Digital Commons Network^™

Comparison Of Five Supervised Feature Selection Algorithms Leading To Top Features And Gene Signatures From Multi-Omics Data In Cancer, Tapas Bhadra, Saurav Mallik, Neaj Hasan, Zhongming Zhao

Faculty, Staff and Student Publications

BACKGROUND: As many complex omics data have been generated during the last two decades, dimensionality reduction problem has been a challenging issue in better mining such data. The omics data typically consists of many features. Accordingly, many feature selection algorithms have been developed. The performance of those feature selection methods often varies by specific data, making the discovery and interpretation of results challenging.

METHODS AND RESULTS: In this study, we performed a comprehensive comparative study of five widely used supervised feature selection methods (mRMR, INMIFS, DFS, SVM-RFE-CBR and VWMRmR) for multi-omics datasets. Specifically, we used five representative datasets: gene expression …

Markers Of Kidney Function, Genetic Variation Related To Cognitive Function, And Cognitive Performance In The Uk Biobank, Erin L Richard, Linda K Mcevoy, Ian J Deary, Gail Davies, Steven Y Cao, Eyal Oren, John E Alcaraz, Andrea Z Lacroix, Jan Bressler, Rany M Salem

Faculty, Staff and Student Publications

BACKGROUND: Chronic kidney disease has been linked to worse cognition. However, this association may be dependent on the marker of kidney function used, and studies assessing modification by genetics are lacking. This study examined associations between multiple measures of kidney function and assessed effect modification by a polygenic score for general cognitive function.

METHODS: In this cross-sectional study of up to 341,208 European ancestry participants from the UK Biobank study, we examined associations between albuminuria and estimated glomerular filtration rate based on creatinine (eGFRcre) or cystatin C (eGFRcys) with cognitive performance on tests of verbal-numeric reasoning, reaction time and visual …

Accessory Genomes Drive Independent Spread Of Carbapenem-Resistant Klebsiella Pneumoniae Clonal Groups 258 And 307 In Houston, Tx, William C Shropshire, An Q Dinh, Michelle Earley, Lauren Komarow, Diana Panesso, Kirsten Rydell, Sara I Gómez-Villegas, Hongyu Miao, Carol Hill, Liang Chen, Robin Patel, Bettina C Fries, Lilian Abbo, Eric Cober, Sara Revolinski, Courtney L Luterbach, Henry Chambers, Vance G Fowler, Robert A Bonomo, Samuel A Shelburne, Barry N Kreiswirth, David Van Duin, Blake M Hanson, Cesar A Arias

Faculty, Staff and Student Publications

Carbapenem-resistant Klebsiella pneumoniae (CRKp) is an urgent public health threat. Worldwide dissemination of CRKp has been largely attributed to clonal group (CG) 258. However, recent evidence indicates the global emergence of a CRKp CG307 lineage. Houston, TX, is the first large city in the United States with detected cocirculation of both CRKp CG307 and CG258. We sought to characterize the genomic and clinical factors contributing to the parallel endemic spread of CG258 and CG307. CRKp isolates were collected as part of the prospective, Consortium on Resistance against Carbapenems in Klebsiella and other Enterobacterales 2 …

Barriers And Motivations To Provide Dental Care To Adult Patients With Movement Disorders, Natalia S Rozas, Hillary D Strassner, June M Sadowsky, Cameron B Jeter

Faculty, Staff and Student Publications

Patients with movement disorders, like Parkinson's and Huntington's diseases, tend to have poor oral health. Although contributing factors have been proposed, the willingness and ability of dentists to treat this patient population are still unknown. Our objective is to understand the current barriers and motivations of dentists to treat this patient population as a path to improved care and quality of life. A total of 176 dentists in Texas were surveyed through a structured questionnaire which contained both closed and open-ended questions. Nearly 30% of participants reported having no barriers to treating these patients and 26.7% reported that no such …

Meal Timing, Meal Frequency And Metabolic Syndrome, Fatema Alkhulaifi, Charles Darkoh

Faculty, Staff and Student Publications

Individuals with metabolic syndrome have increased risk for developing health conditions, including cardiovascular diseases and stroke. Modifiable risk factors, such as exercise and diet, are key components in the prevention and control of metabolic syndrome. Specifically, dietary patterns and habits are extremely successful in controlling more than one of the metabolic syndrome risk factors. Meal timing and frequency have been associated with type 2 diabetes, cardiovascular diseases, and other chronic conditions. However, there is limited evidence linking metabolic syndrome to meal timing and meal frequency. This review summarizes and discusses how meal timing and frequency impact metabolic outcomes in adults.

