Digital Commons Network^™

Myeloid Activation Clears Ascites And Reveals Il27-Dependent Regression Of Metastatic Ovarian Cancer, Brennah Murphy, Taito Miyamoto, Bryan S Manning, Gauri Mirji, Alessio Ugolini, Toshitha Kannan, Kohei Hamada, Yanfang P Zhu, Daniel T Claiborne, Lu Huang, Rugang Zhang, Yulia Nefedova, Andrew Kossenkov, Filippo Veglia, Rahul Shinde, Nan Zhang

Faculty, Staff and Student Publications

Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of < 30% due to the persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of β-glucan and IFNγ (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity. β-glucan alone cleared ascites and eliminated fluid tumor cells by inducing intraperitoneal clotting in the fluid and Dectin-1-Syk-dependent NETosis in the omentum. In omentum tumors, BI expanded a novel subset of immunostimulatory IL27+ macrophages and neutralizing IL27 impaired BI efficacy in vivo. Moreover, BI directly induced IL27 secretion in macrophages where single agent treatment did not. Finally, BI extended mouse survival in a chemoresistant model and significantly improved chemotherapy response in a chemo-sensitive model. In summary, we propose a new therapeutic strategy for the treatment of metastatic OvCa.

Rna Shielding Of P65 Is Required To Potentiate Oncogenic Inflammation In Tet2-Mutated Clonal Hematopoiesis, Nana Adjoa Ben-Crentsil, Wazim Mohammed Ismail, Maria E Balasis, Hannah Newman, Ariel Quintana, Moritz Binder, Traci Kruer, Surendra Neupane, Meghan C Ferrall-Fairbanks, Jenna Fernandez, Terra L Lasho, Christy M Finke, Mohammed L Ibrahim, Kathy L Mcgraw, Michael Wysota, Amy L Aldrich, Christopher B Ryder, Christopher T Letson, Joshua Traina, Amy F Mclemore, Nathalie Droin, Aditi Shastri, Seongseok Yun, Eric Solary, David A Sallman, Amer A Beg, Li Ma, Alexandre Gaspar-Maia, Mrinal M Patnaik, Eric Padron

Faculty, Staff and Student Publications

This work identifies MALAT1 as a requisite downstream effector of oncogenic feedforward inflammatory circuits necessary for the development of TET2-mutated CH and fulminant myeloid malignancy. We elucidate a novel mechanism by which MALAT1 "shields" p65 from dephosphorylation to potentiate this circuit and nominate MALAT1 inhibition as a future therapeutic strategy.

Individualized Functional Magnetic Resonance Imaging Neuromodulation Enhances Visuospatial Perception: A Proof-Of-Concept Study, Anthony Allam, Vincent Allam, Sandy Reddy, Eric M Rohren, Sameer A Sheth, Emmanouil Froudarakis, T Dorina Papageorgiou

Duncan NRI Faculty and Staff Publications

This proof-of-concept study uses individualized functional magnetic resonance imaging neuromodulation (iNM) to explore the mechanisms that enhance BOLD signals in visuospatial perception (VP) networks that are crucial for navigation. Healthy participants (n = 8) performed a VP up- and down-direction discrimination task at full and subthreshold coherence through peripheral vision, and superimposed direction through visual imagery (VI) at central space under iNM and control conditions. iNM targets individualized anatomical and functional middle- and medial-superior temporal (MST) networks that control VP. We found that iNM engaged selective exteroceptive and interoceptive attention (SEIA) and motor planning (MP) networks. Specifically, iNM increased …

