Medical Genetics Commons^™

Genetic Architecture And Biology Of Youth-Onset Type 2 Diabetes, Soo Heon Kwak, Shylaja Srinivasan, Ling Chen, Jennifer Todd, Josep M Mercader, Elizabeth T Jensen, Jasmin Divers, Amy K Mottl, Catherine Pihoker, Rachelle G Gandica, Lori M Laffel, Elvira Isganaitis, Morey W Haymond, Lynne L Levitsky, Toni I Pollin, Jose C Florez, Jason Flannick, Progress In Diabetes Genetics In Youth (Prodigy) Consortium

Faculty, Staff and Students Publications

The prevalence of youth-onset type 2 diabetes (T2D) and childhood obesity has been rising steadily1, producing a growing public health concern1 that disproportionately affects minority groups2. The genetic basis of youth-onset T2D and its relationship to other forms of diabetes are unclear3. Here we report a detailed genetic characterization of youth-onset T2D by analysing exome sequences and common variant associations for 3,005 individuals with youth-onset T2D and 9,777 adult control participants matched for ancestry, including both males and females. We identify monogenic diabetes variants in 2.4% of individuals and three exome-wide significant ( …

Nonchromosomal Birth Defects And Risk Of Childhood Acute Leukemia: An Assessment In 15 000 Leukemia Cases And 46 000 Controls From The Childhood Cancer And Leukemia International Consortium, Philip J Lupo, Tiffany M Chambers, Beth A Mueller, Jacqueline Clavel, John D Dockerty, David R Doody, Friederike Erdmann, Sameera Ezzat, Tommaso Filippini, Johnni Hansen, Julia E Heck, Claire Infante-Rivard, Alice Y Kang, Corrado Magnani, Carlotta Malagoli, Erin L Marcotte, Catherine Metayer, Helen D Bailey, Ana M Mora, Evangelia Ntzani, Eleni Th Petridou, Maria S Pombo-De-Oliveira, Wafaa M Rashed, Eve Roman, Joachim Schüz, Catharina Wesseling, Logan G Spector, Michael E Scheurer

Faculty, Staff and Students Publications

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia …

Epstein-Barr Virus-Based Prognostic Model In Nodular Sclerosis Classic Hodgkin Lymphoma, Chen Jiang, Li-Yun Huang, Ji-Hao Zhou, Zhi-Ming Li, Yu Wang, Shuo Li, Jian-Chang Fu, Qi-Tao Huang, Qin Yan, Yu-Yuan Huang, Min Zuo, Shimin Hu, Robert Peter Gale, Yang Liang, Jing-Ping Yun, Yu-Hua Huang

Faculty, Staff and Student Publications

The role of Epstein-Barr virus (EBV) in lymphoma cells of nodular sclerosis classic Hodgkin lymphoma (NScHL) is controversial. Our aim was to explore this and establish a clinically feasible model for risk stratification. We interrogated data from 542 consecutive subjects with NScHL receiving ABVD therapy and demonstrated EBV-infection in their lymphoma cells with EBV-encoded small RNAs (EBERs) in situ hybridization. Subjects were divided into training and validation datasets. As data from the training dataset suggested EBERs-positivity was the only independent prognostic factor for both progression-free survival (PFS) and overall survival (OS), we developed corresponding prognostic models based on it. Our …

Large Scale Plasma Proteomics Identifies Novel Proteins And Protein Networks Associated With Heart Failure Development, Amil M Shah, Peder L Myhre, Victoria Arthur, Pranav Dorbala, Humaira Rasheed, Leo F Buckley, Brian Claggett, Guning Liu, Jianzhong Ma, Ngoc Quynh Nguyen, Kunihiro Matsushita, Chiadi Ndumele, Adrienne Tin, Kristian Hveem, Christian Jonasson, Håvard Dalen, Eric Boerwinkle, Ron C Hoogeveen, Christie Ballantyne, Josef Coresh, Torbjørn Omland, Bing Yu

Faculty, Staff and Student Publications

Heart failure (HF) causes substantial morbidity and mortality but its pathobiology is incompletely understood. The proteome is a promising intermediate phenotype for discovery of novel mechanisms. We measured 4877 plasma proteins in 13,900 HF-free individuals across three analysis sets with diverse age, geography, and HF ascertainment to identify circulating proteins and protein networks associated with HF development. Parallel analyses in Atherosclerosis Risk in Communities study participants in mid-life and late-life and in Trøndelag Health Study participants identified 37 proteins consistently associated with incident HF independent of traditional risk factors. Mendelian randomization supported causal effects of 10 on HF, HF risk …