Venetoclax Combinations Delay The Time To Deterioration Of Hrqol In Unfit Patients With Acute Myeloid Leukemia, Keith W Pratz, Panayiotis Panayiotidis, Christian Recher, Xudong Wei, Brian A Jonas, Pau Montesinos, Vladimir Ivanov, Andre C Schuh, Courtney D Dinardo, Jan Novak, Vlatko Pejsa, Don Stevens, Su-Peng Yeh, Inho Kim, Mehmet Turgut, Nicola Fracchiolla, Kazuhito Yamamoto, Yishai Ofran, Andrew H Wei, Cat N Bui, Katy Benjamin, Rajesh Kamalakar, Jalaja Potluri, Wellington Mendes, Jacob Devine, Walter Fiedler

Faculty, Staff and Student Publications

Phase 3 trials Viale-A and Viale-C evaluated health-related quality of life (HRQoL) in patients with AML unfit for intensive chemotherapy who received venetoclax (VEN) + (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C) or placebo (PBO) + AZA or LDAC. Patient-reported outcomes included: EORTC QLQ-C30 global health status (GHS/QoL) and physical functioning (PF), PROMIS Cancer Fatigue Short Form 7a (Fatigue), and EQ-5D-5L health status visual analog scale (HS-VAS). Time to deterioration (TTD), defined as worsening from baseline in meaningful change thresholds (MCT) of ≥10, 5, or 7 points for GHS/QoL or PF, fatigue, and HS-VAS, respectively, was assessed; differences between groups …

Ror Activation By Nobiletin Enhances Antitumor Efficacy Via Suppression Of Iκb/Nf-Κb Signaling In Triple-Negative Breast Cancer, Eunju Kim, Yoon-Jin Kim, Zhiwei Ji, Jin Muk Kang, Marvin Wirianto, Keshav Raj Paudel, Joshua A Smith, Kaori Ono, Jin-Ah Kim, Kristin Eckel-Mahan, Xiaobo Zhou, Hyun Kyoung Lee, Ji Young Yoo, Seung-Hee Yoo, Zheng Chen

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by poor response to standard therapies and therefore unfavorable clinical outcomes. Better understanding of TNBC and new therapeutic strategies are urgently needed. ROR nuclear receptors are multifunctional transcription factors with important roles in circadian pathways and other processes including immunity and tumorigenesis. Nobiletin (NOB) is a natural compound known to display anticancer effects, and our previous studies showed that NOB activates RORs to enhance circadian rhythms and promote physiological fitness in mice. Here, we identified several TNBC cell lines being sensitive to NOB, by itself or in combination. Cell and xenograft …

Time Dependent Analysis Of Rat Microglial Surface Markers In Traumatic Brain Injury Reveals Dynamics Of Distinct Cell Subpopulations, Assaf Gottlieb, Naama Toledano-Furman, Karthik S Prabhakara, Akshita Kumar, Henry W Caplan, Supinder Bedi, Charles S Cox, Scott D Olson

Faculty, Staff and Student Publications

Traumatic brain injury (TBI) results in a cascade of cellular responses, which produce neuroinflammation, partly due to the activation of microglia. Accurate identification of microglial populations is key to understanding therapeutic approaches that modify microglial responses to TBI and improve long-term outcome measures. Notably, previous studies often utilized an outdated convention to describe microglial phenotypes. We conducted a temporal analysis of the response to controlled cortical impact (CCI) in rat microglia between ipsilateral and contralateral hemispheres across seven time points, identified microglia through expression of activation markers including CD45, CD11b/c, and p2y12 receptor and evaluated their activation state using additional …

Healthcare Expenditure Associated With Polypharmacy In Older Adults With Cardiovascular Diseases, Min Ji Kwak, Mihyun Chang, Simbo Chiadika, David Aguilar, Elenir Avritscher, Ashish Deshmukh, Parag Goyal, Dae Hyun Kim, Rajender Aparasu, Holly M Holmes

Faculty, Staff and Student Publications

No abstract provided.

