bis, John Blangero, Eugene R. Bleecker

School of Medicine Publications

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this ‘missing heritability’. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability (h2SNP) was estimated from 0.13 to 0.28 (s.e., 0.10–0.13) in European ancestries, with 35–74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5–4 times higher than past estimates based …

Primary Cutaneous Lymphoma: Recommendations For Clinical Trial Design And Staging Update From The Iscl, Usclc, And Eortc, Elise A Olsen, Sean Whittaker, Rein Willemze, Lauren Pinter-Brown, Francine Foss, Larisa Geskin, Lawrence Schwartz, Steven Horwitz, Joan Guitart, John Zic, Youn H Kim, Gary S Wood, Madeleine Duvic, Wei Ai, Michael Girardi, Alejandro Gru, Emmanuella Guenova, Emmilia Hodak, Richard Hoppe, Werner Kempf, Ellen Kim, Mary Jo Lechowicz, Pablo Ortiz-Romero, Evangelia Papadavid, Pietro Quaglino, Mark Pittelkow, H Miles Prince, Jose Antonio Sanches, Makoto Sugaya, Maarten Vermeer, Jasmine Zain, Robert Knobler, Rudolf Stadler, Martine Bagot, Julia Scarisbrick

Faculty, Staff and Student Publications

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), …

Risk Assessment With Low-Pass Whole-Genome Sequencing Of Cell-Free Dna Before Cd19 Car T-Cell Therapy For Large B-Cell Lymphoma, Hua-Jay J Cherng, Ryan Sun, Bryant Sugg, Russell Irwin, Haopeng Yang, Cao Cuong Le, Qing Deng, Luis Fayad, Nathan H Fowler, Simrit Parmar, Raphael Steiner, Fredrick Hagemeister, Ranjit Nair, Hun Ju Lee, Maria Rodriguez, Felipe Samaniego, Swaminathan P Iyer, Christopher R Flowers, Linghua Wang, Loretta J Nastoupil, Sattva S Neelapu, Sairah Ahmed, Paolo Strati, Michael R Green, Jason Westin

Faculty, Staff and Student Publications

Patients with relapsed or refractory large B-cell lymphomas (rrLBCL) can achieve long-term remission after CD19 chimeric antigen receptor T-cell therapy (CART19). However, more than half of recipients will experience treatment failure. Thus, approaches are needed to identify high-risk patients who may benefit from alternative or consolidative therapy. We evaluated low-pass whole-genome sequencing (lpWGS) of cell-free DNA (cfDNA) before CART19 as a new approach for risk stratification. We performed lpWGS on pretreatment plasma samples from 122 patients at time of leukapheresis who received standard-of-care CART19 for rrLBCL to define DNA copy number alterations (CNAs). In multivariable selection, high focal CNA score …

Robust And Efficient Assessment Of Potency (Reap) As A Quantitative Tool For Dose-Response Curve Estimation, Shouhao Zhou, Xinyi Liu, Xinying Fang, Vernon M Chinchilli, Michael Wang, Hong-Gang Wang, Nikolay V Dokholyan, Chan Shen, J Jack Lee

Faculty, Staff and Student Publications

The median-effect equation has been widely used to describe the dose-response relationship and identify compounds that activate or inhibit specific disease targets in contemporary drug discovery. However, the experimental data often contain extreme responses, which may significantly impair the estimation accuracy and impede valid quantitative assessment in the standard estimation procedure. To improve the quantitative estimation of the dose-response relationship, we introduce a novel approach based on robust beta regression. Substantive simulation studies under various scenarios demonstrate solid evidence that the proposed approach consistently provides robust estimation for the median-effect equation, particularly when there are extreme outcome observations. Moreover, simulation …

Muscle And Adipose Tissue Segmentations At The Third Cervical Vertebral Level In Patients With Head And Neck Cancer, Kareem A Wahid, Brennan Olson, Rishab Jain, Aaron J Grossberg, Dina El-Habashy, Cem Dede, Vivian Salama, Moamen Abobakr, Abdallah S R Mohamed, Renjie He, Joel Jaskari, Jaakko Sahlsten, Kimmo Kaski, Clifton D Fuller, Mohamed A Naser