Mendelian Randomization With Incomplete Measurements On The Exposure In The Hispanic Community Health Study/Study Of Latinos, Yilun Li, Kin Yau Wong, Annie Green Howard, Penny Gordon-Larsen, Heather M Highland, Mariaelisa Graff, Kari E North, Carolina G Downie, Christy L Avery, Bing Yu, Kristin L Young, Victoria L Buchanan, Robert Kaplan, Lifang Hou, Brian Thomas Joyce, Qibin Qi, Tamar Sofer, Jee-Young Moon, Dan-Yu Lin

Faculty, Staff and Student Publications

Mendelian randomization has been widely used to assess the causal effect of a heritable exposure variable on an outcome of interest, using genetic variants as instrumental variables. In practice, data on the exposure variable can be incomplete due to high cost of measurement and technical limits of detection. In this paper, we propose a valid and efficient method to handle both unmeasured and undetectable values of the exposure variable in one-sample Mendelian randomization analysis with individual-level data. We estimate the causal effect of the exposure variable on the outcome using maximum likelihood estimation and develop an expectation maximization algorithm for …

Cov2var, A Function Annotation Database Of Sars-Cov-2 Genetic Variation, Yuzhou Feng, Jiahao Yi, Lin Yang, Yanfei Wang, Jianguo Wen, Weiling Zhao, Pora Kim, Xiaobo Zhou

Faculty, Staff and Student Publications

The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, has resulted in the loss of millions of lives and severe global economic consequences. Every time SARS-CoV-2 replicates, the viruses acquire new mutations in their genomes. Mutations in SARS-CoV-2 genomes led to increased transmissibility, severe disease outcomes, evasion of the immune response, changes in clinical manifestations and reducing the efficacy of vaccines or treatments. To date, the multiple resources provide lists of detected mutations without key functional annotations. There is a lack of research examining the relationship between mutations and various factors such as disease severity, pathogenicity, patient age, patient gender, cross-species …

Lung Cancer In Ever- And Never-Smokers: Findings From Multi-Population Gwas Studies, Yafang Li, Xiangjun Xiao, Jianrong Li, Younghun Han, Chao Cheng, Gail F. Fernandes, Shannon E. Slewitzke, Susan M. Rosenberg, Meng Zhu, Jinyoung Byun, Yohan Bossé, James D. Mckay, Demetrios Albanes, Stephan Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, Maria T. Landi, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, David C. Christiani, Gad Rennert, Susanne M. Arnold, Gary E. Goodman, John K. Field, Diptasri Mandal, Et Al

School of Graduate Studies Faculty Publications

BACKGROUND: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. METHODS: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including eQTL colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. RESULTS: Five novel independent loci, GABRA4, inter-genic region 12q24.33, LRRC4C, LINC01088, …

Integrated Multi-Omics Analyses Identify Anti-Viral Host Factors And Pathways Controlling Sars-Cov-2 Infection, Jiakai Hou, Yanjun Wei, Jing Zou, Roshni Jaffery, Long Sun, Shaoheng Liang, Ningbo Zheng, Ashley M Guerrero, Nicholas A Egan, Ritu Bohat, Si Chen, Caishang Zheng, Xiaobo Mao, S Stephen Yi, Ken Chen, Daniel J Mcgrail, Nidhi Sahni, Pei-Yong Shi, Yiwen Chen, Xuping Xie, Weiyi Peng

Faculty, Staff and Student Publications

Host anti-viral factors are essential for controlling SARS-CoV-2 infection but remain largely unknown due to the biases of previous large-scale studies toward pro-viral host factors. To fill in this knowledge gap, we perform a genome-wide CRISPR dropout screen and integrate analyses of the multi-omics data of the CRISPR screen, genome-wide association studies, single-cell RNA-Seq, and host-virus proteins or protein/RNA interactome. This study uncovers many host factors that are currently underappreciated, including the components of V-ATPases, ESCRT, and N-glycosylation pathways that modulate viral entry and/or replication. The cohesin complex is also identified as an anti-viral pathway, suggesting an important role of …

Identifying Factors That Reduce Substance Use Liability, Victoria Allen, Nick Blanch, Sunday Wright, Kelci Straka-Mai, Aarushi Patel, Caleb Bridgwater, Lubidia Menjivar, Cate Vaughn, Courtney Blondino Phd, The Mid-Atlantic Twin Registry, Michael M. Vanyukov Phd, Hermine H.M. Maes Phd, Elizabeth Prom-Wormley Phd

IRBEH/Spit for Science Publications and Presentations

No abstract provided.