Ancestral Diversity Improves Discovery And Fine-Mapping Of Genetic Loci For Anthropometric Traits–The Hispanic/Latino Anthropometry Consortium, Lindsay Fernández-Rhodes, Mariaelisa Graff, Victoria L Buchanan, Anne E Justice, Heather M Highland, Xiuqing Guo, Wanying Zhu, Hung-Hsin Chen, Kristin L Young, Kaustubh Adhikari, Nicholette D Palmer, Jennifer E Below, Jonathan Bradfield, Alexandre C Pereira, Láshauntá Glover, Daeeun Kim, Adam G Lilly, Poojan Shrestha, Alvin G Thomas, Xinruo Zhang, Minhui Chen, Charleston W K Chiang, Sara Pulit, Andrea Horimoto, Jose E Krieger, Marta Guindo-Martínez, Michael Preuss, Claudia Schumann, Roelof A J Smit, Gabriela Torres-Mejía, Victor Acuña-Alonzo, Gabriel Bedoya, Maria-Cátira Bortolini, Samuel Canizales-Quinteros, Carla Gallo, Rolando González-José, Giovanni Poletti, Francisco Rothhammer, Hakon Hakonarson, Robert Igo, Sharon G Adler, Sudha K Iyengar, Susanne B Nicholas, Stephanie M Gogarten, Carmen R Isasi, George Papnicolaou, Adrienne M Stilp, Qibin Qi, Minjung Kho, Jennifer A Smith, Carl D Langefeld, Lynne Wagenknecht, Roberta Mckean-Cowdin, Xiaoyi Raymond Gao, Darryl Nousome, David V Conti, Ye Feng, Matthew A Allison, Zorayr Arzumanyan, Thomas A Buchanan, Yii-Der Ida Chen, Pauline M Genter, Mark O Goodarzi, Yang Hai, Willa Hsueh, Eli Ipp, Fouad R Kandeel, Kelvin Lam, Xiaohui Li, Jerry L Nadler, Leslie J Raffel, Kathryn Roll, Kevin Sandow, Jingyi Tan, Kent D Taylor, Anny H Xiang, Jie Yao, Astride Audirac-Chalifour, Jose De Jesus Peralta Romero, Fernando Hartwig, Bernando Horta, John Blangero, Joanne E Curran, Ravindranath Duggirala, Donna E Lehman, Sobha Puppala, Laura Fejerman, Esther M John, Carlos Aguilar-Salinas, Noël P Burtt, Jose C Florez, Humberto García-Ortíz, Clicerio González-Villalpando, Josep Mercader, Lorena Orozco, Teresa Tusié-Luna, Estela Blanco, Sheila Gahagan, Nancy J Cox, Craig Hanis, Nancy F Butte, Shelley A Cole, Anthony G Comuzzie, V Saroja Voruganti, Rebecca Rohde, Yujie Wang, Tamar Sofer, Elad Ziv, Struan F A Grant, Andres Ruiz-Linares, Jerome I Rotter, Christopher A Haiman, Esteban J Parra, Miguel Cruz, Ruth J F Loos, Kari E North

Faculty, Staff and Student Publications

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS …

Convection Enhanced Delivery Of The Oncolytic Adenovirus Delta24-Rgd In Patients With Recurrent Gbm: A Phase I Clinical Trial Including Correlative Studies, Erik H P Van Putten, Anne Kleijn, Victor W Van Beusechem, David Noske, Cor H J Lamers, Anna L De Goede, Sander Idema, Daphna Hoefnagel, Jenneke J Kloezeman, Juan Fueyo, Frederick F Lang, Charlotte E Teunissen, René M Vernhout, Cathy Bakker, Winald Gerritsen, David T Curiel, Arnold Vulto, Martine L M Lamfers, Clemens M F Dirven

Faculty, Staff and Student Publications

Purpose: Testing safety of Delta24-RGD (DNX-2401), an oncolytic adenovirus, locally delivered by convection enhanced delivery (CED) in tumor and surrounding brain of patients with recurrent glioblastoma.

Patients and methods: Dose-escalation phase I study with 3+3 cohorts, dosing 107 to 1 × 1011 viral particles (vp) in 20 patients. Besides clinical parameters, adverse events, and radiologic findings, blood, cerebrospinal fluid (CSF), brain interstitial fluid, and excreta were sampled over time and analyzed for presence of immune response, viral replication, distribution, and shedding.

Results: Of 20 enrolled patients, 19 received the oncolytic adenovirus Delta24-RGD, which was found to be safe and feasible. …

Applying Requisite Imagination To Safeguard Electronic Health Record Transitions, Dean F Sittig, Priti Lakhani, Hardeep Singh

Faculty, Staff and Student Publications

Over the next decade, many health care organizations (HCOs) will transition from one electronic health record (EHR) to another; some forced by hospital acquisition and others by choice in search of better EHRs. Herein, we apply principles of Requisite Imagination, or the ability to imagine key aspects of the future one is planning, to offer 6 recommendations on how to proactively safeguard these transitions. First, HCOs should implement a proactive leadership structure that values communication. Second, HCOs should implement proactive risk assessment and testing processes. Third, HCOs should anticipate and reduce unwarranted variation in their EHR and clinical processes. Fourth, …

Closing The Loop: Automatically Identifying Abnormal Imaging Results In Scanned Documents, Akshat Kumar, Heath Goodrum, Ashley Kim, Carly Stender, Kirk Roberts, Elmer V Bernstam

Faculty, Staff and Student Publications

OBJECTIVES: Scanned documents (SDs), while common in electronic health records and potentially rich in clinically relevant information, rarely fit well with clinician workflow. Here, we identify scanned imaging reports requiring follow-up with high recall and practically useful precision.