Faculty, Staff and Student Publications

The accurate determination of sarcopenia is critical for disease management in patients with head and neck cancer (HNC). Quantitative determination of sarcopenia is currently dependent on manually-generated segmentations of skeletal muscle derived from computed tomography (CT) cross-sectional imaging. This has prompted the increasing utilization of machine learning models for automated sarcopenia determination. However, extant datasets currently do not provide the necessary manually-generated skeletal muscle segmentations at the C3 vertebral level needed for building these models. In this data descriptor, a set of 394 HNC patients were selected from The Cancer Imaging Archive, and their skeletal muscle and adipose tissue was …

A Large-Scale Genome-Wide Gene-Gene Interaction Study Of Lung Cancer Susceptibility In Europeans With A Trans-Ethnic Validation In Asians, Ruyang Zhang, Sipeng Shen, Yongyue Wei, Ying Zhu, Yi Li, Jiajin Chen, Jinxing Guan, Zoucheng Pan, Yuzhuo Wang, Meng Zhu, Junxing Xie, Xiangjun Xiao, Dakai Zhu, Yafang Li, Demetrios Albanes, Maria Teresa Landi, Neil E Caporaso, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, Gadi Rennert, Susanne Arnold, Paul Brennan, James D Mckay, John K Field, Sanjay S Shete, Loic Le Marchand, Geoffrey Liu, Angeline S Andrew, Lambertus A Kiemeney, Shan Zienolddiny-Narui, Annelie Behndig, Mikael Johansson, Angela Cox, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Juncheng Dai, Hongxia Ma, Yang Zhao, Zhibin Hu, Rayjean J Hung, Christopher I Amos, Hongbing Shen, Feng Chen, David C Christiani

Faculty, Staff and Students Publications

INTRODUCTION: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC).

METHODS: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms …

Induced Cytotoxicity In Crebbp/Ep300mut Head And Neck Squamous Cell Carcinoma, Thomaia Pamplin

Dissertations and Theses (Open Access)

INDUCED CYOTOXICTY IN CREBBP/EP300mut HEAD AND NECK SQUAMOUS CELL CARCINOMA

Thomaia Pamplin

Advisor: Curtis Pickering, Ph.D.

Background: Head and neck squamous cell carcinoma HNSCC is the most common malignancy in the head and neck. Most cases are found in advanced stages and depending on the location can be treated with surgical resection and/or radiation (XRT), chemotherapy, or chemoradiation. Our lab groups have identified that HNSCC with a mutation in its CREBBP/EP300 genes can be sensitized to XRT when the histone acetyltransferase activity of CREBBP/EP300 is inhibited. This radiosensitization manifests in the form of increased cell death for …

Impact Of Somatic Mutations On Survival Outcomes In Patients With Anaplastic Thyroid Carcinoma, Jennifer Rui Wang, Matthew Montierth, Li Xu, Maitrayee Goswami, Xiao Zhao, Gilbert Cote, Wenyi Wang, Priyanka Iyer, Ramona Dadu, Naifa L Busaidy, Stephen Y Lai, Neil D Gross, Renata Ferrarotto, Charles Lu, Gary Brandon Gunn, Michelle D Williams, Mark Routbort, Mark E Zafereo, Maria E Cabanillas

Faculty, Staff and Student Publications

PURPOSE: Anaplastic thyroid carcinoma (ATC) uniformly present with aggressive disease, but the mutational landscape of tumors varies. We aimed to determine whether tumor mutations affect survival outcomes in ATC.

MATERIALS AND METHODS: Patients who underwent mutation sequencing using targeted gene panels between 2005 and 2019 at a tertiary referral center were included. Associations between mutation status and survival outcomes were assessed using Cox proportional hazards models.