The Study Of The Epidemiology Of Pediatric Hypertension Registry (Superhero): Rationale And Methods, Andrew M South, Victoria C Giammattei, Kiri W Bagley, Christine Y Bakhoum, William H Beasley, Morgan B Bily, Shupti Biswas, Aaron M Bridges, Rushelle L Byfield, Jessica Fallon Campbell, Rahul Chanchlani, Ashton Chen, Lucy D'Agostino Mcgowan, Stephen M Downs, Gina M Fergeson, Jason H Greenberg, Taylor A Hill-Horowitz, Elizabeth T Jensen, Mahmoud Kallash, Margret Kamel, Stefan G Kiessling, David M Kline, John R Laisure, Gang Liu, Jackson Londeree, Caroline B Lucas, Sai Sudha Mannemuddhu, Kuo-Rei Mao, Jason M Misurac, Margaret O Murphy, James T Nugent, Elizabeth A Onugha, Ashna Pudupakkam, Kathy M Redmond, Sandeep Riar, Christine B Sethna, Sahar Siddiqui, Ashley L Thumann, Stephen R Uss, Carol L Vincent, Irina V Viviano, Michael J Walsh, Blanche D White, Robert P Woroniecki, Michael Wu, Ikuyo Yamaguchi, Emily Yun, Donald J Weaver

Faculty, Staff and Students Publications

Despite increasing prevalence of hypertension in youth and high adult cardiovascular mortality rates, the long-term consequences of youth-onset hypertension remain unknown. This is due to limitations of prior research, such as small sample sizes, reliance on manual record review, and limited analytic methods, that did not address major biases. The Study of the Epidemiology of Pediatric Hypertension (SUPERHERO) is a multisite, retrospective registry of youth evaluated by subspecialists for hypertension disorders. Sites obtain harmonized electronic health record data using standardized biomedical informatics scripts validated with randomized manual record review. Inclusion criteria are index visit for International Classification of Diseases, 10th …

Urinary Metal Levels, Cognitive Test Performance, And Dementia In The Multi-Ethnic Study Of Atherosclerosis, Arce Domingo-Relloso, Katlyn E Mcgraw, Susan R Heckbert, Jose A Luchsinger, Kathrin Schilling, Ronald A Glabonjat, Irene Martinez-Morata, Melanie Mayer, Yongmei Liu, Alexis C Wood, Jeff Goldsmith, Kathleen M Hayden, Mohamad Habes, Ilya M Nasrallah, R Nick Bryan, Tanweer Rashid, Wendy S Post, Jerome I Rotter, Priya Palta, Linda Valeri, Timothy M Hughes, Ana Navas-Acien

Faculty, Staff and Students Publications

IMPORTANCE: Metals are established neurotoxicants, but evidence of their association with cognitive performance at low chronic exposure levels is limited.

OBJECTIVE: To investigate the association of urinary metal levels, individually and as a mixture, with cognitive tests and dementia diagnosis, including effect modification by apolipoprotein ε4 allele (APOE4).

DESIGN, SETTING, AND PARTICIPANTS: The multicenter prospective cohort Multi-Ethnic Study of Atherosclerosis (MESA) was started from July 2000 to August 2002, with follow-up through 2018. A total of 6303 MESA participants were included. Data analysis was performed from October 12, 2023, to June 13, 2024.

EXPOSURE: Urine samples were collected at baseline …

Neurofeedback: New Territories And Neurocognitive Mechanisms Of Endogenous Neuromodulation, James Sulzer, T Dorina Papageorgiou, Rainer Goebel, Talma Hendler

Faculty, Staff and Students Publications

Neurofeedback (NF) is endogenous neuromodulation of circumscribed brain circuitry. While its use of real-time brain activity in a closed-loop system is similar to brain-computer interfaces, instead of controlling an external device like the latter, the goal of NF is to change a targeted brain function. In this special issue on NF, we present current and future methods for extracting and manipulating neural function, how these methods may reveal new insights about brain function, applications, and rarely discussed ethical considerations of guiding and interpreting the brain activity of others. Together, the articles in this issue outline the possibilities of NF use …

Vps13b Is Localized At The Interface Between Golgi Cisternae And Is A Functional Partner Of Fam177a1, Berrak Ugur, Florian Schueder, Jimann Shin, Michael G Hanna, Yumei Wu, Marianna Leonzino, Maohan Su, Anthony R Mcadow, Catherine Wilson, John Postlethwait, Lilianna Solnica-Krezel, Joerg Bewersdorf, Pietro De Camilli