MATERIALS AND METHODS: We focused on identifying imaging findings for 3 common causes of malpractice claims: (1) potentially malignant breast (mammography) and (2) lung (chest computed tomography [CT]) lesions and (3) long-bone fracture (X-ray) reports. We train our ClinicalBERT-based pipeline on existing typed/dictated reports classified manually or using ICD-10 codes, evaluate using a test set of manually classified SDs, and compare against …

Cngpld: Case-Control Copy-Number Analysis Using Gaussian Process Latent Difference, David J H Shih, Ruoxing Li, Peter Müller, W Jim Zheng, Kim-Anh Do, Shiaw-Yih Lin, Scott L Carter

Faculty, Staff and Student Publications

MOTIVATION: Cross-sectional analyses of primary cancer genomes have identified regions of recurrent somatic copy-number alteration, many of which result from positive selection during cancer formation and contain driver genes. However, no effective approach exists for identifying genomic loci under significantly different degrees of selection in cancers of different subtypes, anatomic sites or disease stages.

RESULTS: CNGPLD is a new tool for performing case-control somatic copy-number analysis that facilitates the discovery of differentially amplified or deleted copy-number aberrations in a case group of cancer compared with a control group of cancer. This tool uses a Gaussian process statistical framework in order …

Ndrg1 In Aggressive Breast Cancer Progression And Brain Metastasis, Emilly S Villodre, Xiaoding Hu, Bedrich L Eckhardt, Richard Larson, Lei Huo, Ester C Yoon, Yun Gong, Juhee Song, Shuying Liu, Naoto T Ueno, Savitri Krishnamurthy, Stefan Pusch, Debu Tripathy, Wendy A Woodward, Bisrat G Debeb

Faculty, Staff and Student Publications

BACKGROUND: N-Myc downstream regulated gene 1 (NDRG1) suppresses metastasis in many human malignancies, including breast cancer, yet has been associated with worse survival in patients with inflammatory breast cancer. The role of NDRG1 in the pathobiology of aggressive breast cancers remains elusive.

METHODS: To study the role of NDRG1 in tumor growth and brain metastasis in vivo, we transplanted cells into cleared mammary fat pads or injected them in tail veins of SCID/Beige mice (n = 7-10 per group). NDRG1 protein expression in patient breast tumors (n = 216) was assessed by immunohistochemical staining. Kaplan-Meier method with 2-sided log-rank test …

Bismuth Nanoparticle And Polyhydroxybutyrate Coatings Enhance The Radiopacity Of Absorbable Inferior Vena Cava Filters For Fluoroscopy-Guided Placement And Longitudinal Computed Tomography Monitoring In Pigs, Jossana A Damasco, Steven Y Huang, Joy Vanessa D Perez, John Andrew T Manongdo, Katherine A Dixon, Malea L Williams, Megan C Jacobsen, Roland Barbosa, Gino Martin Canlas, Gouthami Chintalapani, Adam D Melancon, Rick R Layman, Natalie W Fowlkes, Elizabeth M Whitley, Marites P Melancon

Faculty, Staff and Student Publications

Inferior vena cava filters (IVCFs) constructed with poly-

Mechanistic Origin Of Different Binding Affinities Of Sars-Cov And Sars-Cov-2 Spike Rbds To Human Ace2, Zhi-Bi Zhang, Yuan-Ling Xia, Jian-Xin Shen, Wen-Wen Du, Yun-Xin Fu, Shu-Qun Liu

Faculty, Staff and Student Publications

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (RBDCoV2) has a higher binding affinity to the human receptor angiotensin-converting enzyme 2 (ACE2) than the SARS-CoV RBD (RBDCoV). Here, we performed molecular dynamics (MD) simulations, binding free energy (BFE) calculations, and interface residue contact network (IRCN) analysis to explore the mechanistic origin of different ACE2-binding affinities of the two RBDs. The results demonstrate that, when compared to the RBDCoV2-ACE2 complex, RBDCoV-ACE2 features enhanced dynamicsand inter-protein positional movements and increased conformational entropy and conformational diversity. Although the inter-protein electrostatic attractive interactions are the primary determinant for the high ACE2-binding affinities of …