Autochthonous Plasmodium Vivax Infections, Florida, Usa, 2023, Swamy Rakesh Adapa, Kami Kim, Liwang Cui

College of Medicine & TGH Faculty Publications

During May–July 2023, a cluster of 7 patients at local hospitals in Florida, USA, received a diagnosis of Plasmodium vivax malaria. Whole-genome sequencing of the organism from 4 patients and phylogenetic analysis with worldwide representative P. vivax genomes indicated probable single parasite introduction from Central/South America.

Identification Of Novel 3d-Genome Altering And Complex Structural Variants Underlying Retinitis Pigmentosa Type 17 Through A Multistep And High-Throughput Approach, Suzanne E De Bruijn, Daan M Panneman, Nicole Weisschuh, Elizabeth L Cadena, Erica G M Boonen, Lara K Holtes, Galuh D N Astuti, Frans P M Cremers, Nico Leijsten, Jordi Corominas, Christian Gilissen, Anna Skowronska, Jessica Woodley, Andrew D Beggs, Vasileios Toulis, Di Chen, Michael E Cheetham, Alison J Hardcastle, Terri L Mclaren, Tina M Lamey, Jennifer A Thompson, Fred K Chen, John N De Roach, Isabella R Urwin, Lori S Sullivan, Susanne Roosing

Faculty, Staff and Student Publications

INTRODUCTION: Autosomal dominant retinitis pigmentosa type 17 (adRP, type RP17) is caused by complex structural variants (SVs) affecting a locus on chromosome 17 (chr17q22). The SVs disrupt the 3D regulatory landscape by altering the topologically associating domain (TAD) structure of the locus, creating novel TAD structures (neo-TADs) and ectopic enhancer-gene contacts. Currently, screening for RP17-associated SVs is not included in routine diagnostics given the complexity of the variants and a lack of cost-effective detection methods. The aim of this study was to accurately detect novel RP17-SVs by establishing a systematic and efficient workflow.

METHODS: Genetically unexplained probands diagnosed with adRP …

The Relationship Of Neighborhood Disadvantage, Biological Aging, And Psychosocial Risk And Resilience Factors In Heart Failure Incidence Among Black Persons: A Moderated Mediation Analysis, Ganga S Bey, James R Pike, Anthony S Zannas, Qian Xiao, Bing Yu, Amil M Shah, Priya Palta

Faculty, Staff and Student Publications

Objectives: Deprived living environments contribute to greater heart failure (HF) risk among non-Hispanic Black persons, who disproportionately occupy disadvantaged neighborhoods. The mechanisms for these effects are not fully explicated, partially attributable to an insufficient understanding of the individual factors that contribute additional risk or resilience to the impact of neighborhood disadvantage on health. The objective of this study was, therefore, to clarify the complex pathways over which such exposures act to facilitate more targeted, effective interventions. Given the evidence for a mediating role of biological age and a moderating role of individual psychosocial characteristics in the neighborhood disadvantage-HF link, we …

Association Of Perceived Neighborhood Air Quality Problems With Attempt To Quit Cigarette Smoking: A Cross-Sectional Study In Texas, Monalisa Chandra, Joel Fokom Domgue, Robert Yu, Sanjay Shete

Faculty, Staff and Student Publications

Background: Cigarette smoking is the major preventable cause of premature deaths in the United States. Attempting to quit smoking is an important step toward smoking cessation. Although it has been studied extensively, limited information on the association between attempts to quit smoking and neighborhood air quality problems is available. Therefore, we examined the association between attempts to quit smoking in the past year and perceived neighborhood air quality problems among adult Texans who smoke.