2020-Current year OA Pubs

Mutations in VPS13B, a member of a protein family implicated in bulk lipid transport between adjacent membranes, cause Cohen syndrome. VPS13B is known to be concentrated in the Golgi complex, but its precise location within this organelle and thus the site(s) where it achieves lipid transport remains unclear. Here, we show that VPS13B is localized at the interface between proximal and distal Golgi subcompartments and that Golgi complex reformation after Brefeldin A (BFA)-induced disruption is delayed in VPS13B KO cells. This delay is phenocopied by the loss of FAM177A1, a Golgi complex protein of unknown function reported to be a …

Heterozygous Btnl8 Variants In Individuals With Multisystem Inflammatory Syndrome In Children (Mis-C), Evangelos Bellos, Erica G Schmitt, Et Al.

2020-Current year OA Pubs

Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, "burdenMC," which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5-5.3, P < 10-6). BTNL8 encodes an intestinal epithelial regulator of Vγ4+γδ T cells implicated in regulating gut homeostasis. Enrichment was exclusive to MIS-C, being absent in patients with COVID-19 or bacterial disease. Using an available functional test for BTNL8, rare variants from a larger cohort of MIS-C patients (n = 835) were tested which identified eight variants in 18 patients (2.2%) with impaired engagement of Vγ4+γδ T cells. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status. These findings were associated with altered intestinal permeability, suggesting a possible link between disrupted gut homeostasis and MIS-C-associated enteropathy triggered by SARS-CoV-2.

Neuroanatomical Variability And Substance Use Initiation In Late Childhood And Early Adolescence, Alex P Miller, David A A Baranger, Sarah E Paul, Hugh Garavan, Scott Mackey, Susan F Tapert, Kimberly H Leblanc, Arpana Agrawal, Ryan Bogdan

2020-Current year OA Pubs

IMPORTANCE: The extent to which neuroanatomical variability associated with early substance involvement, which is associated with subsequent risk for substance use disorder development, reflects preexisting risk and/or consequences of substance exposure remains poorly understood.

OBJECTIVE: To examine neuroanatomical features associated with early substance use initiation and to what extent associations may reflect preexisting vulnerability.

DESIGN, SETTING, AND PARTICIPANTS: Cohort study using data from baseline through 3-year follow-up assessments of the ongoing longitudinal Adolescent Brain Cognitive Development Study. Children aged 9 to 11 years at baseline were recruited from 22 sites across the US between June 1, 2016, and October 15, …

Major Depressive Disorder And Driving Behavior Among Older Adults, Ganesh M Babulal, Ling Chen, Jean-Francois Trani, David C Brown, David B Carr, Beau M Ances, Eric J Lenze, Drives Project

2020-Current year OA Pubs

IMPORTANCE: Depression and antidepressant use are independently associated with crash risk among older drivers. However, it is unclear what factors impact daily driving that increase safety risk for drivers with depression.

OBJECTIVE: To examine differences in naturalistic driving behavior and safety between older adults with and without major depressive disorder (MDD).

DESIGN, SETTING, AND PARTICIPANTS: A prospective longitudinal cohort study was conducted among older adults (≥65 years) from the Driving Real-World In-Vehicle Evaluation System Project collected from July 1, 2021, to December 30, 2023. The sample included 85 participants with MDD and 310 participants without. Neurological, clinical, mood, and neuropsychological …

A Framework For Sharing Of Clinical And Genetic Data For Precision Medicine Applications., Ahmed Elhussein, Ulugbek Baymuradov, Nygc Als Consortium, Noémie Elhadad, Karthik Natarajan, Gamze Gürsoy

Faculty Research 2024

Precision medicine has the potential to provide more accurate diagnosis, appropriate treatment and timely prevention strategies by considering patients' biological makeup. However, this cannot be realized without integrating clinical and omics data in a data-sharing framework that achieves large sample sizes. Systems that integrate clinical and genetic data from multiple sources are scarce due to their distinct data types, interoperability, security and data ownership issues. Here we present a secure framework that allows immutable storage, querying and analysis of clinical and genetic data using blockchain technology. Our platform allows clinical and genetic data to be harmonized by combining them under …