Mendelian Randomization Supports Bidirectional Causality Between Telomere Length And Clonal Hematopoiesis Of Indeterminate Potential, Tetsushi Nakao, Alexander G Bick, Margaret A Taub, Seyedeh M Zekavat, Md M Uddin, Abhishek Niroula, Cara L Carty, John Lane, Michael C Honigberg, Joshua S Weinstock, Akhil Pampana, Christopher J Gibson, Gabriel K Griffin, Shoa L Clarke, Romit Bhattacharya, Themistocles L Assimes, Leslie S Emery, Adrienne M Stilp, Quenna Wong, Jai Broome, Cecelia A Laurie, Alyna T Khan, Albert V Smith, Thomas W Blackwell, Veryan Codd, Christopher P Nelson, Zachary T Yoneda, Juan M Peralta, Donald W Bowden, Marguerite R Irvin, Meher Boorgula, Wei Zhao, Lisa R Yanek, Kerri L Wiggins, James E Hixson, C Charles Gu, Gina M Peloso, Dan M Roden, Muagututi'a S Reupena, Chii-Min Hwu, Dawn L Demeo, Kari E North, Shannon Kelly, Solomon K Musani, Joshua C Bis, Donald M Lloyd-Jones, Jill M Johnsen, Michael Preuss, Russell P Tracy, Patricia A Peyser, Dandi Qiao, Pinkal Desai, Joanne E Curran, Barry I Freedman, Hemant K Tiwari, Sameer Chavan, Jennifer A Smith, Nicholas L Smith, Tanika N Kelly, Bertha Hidalgo, L Adrienne Cupples, Daniel E Weeks, Nicola L Hawley, Ryan L Minster, Samoan Obesity, Lifestyle And Genetic Adaptations Study (Olaga) Group, Ranjan Deka, Take T Naseri, Lisa De Las Fuentes, Laura M Raffield, Alanna C Morrison, Paul S Vries, Christie M Ballantyne, Eimear E Kenny, Stephen S Rich, Eric A Whitsel, Michael H Cho, M Benjamin Shoemaker, Betty S Pace, John Blangero, Nicholette D Palmer, Braxton D Mitchell, Alan R Shuldiner, Kathleen C Barnes, Susan Redline, Sharon L R Kardia, Gonçalo R Abecasis, Lewis C Becker, Susan R Heckbert, Jiang He, Wendy Post, Donna K Arnett, Ramachandran S Vasan, Dawood Darbar, Scott T Weiss, Stephen T Mcgarvey, Mariza De Andrade, Yii-Der Ida Chen, Robert C Kaplan, Deborah A Meyers, Brian S Custer, Adolfo Correa, Bruce M Psaty, Myriam Fornage, Joann E Manson, Eric Boerwinkle, Barbara A Konkle, Ruth J F Loos, Jerome I Rotter, Edwin K Silverman, Charles Kooperberg, John Danesh, Nilesh J Samani, Siddhartha Jaiswal, Peter Libby, Patrick T Ellinor, Nathan Pankratz, Benjamin L Ebert, Alexander P Reiner, Rasika A Mathias, Ron Do, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Pradeep Natarajan

Faculty, Staff and Student Publications

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD.

Exploring Preventive Healthcare In A High-Risk Vulnerable Population, Trisha L Amboree, Jane R Montealegre, Kayo Fujimoto, Osaro Mgbere, Charles Darkoh, Paige Padgett Wermuth

Faculty, Staff and Student Publications

This study describes preventive care behaviors and explores opportunities to deliver preventive sexual healthcare to a high-risk vulnerable population. Data from the National HIV Behavioral Surveillance (NHBS) system high-risk heterosexuals (HET) cycle (2019) in Houston, Texas, was used to describe preventive care utilization and assess the relationship between healthcare utilization and sociodemographic characteristics. More than 47% reported having no usual source of healthcare, and 94.6% reported receiving no non-HIV STI testing in the past 12 months. Additionally, many sociodemographic factors were associated with healthcare utilization and having a usual source of healthcare. Future efforts should be targeted at increasing preventive …