Methods: In 2018, a cross-sectional multistage area probability design-based survey was administered to collect sociodemographic, behavioral, and health-related information from a representative sample of 2050 Texas …

Accelerate Vaccine Development Using Seamless Phase 2/3 Trial Designs, Jia-Ying Yang, Guo-Chun Li, Ying Yuan

Faculty, Staff and Student Publications

Background: Traditional vaccine development, often a lengthy and costly process of three separated phases. However, the swift development of COVID-19 vaccines highlighted the critical importance of accelerating the approval of vaccines. This article showcases a seamless phase 2/3 trial design to expedite the development process, particularly for multi-valent vaccines.

Research design and methods: This study utilizes simulation to compare the performance of seamless phase 2/3 design with that of conventional trial design, specifically by re-envisioning a 9-valent HPV vaccine trial. Across three cases, several key performance metrics are evaluated: overall power, type I error rate, average sample size, trial duration, …

Postprogression Therapy And Confounding For The Estimated Treatment Effect On Overall Survival In Phase Iii Oncology Trials, Alexander D Sherry, Pavlos Msaouel, Timothy A Lin, Joseph Abi Jaoude, Ramez Kouzy, Esther J Beck, Avital M Miller, Adina H Passy, Gabrielle S Kupferman, Eugene J Koay, Clifton David Fuller, Charles R Thomas, Zachary R Mccaw, Ethan B Ludmir

Faculty, Staff and Student Publications

Objective: Estimations of the treatment effect on overall survival (OS) may be influenced by post-progression therapies (PPTs). It is unclear how often OS analyses account for PPT effects. The purpose of this cross-sectional analysis was to determine the prevalence of OS analyses accounting for PPT effects in phase III oncology trials.

Methods and analysis: We screened two-arm, superiority design, phase III, randomised, oncology trials reporting OS from ClinicalTrials.gov. The primary outcome was the frequency of OS analyses adjusting for PPT confounding. Logistic regressions computed ORs for the association between trial-level covariates and the outcome.

Results: A total of 334 phase …

Dna Mismatch Repair Defect And Intratumor Heterogeneous Deficiency Differently Impact Immune Responses In Diffuse Large B-Cell Lymphoma, Zijun Y Xu-Monette, Cancan Luo, Li Yu, Yong Li, Govind Bhagat, Alexandar Tzankov, Carlo Visco, Xiangshan Fan, Karen Dybkaer, Ali Sakhdari, Nicholas T Wang, Alyssa F Yuan, April Chiu, Wayne Tam, Youli Zu, Eric D Hsi, Anamarija M Perry, Wenting Song, Dennis O'Malley, Qingyan Au, Harry Nunns, Heounjeong Go, Michael B Møller, Benjamin M Parsons, Santiago Montes-Moreno, Maurilio Ponzoni, Andrés J M Ferreri, Aliyah R Sohani, Jeremy S Abramson, Bing Xu, Ken H Young

Faculty, Staff and Students Publications

Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression …

The Next-Generation Dna Vaccine Platforms And Delivery Systems: Advances, Challenges And Prospects, Bowen Lu, Jing Ming Lim, Boyue Yu, Siyuan Song, Praveen Neeli, Navid Sobhani, Pavithra K, Srinivasa Reddy Bonam, Rajendra Kurapati, Junnian Zheng, Dafei Chai

Faculty, Staff and Students Publications

Vaccines have proven effective in the treatment and prevention of numerous diseases. However, traditional attenuated and inactivated vaccines suffer from certain drawbacks such as complex preparation, limited efficacy, potential risks and others. These limitations restrict their widespread use, especially in the face of an increasingly diverse range of diseases. With the ongoing advancements in genetic engineering vaccines, DNA vaccines have emerged as a highly promising approach in the treatment of both genetic diseases and acquired diseases. While several DNA vaccines have demonstrated substantial success in animal models of diseases, certain challenges need to be addressed before application in human subjects. …

A Comprehensive Analysis Of Neuroblastoma Incidence, Survival, And Racial And Ethnic Disparities From 2001 To 2019, Kevin Campbell, David A Siegel, Puja J Umaretiya, Shifan Dai, Andras Heczey, Philip J Lupo, Jeremy M Schraw, Trevor D Thompson, Michael E Scheurer, Jennifer H Foster

Faculty, Staff and Students Publications

BACKGROUND: We characterize the incidence and 5-year survival of children and adolescents with neuroblastoma stratified by demographic and clinical factors based on the comprehensive data from United States Cancer Statistics (USCS) and the National Program of Cancer Registries (NPCR).