Investigating Impacts Of The Mycothiazole Chemotype As A Chemical Probe For The Study Of Mitochondrial Function And Aging., Naibedya Dutta, Joe A Gerke, Sofia F. Odron, Joseph D. Morris, Adam Hruby, Juri Kim, Toni Castro Torres, Sarah J. Shemtov, Jacqueline G. Clarke, Michelle C. Chang, Hooriya Shaghasi, Marissa N. Ray, Maxim Averbukh, Sally Hoang, Maria Oorloff, Athena Alcala, Matthew Vega, Hemal H Mehta, Max A Thorwald, Phillip Crews, Marc Vermulst, Gilberto Garcia, Tyler A. Johnson, Ryo Higuchi-Sanabria

Natural Sciences and Mathematics | Faculty Scholarship

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine sponge C. mycofijiensis and its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), MTZ, a newly employed ETC complex I inhibitor, exhibited higher cytotoxicity against cancer cell lines compared to certain non-cancer cell lines. Interestingly, 8-OAc demonstrated greater selectivity for cancer cells …

A Graph Theoretical Approach To Experimental Prioritization In Genome-Scale Investigations., Stephen K Grady, Kevin A Peterson, Stephen A Murray, Erich J Baker, Michael A Langston, Elissa J Chesler

Faculty Research 2024

The goal of systems biology is to gain a network level understanding of how gene interactions influence biological states, and ultimately inform upon human disease. Given the scale and scope of systems biology studies, resource constraints often limit researchers when validating genome-wide phenomena and potentially lead to an incomplete understanding of the underlying mechanisms. Further, prioritization strategies are often biased towards known entities (e.g. previously studied genes/proteins with commercially available reagents), and other technical issues that limit experimental breadth. Here, heterogeneous biological information is modeled as an association graph to which a high-performance minimum dominating set solver is applied to …

Citation Bias, Diversity, And Ethics, Keisha S Ray, Perry Zurn, Jordan D Dworkin, Dani S Bassett, David B Resnik

Faculty and Staff Publications

How often a researcher is cited usually plays a decisive role in that person's career advancement, because academic institutions often use citation metrics, either explicitly or implicitly, to estimate research impact and productivity. Research has shown, however, that citation patterns and practices are affected by various biases, including the prestige of the authors being cited and their gender, race, and nationality, whether self-attested or perceived. Some commentators have proposed that researchers can address biases related to social identity or position by including a Citation Diversity Statement in a manuscript submitted for publication. A Citation Diversity Statement is a paragraph placed …

The Primate Gut Microbiota Contributes To Interspecific Differences In Host Metabolism., Elizabeth K Mallott, Sahana Kuthyar, Won Lee, Derek Reiman, Hongmei Jiang, Sriram Chitta, E Alexandria Waters, Brian T Layden, Ronen Sumagin, Laura D Manzanares, Guan-Yu Yang, Maria Luisa Savo Sardaro, Stanton Gray, Lawrence E Williams, Yang Dai, James P Curley, Chad R Haney, Emma R Liechty, Christopher W Kuzawa, Katherine R Amato

Faculty Research 2024

Because large brains are energetically expensive, they are associated with metabolic traits that facilitate energy availability across vertebrates. However, the biological underpinnings driving these traits are not known. Given its role in regulating host metabolism in disease studies, we hypothesized that the gut microbiome contributes to variation in normal cross-vertebrate species differences in metabolism, including those associated with the brain's energetic requirements. By inoculating germ-free mice with the gut microbiota (GM) of three primate species - two with relatively larger brains and one with a smaller brain - we demonstrated that the GM of larger-brained primates shifts host metabolism towards …

Lessons Learned From 20 Years Of Preclinical Testing In Pediatric Cancers., Malcolm A Smith, Peter J Houghton, Richard B Lock, John M Maris, Richard Gorlick, Raushan T Kurmasheva, Xiao-Nan Li, Beverly A Teicher, Jeffrey Chuang, Filemon S Dela Cruz, Michael A Dyer, Andrew L Kung, Michael W Lloyd, Yael P Mossé, Timothy M Stearns, Elizabeth A Stewart, Carol J Bult, Stephen W Erickson