Meta-Analysis Of Genome-Wide Association Studies Identifies Ancestry-Specific Associations Underlying Circulating Total Tau Levels, Chloé Sarnowski, Mohsen Ghanbari, Joshua C Bis, Mark Logue, Myriam Fornage, Aniket Mishra, Shahzad Ahmad, Alexa S Beiser, Eric Boerwinkle, Vincent Bouteloup, Vincent Chouraki, L Adrienne Cupples, Vincent Damotte, Charles S Decarli, Anita L Destefano, Luc Djoussé, Alison E Fohner, Carol E Franz, Tiffany F Kautz, Jean-Charles Lambert, Michael J Lyons, Thomas H Mosley, Kenneth J Mukamal, Matthew P Pase, Eliana C Portilla Fernandez, Robert A Rissman, Claudia L Satizabal, Ramachandran S Vasan, Amber Yaqub, Stephanie Debette, Carole Dufouil, Lenore J Launer, William S Kremen, William T Longstreth, M Arfan Ikram, Sudha Seshadri

Faculty, Staff and Student Publications

Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10-8. We additionally detected 14 novel loci at P < 5 × 10-7, specific to either Europeans or African Americans. Using whole-exome sequence data in 2,279 European participants, we identified ten genes associated with circulating total-tau when aggregating rare variants. Our genetic study sheds light on genes reported to be associated with neurological diseases including stroke, Alzheimer's, and Parkinson's (F5, MAP1B, and BCAS3), with Alzheimer's pathological hallmarks (ADAMTS12, IL15, and FHIT), or with an important function in the brain (PARD3, ELFN2, UBASH3B, SLIT3, and NSD3), and suggests that the genetic architecture of circulating total-tau may differ according to ancestry.

In-Depth Analysis Of Sars-Cov-2-Specific T Cells Reveals Diverse Differentiation Hierarchies In Vaccinated Individuals, Li Li, Muharrem Muftuoglu, Shaoheng Liang, Mahesh Basyal, Jiangxing Lv, Mehmet Emin Akdogan, Ken Chen, Michael Andreeff, Christopher R Flowers, Simrit Parmar

Faculty, Staff and Student Publications

SARS-CoV-2 vaccines pose as the most effective approach for mitigating the COVID-19 pandemic. High-degree efficacy of SARS-CoV-2 vaccines in clinical trials indicates that vaccination invariably induces an adaptive immune response. However, the emergence of breakthrough infections in vaccinated individuals suggests that the breadth and magnitude of vaccine-induced adaptive immune response may vary. We assessed vaccine-induced SARS-CoV-2 T cell response in 21 vaccinated individuals and found that SARS-CoV-2-specific T cells, which were mainly CD4+ T cells, were invariably detected in all individuals but the response was varied. We then investigated differentiation states and cytokine profiles to identify immune features associated with …

The Impact Of Pediatric Opioid-Related Visits On Us Emergency Departments, Tiffany Champagne-Langabeer, Marylou Cardenas-Turanzas, Irma T Ugalde, Christine Bakos-Block, Angela L Stotts, Lisa Cleveland, Steven Shoptaw, James R Langabeer

Faculty, Staff and Student Publications

BACKGROUND: While there is significant research exploring adults' use of opioids, there has been minimal focus on the opioid impact within emergency departments for the pediatric population.

METHODS: We examined data from the Agency for Healthcare Research, the National Emergency Department Sample (NEDS), and death data from the Centers for Disease Control and Prevention. Sociodemographic and financial variables were analyzed for encounters during 2014-2017 for patients under age 18, matching diagnoses codes for opioid-related overdose or opioid use disorder.

RESULTS: During this period, 59,658 children presented to an ED for any diagnoses involving opioids. The majority (68.5%) of visits were …

Repurposing Probenecid For The Treatment Of Heart Failure (Re-Prosper-Hf): A Study Protocol For A Randomized Placebo-Controlled Clinical Trial, Jack Rubinstein, Nathan Robbins, Karen Evans, Gabrielle Foster, Kevin Mcconeghy, Toluwalope Onadeko, Julie Bunke, Melanie Parent, Xi Luo, Jacob Joseph, Wen-Chih Wu

Faculty, Staff and Student Publications

BACKGROUND: Improving contractility in heart failure with reduced ejection fraction (HFrEF) has resurfaced as a potential treatment goal. Inotropic therapy is now better understood through its underlying mechanism as opposed to the observed effect of increasing contractility. Calcitropes are a subgroup of inotropes that largely depend on the stimulation of adenylyl cyclase to transform ATP into cyclic adenosine monophosphate (cAMP). At least two clinically relevant calcitropes-istaroxime and probenecid-improve contractility through an increase in systolic intracellular calcium without activating cAMP production. Probenecid, which has been safely used clinically for decades in non-cardiac conditions, has recently been identified as an agonist of …