METHODS: We analyzed the incidence of neuroblastoma from USCS (2003-2019) and survival data from NPCR (2001-2018) for patients less than 20 years old. Incidence trends were calculated by average annual percent change (AAPC) using joinpoint regression. Differences in relative survival were estimated comparing non-overlapping confidence intervals (CI).

RESULTS: We identified 11,543 primary neuroblastoma cases in USCS. Age-adjusted incidence was 8.3 per …

Prevalence Of Congenital Anomalies According To Maternal Race And Ethnicity, Texas, 1999–2018, Jeremy M Schraw, Elwin Jaime, Charles J Shumate, Mark A Canfield, Philip J Lupo

Faculty, Staff and Students Publications

BACKGROUND: Few studies of congenital anomalies provide prevalence estimates stratified by maternal race/ethnicity. We sought to determine whether the prevalence of a broad spectrum of anomalies varies among offspring of women from different race/ethnic groups.

METHODS: We obtained information on cases with anomalies from the population-based Texas Birth Defects Registry, and denominator data on livebirths among Texas residents during 1999-2018 from the Texas Center for Health Statistics. We estimated the prevalence ratio (PR) and 95% confidence interval (CI) of N = 145 anomalies among offspring of Hispanic and non-Hispanic Black relative to non-Hispanic White women using Poisson regression, adjusting for …

Artificial Intelligence-Powered Discovery Of Small Molecules Inhibiting Ctla-4 In Cancer, Navid Sobhani, Dana Rae Tardiel-Cyril, Dafei Chai, Daniele Generali, Jian-Rong Li, Jonathan Vazquez-Perez, Jing Ming Lim, Rachel Morris, Zaniqua N Bullock, Aram Davtyan, Chao Cheng, William K Decker, Yong Li

Faculty, Staff and Students Publications

BACKGROUND/OBJECTIVES: Checkpoint inhibitors, which generate durable responses in many cancer patients, have revolutionized cancer immunotherapy. However, their therapeutic efficacy is limited, and immune-related adverse events are severe, especially for monoclonal antibody treatment directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with the B7 proteins CD80 and CD86. Small molecules impairing the CTLA-4/CD80 interaction have been developed; however, they directly target CD80, not CTLA-4.

SUBJECTS/METHODS: In this study, we performed artificial intelligence (AI)-powered virtual screening of approximately ten million compounds to identify those targeting CTLA-4. We validated the …

Timigp: An R Package To Depict The Tumor Microenvironment From Bulk Transcriptomics, Chenyang Li, Jianjun Zhang, Chao Cheng

Faculty, Staff and Students Publications

Exploring the clinical relevance of diverse immune cell types within the tumor microenvironment is pivotal for unraveling cancer intricacies and developing treatments. Here, we present a protocol for using tumor immune microenvironment illustration based on gene pairs, an R package to deduce cell-cell interactions, unveiling the association between immune cell relative abundance and patient prognoses from bulk gene expression and survival data. We describe steps for harnessing cell-type markers derived from single-cell RNA sequencing data to map the tumor immune microenvironment across a spectrum of cancer types. For complete details on the use and execution of this protocol, please refer …

The Dna Glycosylase Neil2 Is Protective During Sars-Cov-2 Infection, Nisha Tapryal, Anirban Chakraborty, Kaushik Saha, Azharul Islam, Lang Pan, Koa Hosoki, Ibrahim M Sayed, Jason M Duran, Joshua Alcantara, Vanessa Castillo, Courtney Tindle, Altaf H Sarker, Maki Wakamiya, Victor J Cardenas, Gulshan Sharma, Laura E Crotty Alexander, Sanjiv Sur, Debashis Sahoo, Gourisankar Ghosh, Soumita Das, Pradipta Ghosh, Istvan Boldogh, Tapas K Hazra

Faculty, Staff and Students Publications

SARS-CoV-2 infection-induced aggravation of host innate immune response not only causes tissue damage and multiorgan failure in COVID-19 patients but also induces host genome damage and activates DNA damage response pathways. To test whether the compromised DNA repair capacity of individuals modulates the severity of COVID-19 infection, we analyze DNA repair gene expression in publicly available patient datasets and observe a lower level of the DNA glycosylase NEIL2 in the lungs of severely infected COVID-19 patients. This observation of lower NEIL2 levels is further validated in infected patients, hamsters and ACE2 receptor-expressing human A549 (A549-ACE2) cells. Furthermore, delivery of recombinant …