RESULTS: A total of 202 patients were included, where 122 died of ATC (60%). The median follow-up was 31 months (interquartile range, 18-45 months). The most common mutations were in

CONCLUSION: Mutation analysis provides …

Ankle2-Related Microcephaly: A Variable Microcephaly Syndrome Resembling Zika Infection, Ajay X Thomas, Nichole Link, Laurie A Robak, Gail Demmler-Harrison, Emily C Pao, Audrey E Squire, Savannah Michels, Julie S Cohen, Anne Comi, Paolo Prontera, Alberto Verrotti Di Pianella, Giuseppe Di Cara, Livia Garavelli, Stefano Giuseppe Caraffi, Carlo Fusco, Roberta Zuntini, Kendall C Parks, Elliott H Sherr, Mais O Hashem, Sateesh Maddirevula, Fowzan S Alkuraya, Isphana A F Contractar, Jennifer E Neil, Christopher A Walsh, Hugo J Bellen, Hsiao-Tuan Chao, Robin D Clark, Ghayda M Mirzaa

Duncan NRI Faculty and Staff Publications

Objective: This study delineates the clinical and molecular spectrum of ANKLE2-related microcephaly (MIC), as well as highlights shared pathological mechanisms between ANKLE2 and the Zika virus.

Methods: We identified 12 individuals with MIC and variants in ANKLE2 with a broad range of features. Probands underwent thorough phenotypic evaluations, developmental assessments, and anthropometric measurements. Brain imaging studies were systematically reviewed for developmental abnormalities. We functionally interrogated a subset of identified ANKLE2 variants in Drosophila melanogaster.

Results: All individuals had MIC (z-score ≤ -3), including nine with congenital MIC. We identified a broad range of brain abnormalities including simplified cortical gyral pattern, …

Ablation Of Long Noncoding Rna Malat1 Activates Antioxidant Pathway And Alleviates Sepsis In Mice, Jingshu Chen, Shu Tang, Sui Ke, James J Cai, Daniel Osorio, Andrei Golovko, Benjamin Morpurgo, Shaodong Guo, Yuxiang Sun, Melanie Winkle, George A Calin, Yanan Tian

Faculty, Staff and Student Publications

The metastasis-associated lung adenocarcinoma transcript1 (MALAT1) is a long noncoding RNA (lncRNA) and is known for its role in cancer development and prognosis. In this study, we report that MALAT1 plays an important role in regulating acute inflammatory responses in sepsis. In patient samples, MALAT1 expression was positively correlated with severity of sepsis. In cultured macrophages, LPS treatment significantly induced MALAT1 expression, while genetic ablation of MALAT1 greatly reduced proinflammatory cytokine levels. Furthermore, MALAT1-ablated mice had significantly increased survival rates in cecal ligation and puncture (CLP)-induced sepsis and LPS-induced endotoxemia. One novel and salient feature of MALAT1-ablated mice is greatly …

Sexual Orientation And Gender Identity Data Collection In Oncology Practice: Findings Of An Asco Survey, Charles S Kamen, Mandi L Pratt-Chapman, Stephen C Meersman, Gwendolyn P Quinn, Matthew B Schabath, Shail Maingi, Janette K Merrill, Elizabeth Garrett-Mayer, Melinda Kaltenbaugh, Caroline Schenkel, Shine Chang

Faculty, Staff and Student Publications

Purpose: Lack of collection of sexual orientation and gender identity (SOGI) data in oncology practices limits assessment of sexual and gender minority (SGM) cancer patients' experiences and restricts opportunities to improve health outcomes of SGM patients. Despite national calls for routine SOGI data collection, individual-level and institutional barriers hinder progress. This study aimed to identify these barriers in oncology.