Predicted Gene Expression In Ancestrally Diverse Populations Leads To Discovery Of Susceptibility Loci For Lifestyle And Cardiometabolic Traits, Heather M Highland, Genevieve L Wojcik, Mariaelisa Graff, Katherine K Nishimura, Chani J Hodonsky, Antoine R Baldassari, Alanna C Cote, Iona Cheng, Christopher R Gignoux, Ran Tao, Yuqing Li, Eric Boerwinkle, Myriam Fornage, Jeffrey Haessler, Lucia A Hindorff, Yao Hu, Anne E Justice, Bridget M Lin, Danyu Lin, Daniel O Stram, Christopher A Haiman, Charles Kooperberg, Loic Le Marchand, Tara C Matise, Eimear E Kenny, Christopher S Carlson, Eli A Stahl, Christy L Avery, Kari E North, Jose Luis Ambite, Steven Buyske, Ruth J Loos, Ulrike Peters, Kristin L Young, Stephanie A Bien, Laura M Huckins

Faculty, Staff and Student Publications

One mechanism by which genetic factors influence complex traits and diseases is altering gene expression. Direct measurement of gene expression in relevant tissues is rarely tenable; however, genetically regulated gene expression (GReX) can be estimated using prediction models derived from large multi-omic datasets. These approaches have led to the discovery of many gene-trait associations, but whether models derived from predominantly European ancestry (EA) reference panels can map novel associations in ancestrally diverse populations remains unclear. We applied PrediXcan to impute GReX in 51,520 ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) participants (35% African American, 45% Hispanic/Latino, 10% Asian, …

Hsp90-Cdc37 Functions As A Chaperone For The Oncogenic Fgfr3-Tacc3 Fusion, Tao Li, Farideh Mehraein-Ghomi, M Elizabeth Forbes, Sanjeev V Namjoshi, E Ashley Ballard, Qianqian Song, Ping-Chieh Chou, Xuya Wang, Brittany C Parker Kerrigan, Frederick F Lang, Glenn Lesser, Waldemar Debinski, Xuejun Yang, Wei Zhang

Faculty, Staff and Student Publications

The FGFR3-TACC3 (F3-T3) fusion gene was discovered as an oncogenic molecule in glioblastoma and bladder cancers, and has subsequently been found in many cancer types. Notably, F3-T3 was found to be highly expressed in both untreated and matched recurrence glioblastoma under the concurrent radiotherapy and temozolomide (TMZ) treatment, suggesting that targeting F3-T3 is a valid strategy for treatment. Here, we show that the F3-T3 protein is a client of heat shock protein 90 (HSP90), forming a ternary complex with the cell division cycle 37 (CDC37). Deprivation of HSP90 or CDC37 disrupts the formation of the ternary complex, which destabilizes glycosylated …

Gestational Age Variation In Human Placental Drug Transporters, Laura Goetzl, Nune Darbinian, Nana Merabova, Lindsay C Devane, Sammanda Ramamoorthy

Faculty, Staff and Student Publications

Patient and providers' fear of fetal exposure to medications may lead to discontinuation of treatment, disease relapse, and maternal morbidity. Placental drug transporters play a critical role in fetal exposure through active transport but the majority of data are limited to the 3rd trimester, when the majority of organogenesis has already occurred. Our objective was to define gestational age (GA) dependent changes in protein activity, expression and modifications of five major placental drug transporters: SERT, P-gp, NET, BCRP and MRP3. Apical brush border membrane fractions were prepared from fresh 1st, 2nd and 3rd trimester human placentas collected following elective pregnancy …

Protein Tyrosine Phosphatase Receptor Δ Serves As The Orexigenic Asprosin Receptor, Ila Mishra, Wei Rose Xie, Juan C Bournat, Yang He, Chunmei Wang, Elizabeth Sabath Silva, Hailan Liu, Zhiqiang Ku, Yinghua Chen, Bernadette O Erokwu, Peilin Jia, Zhongming Zhao, Zhiqiang An, Chris A Flask, Yanlin He, Yong Xu, Atul R Chopra

Faculty, Staff and Student Publications

Asprosin is a fasting-induced glucogenic and centrally acting orexigenic hormone. The olfactory receptor Olfr734 is known to be the hepatic receptor for asprosin that mediates its effects on glucose production, but the receptor for asprosin's orexigenic function has been unclear. Here, we have identified protein tyrosine phosphatase receptor δ (Ptprd) as the orexigenic receptor for asprosin. Asprosin functions as a high-affinity Ptprd ligand in hypothalamic AgRP neurons, regulating the activity of this circuit in a cell-autonomous manner. Genetic ablation of Ptprd results in a strong loss of appetite, leanness, and an inability to respond to the orexigenic effects of asprosin. …