Chromosome 10q2432 Variants Associate With Brain Arterial Diameters In Diverse Populations: A Genome-Wide Association Study, Minghua Liu, Farid Khasiyev, Sanjeev Sariya, Antonio Spagnolo-Allende, Danurys L Sanchez, Howard Andrews, Qiong Yang, Alexa Beiser, Ye Qiao, Emy A Thomas, Jose Rafael Romero, Tatjana Rundek, Adam M Brickman, Jennifer J Manly, Mitchell Sv Elkind, Sudha Seshadri, Christopher Chen, Saima Hilal, Bruce A Wasserman, Giuseppe Tosto, Myriam Fornage, Jose Gutierrez

Faculty, Staff and Student Publications

Background: Brain arterial diameters (BADs) are novel imaging biomarkers of cerebrovascular disease, cognitive decline, and dementia. Traditional vascular risk factors have been associated with BADs, but whether there may be genetic determinants of BADs is unknown.

Methods and results: The authors studied 4150 participants from 6 geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). Brain arterial diameters for 13 segments were measured and averaged to obtain a global measure of BADs as well as the posterior and anterior circulations. A genome-wide association study revealed 14 variants at one locus associated with global BAD at genome-wide …

Quantitative Dual-Energy Computed Tomography With Cesium As A Novel Contrast Agent For Localization Of Thermochemical Ablation In Phantoms And Ex Vivo Models, Emily A Thompson, Megan C Jacobsen, David T Fuentes, Rick R Layman, Erik N K Cressman

Faculty, Staff and Student Publications

Background: Thermochemical ablation (TCA) is a minimally invasive therapy under development for hepatocellular carcinoma. TCA simultaneously delivers an acid (acetic acid, AcOH) and base (sodium hydroxide, NaOH) directly into the tumor, where the acid/base chemical reaction produces an exotherm that induces local ablation. However, AcOH and NaOH are not radiopaque, making monitoring TCA delivery difficult.

Purpose: We address the issue of image guidance for TCA by utilizing cesium hydroxide (CsOH) as a novel theranostic component of TCA that is detectable and quantifiable with dual-energy CT (DECT).

Materials and methods: To quantify the minimum concentration of CsOH that can be positively …

The Impact Of Covid-19 On Managing Ophthalmic Diseases: An International, Descriptive Study, Ethan Waisberg, Joshua Ong, Nasif Zaman, Sharif Amit Kamran, Alireza Tavakkoli, Andrew G Lee

Faculty, Staff and Student Publications

Background: Anecdotally, the COVID-19 pandemic has resulted in more severe cases of eye disease, decreased medication compliance/availability, and decreased treatment volume due to the lockdown.

Aims: We aim to quantify and bring together a variety of international perspectives from ophthalmologists of different subspecialties to characterize the global impact of COVID-19 on managing various ophthalmic disease.

Methods: An online survey of 10 questions was conducted among ophthalmologists using a specialized survey program.

Results: Fifty-two ophthalmologists were successfully contacted. Survey respondents include ophthalmologists from USA, Canada, Korea, Mexico, and New Zealand. Based on the results of our survey, 1 year after the …

Anaerobic Pathogens Associated With Osa May Contribute To Pathophysiology Via Amino-Acid Depletion, Michael Elgart, Ying Zhang, Yuan Zhang, Bing Yu, Youngmee Kim, Phyllis C Zee, Marc D Gellman, Eric Boerwinkle, Martha L Daviglus, Jianwen Cai, Susan Redline, Robert D Burk, Robert Kaplan, Tamar Sofer

Faculty, Staff and Student Publications

BACKGROUND: The human microbiome is linked to multiple metabolic disorders such as obesity and diabetes. Obstructive sleep apnoea (OSA) is a common sleep disorder with several metabolic risk factors. We investigated the associations between the gut microbiome composition and function, and measures of OSA severity in participants from a prospective community-based cohort study: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

METHODS: Bacterial-Wide Association Analysis (BWAS) of gut microbiome measured via metagenomics with OSA measures was performed adjusting for clinical, lifestyle and co-morbidities. This was followed by functional analysis of the OSA-enriched bacteria. We utilized additional metabolomic and transcriptomic associations …