Faculty Research 2024

Programs for preclinical testing of targeted cancer agents in murine models of childhood cancers have been supported by the National Cancer Institute (NCI) since 2004. These programs were established to work collaboratively with industry partners to address the paucity of targeted agents for pediatric cancers compared with the large number of agents developed and approved for malignancies primarily affecting adults. The distinctive biology of pediatric cancers and the relatively small numbers of pediatric cancer patients are major challenges for pediatric oncology drug development. These factors are exacerbated by the division of cancers into multiple subtypes that are further sub-classified by …

Biomechanics And Clinical Implications Of Fontan Upsizing, Vijay Govindarajan, Akshita Sahni, Emily Eickhoff, Peter Hammer, David M Hoganson, Rahul H Rathod, Pedro J Del Nido

Faculty, Staff and Student Publications

Background: The Fontan operation, a palliative procedure for single ventricle patients, has evolved to improve outcomes and reduce complications. While extracardiac conduit (ECC) is favored for its simplicity and potential hemodynamic benefits, concerns arise about conduit size adequacy over time. Undersized ECC conduits may cause hemodynamic inefficiencies and long-term complications, while oversizing can lead to flow disturbances, stagnation, and thrombosis, necessitating surgical revision or upsizing to optimize hemodynamics.

Objectives: The study aimed to predict the impact of upsizing by developing a patient-specific workflow using cardiac magnetic resonance-based imaging and computational fluid dynamics to assess Fontan hemodynamic changes and determine the …

Dysfunctional Alpha Modulation As A Mechanism Of Working Memory Impairment In Serious Mental Illness, Molly A Erickson, Megan A Boudewyn, Kurt Winsler, Charlotte Li, Deanna M Barch, Cameron S Carter, Michael J Frank, James M Gold, Angus W Macdonald 3rd, John D Ragland, Steven M Silverstein, Andrew Yonelinas, Steven J Luck

2020-Current year OA Pubs

BACKGROUND: People with psychosis and mood disorders experience disruptions in working memory; however, the underlying mechanism remains unknown. We focused on 2 potential mechanisms: poor attentional engagement should be associated with elevated levels of prestimulus alpha-band activity within the electroencephalogram (EEG), whereas impaired working memory encoding should be associated with reduced poststimulus alpha suppression.

METHODS: We collected EEG data from 68 people with schizophrenia, 43 people with bipolar disorder with a history of psychosis, 53 people with major depressive disorder, and 90 healthy comparison subjects while they completed a spatial working memory task. We quantified attention lapsing, memory precision, and …

Targeting The Glutamine-Arginine-Proline Metabolism Axis In Cancer, Di Wang, Jiang-Jie Duan, Yu-Feng Guo, Jun-Jie Chen, Tian-Qing Chen, Jun Wang, Shi-Cang Yu

Faculty, Staff and Student Publications

Metabolic abnormalities are an important feature of tumours. The glutamine-arginine-proline axis is an important node of cancer metabolism and plays a major role in amino acid metabolism. This axis also acts as a scaffold for the synthesis of other nonessential amino acids and essential metabolites. In this paper, we briefly review (1) the glutamine addiction exhibited by tumour cells with accelerated glutamine transport and metabolism; (2) the methods regulating extracellular glutamine entry, intracellular glutamine synthesis and the fate of intracellular glutamine; (3) the glutamine, proline and arginine metabolic pathways and their interaction; and (4) the research progress in tumour therapy …

Biological Validation Of Peak-Width Of Skeletonized Mean Diffusivity As A Vcid Biomarker: The Markvcid Consortium, Alison M Luckey, Saptaparni Ghosh, Chen-Pin Wang, Alexa Beiser, Rebecca Bernal, Zhiguang Li, Djass Mbangdadji, Elyas Fadaee, Haykel Snoussi, Angel Gabriel Velarde Dediós, Hector A Trevino, Monica Goss, Laura J Hillmer, Christopher E Bauer, Adam M Staffaroni, Lara Stables, Marilyn Albert, Jayandra J Himali, Thomas H Mosley, Lars Forsberg, Vilmundur Guðnason, Baljeet Singh, Herpreet Singh, Kristin Schwab, Joel H Kramer, Gary A Rosenberg, Karl G Helmer, Steven M Greenberg, Mohamad Habes, Danny J J Wang, Brian T Gold, Hanzhang Lu, Arvind Caprihan, Myriam Fornage, Lenore J Launer, Konstantinos Arfanakis, Sudha Seshadri, Charles Decarli, Pauline Maillard, Claudia L Satizabal