Methods: An online survey of ASCO members and others assessed SOGI data collection in oncology practices, institutional characteristics related to SOGI data collection, respondents' attitudes about SOGI data and SGM patients, and respondent demographics. Logistic regression calculated adjusted odds ratios (ORs) …

Clinical Research In Ovarian Cancer: Consensus Recommendations From The Gynecologic Cancer Intergroup, Ignace Vergote, Antonio Gonzalez-Martin, Domenica Lorusso, Charlie Gourley, Mansoor Raza Mirza, Jean-Emmanuel Kurtz, Aikou Okamoto, Kathleen Moore, Frédéric Kridelka, Iain Mcneish, Alexander Reuss, Bénédicte Votan, Andreas Du Bois, Sven Mahner, Isabelle Ray-Coquard, Elise C Kohn, Jonathan S Berek, David S P Tan, Nicoletta Colombo, Rongyu Zang, Nicole Concin, Dearbhaile O'Donnell, Alejandro Rauh-Hain, C Simon Herrington, Christian Marth, Andres Poveda, Keiichi Fujiwara, Gavin C E Stuart, Amit M Oza, Michael A Bookman, Participants Of The 6th Gynecologic Cancer Intergroup (Gcig) Ovarian Cancer Consensus Conference On Clinical Research

Faculty, Staff and Student Publications

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with …

Novel Mitochondria-Targeting Compounds Selectively Kill Human Leukemia Cells, Svetlana B Panina, Jingqi Pei, Natalia Baran, Elissa Tjahjono, Shraddha Patel, Gheath Alatrash, Sergej Konoplev, Leonid A Stolbov, Vladimir V Poroikov, Marina Konopleva, Natalia V Kirienko

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is a heterogeneous group of aggressive hematological malignancies commonly associated with treatment resistance, high risk of relapse, and mitochondrial dysregulation. We identified six mitochondria-affecting compounds (PS compounds) that exhibit selective cytotoxicity against AML cells in vitro. Structure-activity relationship studies identified six analogs from two original scaffolds that had over an order of magnitude difference between LD50 in AML and healthy peripheral blood mononuclear cells. Mechanistically, all hit compounds reduced ATP and selectively impaired both basal and ATP-linked oxygen consumption in leukemic cells. Compounds derived from PS127 significantly upregulated production of reactive oxygen species (ROS) in AML …

Advances In Head And Neck Cancer Pain, Y Ye, D D Jensen, C T Viet, H L Pan, W M Campana, M Amit, M D Boada

Faculty, Staff and Student Publications

Head and neck cancer (HNC) affects over 890,000 people annually worldwide and has a mortality rate of 50%. Aside from poor survival, HNC pain impairs eating, drinking, and talking in patients, severely reducing quality of life. Different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between cancers. Poor pathologic features (e.g., perineural invasion, lymph node metastasis) are associated with increased pain. The use of syngeneic/immunocompetent animal models, as well as a new mouse model of perineural invasion, provides novel insights into the pathobiology of HNC pain. Glial and immune …

Preventing Cholesterol-Induced Perk (Protein Kinase Rna-Like Endoplasmic Reticulum Kinase) Signaling In Smooth Muscle Cells Blocks Atherosclerotic Plaque Formation, Abhijnan Chattopadhyay, Pujun Guan, Suravi Majumder, Kaveeta Kaw, Zhen Zhou, Chen Zhang, Siddharth K Prakash, Anita Kaw, L Maximillian Buja, Callie S Kwartler, Dianna M Milewicz

Faculty, Staff and Student Publications

BACKGROUND: Vascular smooth muscle cells (SMCs) undergo complex phenotypic modulation with atherosclerotic plaque formation in hyperlipidemic mice, which is characterized by de-differentiation and heterogeneous increases in the expression of macrophage, fibroblast, osteogenic, and stem cell markers. An increase of cellular cholesterol in SMCs triggers similar phenotypic changes in vitro with exposure to free cholesterol due to cholesterol entering the endoplasmic reticulum, triggering endoplasmic reticulum stress and activating Perk (protein kinase RNA-like endoplasmic reticulum kinase) signaling.

METHODS: We generated an SMC-specific

RESULTS: SMC-specific deletion of Perk reduces atherosclerotic plaque formation in male hyperlipidemic mice by 80%. Single-cell transcriptomic data identify 2 …