Tumor-Infiltrating Normal B Cells Revealed By Immunoglobulin Repertoire Clonotype Analysis Are Highly Prognostic And Crucial For Antitumor Immune Responses In Dlbcl, Zijun Y Xu-Monette, Yong Li, Thomas Snyder, Tiantian Yu, Tingxun Lu, Alexandar Tzankov, Carlo Visco, Govind Bhagat, Wenbin Qian, Karen Dybkaer, April Chiu, Wayne Tam, Youli Zu, Eric D Hsi, Fredrick B Hagemeister, Yingjun Wang, Heounjeong Go, Maurilio Ponzoni, Andrés J M Ferreri, Michael B Møller, Benjamin M Parsons, Xiangshan Fan, J Han Van Krieken, Miguel A Piris, Jane N Winter, Qingyan Au, Ilan Kirsch, Mingzhi Zhang, John Shaughnessy, Bing Xu, Ken H Young

Faculty, Staff and Students Publications

PURPOSE: Tumor-infiltrating B lymphocytes (TIL-B) have demonstrated prognostic and predictive significance in solid cancers. In this study, we aimed to distinguish TIL-Bs from malignant B-cells in diffuse large B-cell lymphoma (DLBCL) and determine the clinical and biological significance.

EXPERIMENTAL DESIGN: A total of 269 patients with de novo DLBCL from the International DLBCL R-CHOP Consortium Program were studied. Ultra-deep sequencing of the immunoglobulin genes was performed to determine B-cell clonotypes. The frequencies and numbers of TIL-B clonotypes in individual repertoires were correlated with patient survival, gene expression profiling (GEP) data, and frequencies of DLBCL-infiltrating immune cells quantified by fluorescent multiplex …

Feasibility Of Pevonedistat Combined With Azacitidine, Fludarabine, Cytarabine In Pediatric Relapsed/Refractory Aml: Results From Cog Advl1712, Katherine Tarlock, Xiaowei Liu, Charles G Minard, Emasenyie A Isikwei, Joel M Reid, Terzah M Horton, Elizabeth Fox, Brenda J Weigel, Todd Cooper

Faculty, Staff and Students Publications

Background:

Outcomes for children with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are poor and new therapies are needed. Pevonedistat is an inhibitor of the NEDD-8 activating enzyme, a key regulator of the ubiquitin proteasome system that is responsible for protein turnover, with protein degradation regulating cell growth and survival.

Procedure:

We evaluated the feasibility, toxicity, and pharmacokinetics (PK) of pevonedistat (20 mg/m² days 1, 3, 5) in combination with azacitidine, fludarabine, cytarabine (aza-FLA) in children with R/R AML and MDS (NCT03813147). Twelve patients were enrolled, median age was 13 years (range 1-21). Median …

Mechanisms Of Ferroptosis And Targeted Therapeutic Approaches In Lymphoma, Tiantian Yu, Zijun Y Xu-Monette, Li Yu, Yong Li, Ken H Young

Faculty, Staff and Students Publications

Lymphoma is the sixth most common type of cancer worldwide. Under the current treatment standards, patients with lymphoma often fail to respond to treatment or relapse early and require further therapy. Hence, novel therapeutic strategies need to be explored and our understanding of the molecular underpinnings of lymphomas should be expanded. Ferroptosis, a non-apoptotic regulated cell death, is characterized by increased reactive oxygen species and lipid peroxidation due to metabolic dysfunction. Excessive or lack of ferroptosis has been implicated in tumor development. Current preclinical evidences suggest that ferroptosis participates in tumorigenesis, progression, and drug resistance of lymphoma, identifying a potential …

Circulating Metabolites May Illustrate Relationship Of Alcohol Consumption With Cardiovascular Disease, Yi Li, Mengyao Wang, Xue Liu, Jian Rong, Patricia Emogene Miller, Roby Joehanes, Tianxiao Huan, Xiuqing Guo, Jerome I Rotter, Jennifer A Smith, Bing Yu, Matthew Nayor, Daniel Levy, Chunyu Liu, Jiantao Ma

Faculty, Staff and Student Publications

BACKGROUND: Metabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD.

METHODS: Cumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine, and liquor on average of 19 years in 2428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women). We used linear mixed models to investigate the associations of alcohol consumption with 211 log-transformed plasma metabolites, adjusting for age, sex, batch, smoking, diet, …