Faculty, Staff and Student Publications

BACKGROUND: Peak-width of skeletonized mean diffusivity (PSMD), a neuroimaging marker of cerebral small vessel disease (SVD), has shown excellent instrumental properties. Here, we extend our work to perform a biological validation of PSMD.

METHODS: We included 396 participants from the Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia (MarkVCID-1) Consortium and three replication samples (Cohorts for Heart and Aging Research in Genomic Epidemiology = 6172, Rush University Medical Center = 287, University of California Davis Alzheimer's Disease Research Center = 567). PSMD was derived from diffusion tensor imaging using an automated algorithm. We related PSMD to a composite measure …

Nuclear Expression Of Dynamin 2 Is Associated With Tumor Aggressiveness In Bladder Cancer Patients: A Bioinformatics And Experimental Approach, Mahdieh Razmi, Leili Saeednejad Zanjani, Mandana Rahimi, Roya Sajed, Sadegh Safaei, Zahra Madjd, Roya Ghods

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Dynamin 2 (DNM2) is aberrantly expressed in different malignancies and exerts a function in tumor progression.

AIMS: This study, for the first time, aimed to evaluate the clinical and prognostic value of DNM2 in the pathophysiology of bladder cancer using bioinformatics analysis and experimental evaluation.

METHODS AND RESULTS: We analyzed gene expression of DNM2 in bladder tumor by GEPIA2 and GENT2 platforms. Cluster subnetworks were recognized from the protein-protein interaction (PPI) network using the MCODE plugin to screen the key genes. Subsequently, the pathway enrichment analysis was evaluated. Then, the immunohistochemical examination was conducted on 209 paraffin-embedded bladder cancer …

Are Prediction Models Moving Closer To Clinical Application In The Diagnosis Of Type Of Diabetes In Youth?, Fida Bacha

Children’s Nutrition Research Center Staff Publications

No abstract provided.

Genetic Architecture Of Cerebrospinal Fluid And Brain Metabolite Levels And The Genetic Colocalization Of Metabolites With Human Traits, Ciyang Wang, Chengran Yang, Daniel Western, Muhammad Ali, Yueyao Wang, Chia-Ling Phuah, John Budde, Lihua Wang, Priyanka Gorijala, Jigyasha Timsina, Agustin Ruiz, Pau Pastor, Maria Victoria Fernandez, Dominantly Inherited Alzheimer Network (Dian), Alzheimer’S Disease Neuroimaging Initiative (Adni), Daniel J Panyard, Corinne D Engelman, Yuetiva Deming, Merce Boada, Amanda Cano, Pablo Garcia-Gonzalez, Neill R Graff-Radford, Hiroshi Mori, Jae-Hong Lee, Richard J Perrin, Laura Ibanez, Yun Ju Sung, Carlos Cruchaga

Faculty, Staff and Student Publications

Brain metabolism perturbation can contribute to traits and diseases. We conducted a genome-wide association study for cerebrospinal fluid (CSF) and brain metabolite levels, identifying 205 independent associations (47.3% new signals, containing 11 new loci) for 139 CSF metabolites, and 32 independent associations (43.8% new signals, containing 4 new loci) for 31 brain metabolites. Of these, 96.9% (CSF) and 71.4% (brain) of the new signals belonged to previously analyzed metabolites in blood or urine. We integrated the metabolite quantitative trait loci (MQTLs) with 23 neurological, psychiatric and common human traits and diseases through colocalization to identify metabolites and biological processes implicated …

Off-Protocol Radiation Therapy In Phase 3 Metastatic Solid Tumor Trials, Alexander D Sherry, Timothy A Lin, Zachary R Mccaw, Esther J Beck, Ramez Kouzy, Joseph Abi Jaoude, Adina H Passy, Avital M Miller, Gabrielle S Kupferman, Clifton David Fuller, Charles R Thomas, Eugene J Koay, Chad Tang, Pavlos Msaouel, Ethan B Ludmir

Faculty, Staff and Student Publications

Purpose: Increasing data suggest that radiation therapy, particularly ablative radiation therapy, alters the natural history of metastatic disease. For patients with metastatic disease enrolled in prospective trials testing systemic therapy, the use of off-protocol radiation therapy to improve clinical symptoms or extend the duration of study systemic therapy may influence study endpoints. We sought to evaluate how often off-protocol radiation therapy was permitted among systemic therapy phase 3 trials, how often off-protocol radiation therapy is used, and whether off-protocol radiation therapy correlated with study outcomes.

Methods and materials: Two-arm, superiority-design, phase 3 randomized trials testing systemic therapy were screened from …

Prediagnostic Amino Acid Metabolites And Risk Of Gout, Accounting For Serum Urate: Prospective Cohort Study And Mendelian Randomization, Natalie Mccormick, Amit D Joshi, Chio Yokose, Bing Yu, Adrienne Tin, Robert Terkeltaub, Tony R Merriman, Oana Zeleznik, A Heather Eliassen, Gary C Curhan, Hang-Korng Ea, Matthew Nayor, Laura M Raffield, Hyon K Choi

Faculty, Staff and Student Publications

Objective: Our objective was to prospectively investigate prediagnostic population-based metabolome for risk of hospitalized gout (ie, most accurate, severe, and costly cases), accounting for serum urate.

Methods: We conducted prediagnostic metabolome-wide analyses among 249,677 UK Biobank participants with nuclear magnetic resonance metabolomic profiling (N = 168 metabolites, including eight amino acids) from baseline blood samples (2006-2010) without a history of gout. We calculated multivariable hazard ratios (HRs) for hospitalized incident gout, before and after adjusting for serum urate levels; we included patients with nonhospitalized incident gout in a sensitivity analysis. Potential causal effects were evaluated with two-sample Mendelian randomization.

Results: …

Economic Disadvantage During Childhood, Obesity, And Diabetes Across Three Birth Cohorts Of Older Mexicans, Jesús-Daniel Zazueta-Borboa, Rafael Samper-Ternent, Rebeca Wong, Neil Mehta

Faculty, Staff and Student Publications

OBJECTIVES: Diabetes prevalence has increased markedly in Mexico. We examined the individual and joint contributions of economic disadvantage during childhood (EDDC) and elevated body weight on diabetes prevalence in 3 cohorts of Mexican adults.

METHODS: Data on those 60-69 years old from the 1930-1939, 1940-1949, and 1950-1959 birth cohorts in Waves 1 (2001), 3 (2012), and 5 (2018) of the Mexican Health and Aging Study were used. EDDC was defined as the absence of a toilet in the household before age 10. Body mass status was defined using self-reported perceived body image at age 50. Diabetes was based on respondent …

Prevalence, Diagnostic Features, And Medical Outcomes Of Females With Turner Syndrome With A Trisomy X Cell Line (45, X/47, Xxx): Results From The Insights Registry, Natalia Klamut, Samantha Bothwell, Alexandra E Carl, Vaneeta Bamba, Jennifer R Law, Wendy J Brickman, Karen O Klein, Roopa Kanakatti Shankar, Catherina T Pinnaro, Patricia Y Fechner, Siddharth K Prakash, Iris Gutmark-Little, Susan Howell, Nicole Tartaglia, Marybel Good, Kelly C Ranallo, Shanlee M Davis

Faculty, Staff and Student Publications

Turner syndrome (TS) is defined by partial or complete absence of a sex chromosome. Little is known about the phenotype of individuals with TS mosaic with trisomy X (45,X/47,XXX or 45,X/46,XX/47,XXX) (~3% of TS). We compared the diagnostic, perinatal, medical, and neurodevelopmental comorbidities of mosaic 45,X/47,XXX (n = 35, 9.4%) with nonmosaic 45,X (n = 142) and mosaic 45,X/46,XX (n = 66). Females with 45,X/47,XXX had fewer neonatal concerns and lower prevalence of several TS-related diagnoses compared with 45,X; however the prevalence of neurodevelopmental and psychiatric diagnoses were not different. Compared to females with 45,X/46,XX, the 45,X/47,XXX group was significantly …

Covid-19 Risk Assessment Among Vulnerable Small Business Owners In El Paso County, Texas, Sadie H Conway, Denise Vasquez, Kristina D Mena, Louis D Brown, Soyoung Kwon, Janelle Rios

Faculty, Staff and Student Publications

Background: Our objective was to deliver actionable, worksite-specific COVID-19 risk assessments and mitigation strategies tailored to vulnerable workers in one of the highest-risk areas in the US.

Methods: Four trained, bilingual (English/Spanish) community health workers (CHWs) recruited small businesses (ie, ≤20 employees) across various industries and executed novel on-site infectious disease risk assessment surveys of at least one employer and one employee.

Results: Of 102 participating businesses (95% Hispanic-owned), 96% were characterized as "high risk" or "very high risk" for disease transmission. All businesses reported implementing at least one practice to reduce disease transmission; however, almost half of businesses lacked …

Bivariate Genome-Wide Association Study Of Circulating Fibrinogen And C-Reactive Protein Levels, Julie Hahn, Gerard Temprano-Sagrera, Natalie R Hasbani, Symen Ligthart, Abbas Dehghan, Alisa S Wolberg, Nicholas L Smith, Maria Sabater-Lleal, Alanna C Morrison, Paul S De Vries

Faculty, Staff and Student Publications

Background: Fibrinogen and C-reactive protein (CRP) play an important role in inflammatory pathways and share multiple genetic loci reported in previously published genome-wide association studies (GWAS), highlighting their common genetic background. Leveraging the shared biology may identify further loci pleiotropically associated with both fibrinogen and CRP.

Objectives: To identify novel genetic variants that are pleiotropic and associated with both fibrinogen and CRP, by integrating both phenotypes in a bivariate GWAS by using a multitrait GWAS.

Methods: We performed a bivariate GWAS to identify further pleiotropic genetic loci, using summary statistics of previously published GWAS on fibrinogen (n = 120 246) …

Identification Of Proteins Associated With Type 2 Diabetes Risk In Diverse Racial And Ethnic Populations, Shuai Liu, Jingjing Zhu, Hua Zhong, Chong Wu, Haoran Xue, Burcu F Darst, Xiuqing Guo, Peter Durda, Russell P Tracy, Yongmei Liu, W Craig Johnson, Kent D Taylor, Ani W Manichaikul, Mark O Goodarzi, Robert E Gerszten, Clary B Clish, Yii-Der Ida Chen, Heather Highland, Christopher A Haiman, Christopher R Gignoux, Leslie Lange, David V Conti, Laura M Raffield, Lynne Wilkens, Loïc Le Marchand, Kari E North, Kristin L Young, Ruth J Loos, Steve Buyske, Tara Matise, Ulrike Peters, Charles Kooperberg, Alexander P Reiner, Bing Yu, Eric Boerwinkle, Quan Sun, Mary R Rooney, Justin B Echouffo-Tcheugui, Martha L Daviglus, Qibin Qi, Nicholas Mancuso, Changwei Li, Youping Deng, Alisa Manning, James B Meigs, Stephen S Rich, Jerome I Rotter, Lang Wu

Faculty, Staff and Student Publications

Aims/hypothesis: Several studies have reported associations between specific proteins and type 2 diabetes risk in European populations. To better understand the role played by proteins in type 2 diabetes aetiology across diverse populations, we conducted a large proteome-wide association study using genetic instruments across four racial and ethnic groups: African; Asian; Hispanic/Latino; and European.

Methods: Genome and plasma proteome data from the Multi-Ethnic Study of Atherosclerosis (MESA) study involving 182 African, 69 Asian, 284 Hispanic/Latino and 409 European individuals residing in the USA were used to establish protein prediction models by using potentially associated cis- and trans-SNPs. The models were …