New Insights Into The Genetic Etiology Of Alzheimer's Disease And Related Dementias, Céline Bellenguez, Fahri Küçükali, Iris E Jansen, Luca Kleineidam, Sonia Moreno-Grau, Najaf Amin, Adam C Naj, Rafael Campos-Martin, Benjamin Grenier-Boley, Victor Andrade, Peter A Holmans, Anne Boland, Vincent Damotte, Sven J Van Der Lee, Marcos R Costa, Teemu Kuulasmaa, Qiong Yang, Itziar De Rojas, Joshua C Bis, Amber Yaqub, Ivana Prokic, Julien Chapuis, Shahzad Ahmad, Vilmantas Giedraitis, Dag Aarsland, Pablo Garcia-Gonzalez, Carla Abdelnour, Emilio Alarcón-Martín, Daniel Alcolea, Montserrat Alegret, Ignacio Alvarez, Victoria Álvarez, Nicola J Armstrong, Anthoula Tsolaki, Carmen Antúnez, Ildebrando Appollonio, Marina Arcaro, Silvana Archetti, Alfonso Arias Pastor, Beatrice Arosio, Lavinia Athanasiu, Henri Bailly, Nerisa Banaj, Miquel Baquero, Sandra Barral, Alexa Beiser, Ana Belén Pastor, Jennifer E Below, Penelope Benchek, Luisa Benussi, Claudine Berr, Céline Besse, Valentina Bessi, Giuliano Binetti, Alessandra Bizarro, Rafael Blesa, Mercè Boada, Eric Boerwinkle, Barbara Borroni, Silvia Boschi, Paola Bossù, Geir Bråthen, Jan Bressler, Catherine Bresner, Henry Brodaty, Keeley J Brookes, Luis Ignacio Brusco, Dolores Buiza-Rueda, Katharina Bûrger, Vanessa Burholt, William S Bush, Miguel Calero, Laura B Cantwell, Geneviève Chene, Jaeyoon Chung, Michael L Cuccaro, Ángel Carracedo, Roberta Cecchetti, Laura Cervera-Carles, Camille Charbonnier, Hung-Hsin Chen, Caterina Chillotti, Simona Ciccone, Jurgen A H R Claassen, Christopher Clark, Elisa Conti, Anaïs Corma-Gómez, Emanuele Costantini, Carlo Custodero, Delphine Daian, Maria Carolina Dalmasso, Antonio Daniele, Efthimios Dardiotis, Jean-François Dartigues, Peter Paul De Deyn, Katia De Paiva Lopes, Lot D De Witte, Stéphanie Debette, Jürgen Deckert, Teodoro Del Ser, Nicola Denning, Anita Destefano, Martin Dichgans, Janine Diehl-Schmid, Mónica Diez-Fairen, Paolo Dionigi Rossi, Srdjan Djurovic, Emmanuelle Duron, Emrah Düzel, Carole Dufouil, Gudny Eiriksdottir, Sebastiaan Engelborghs, Valentina Escott-Price, Ana Espinosa, Michael Ewers, Kelley M Faber, Tagliavini Fabrizio, Sune Fallgaard Nielsen, David W Fardo, Lucia Farotti, Chiara Fenoglio, Marta Fernández-Fuertes, Raffaele Ferrari, Catarina B Ferreira, Evelyn Ferri, Bertrand Fin, Peter Fischer, Tormod Fladby, Klaus Fließbach, Bernard Fongang, Myriam Fornage, Juan Fortea, Tatiana M Foroud, Silvia Fostinelli, Nick C Fox, Emlio Franco-Macías, María J Bullido, Ana Frank-García, Lutz Froelich, Brian Fulton-Howard, Daniela Galimberti, Jose Maria García-Alberca, Pablo García-González, Sebastian Garcia-Madrona, Guillermo Garcia-Ribas, Roberta Ghidoni, Ina Giegling, Giaccone Giorgio, Alison M Goate, Oliver Goldhardt, Duber Gomez-Fonseca, Antonio González-Pérez, Caroline Graff, Giulia Grande, Emma Green, Timo Grimmer, Edna Grünblatt, Michelle Grunin, Vilmundur Gudnason, Tamar Guetta-Baranes, Annakaisa Haapasalo, Georgios Hadjigeorgiou, Jonathan L Haines, Kara L Hamilton-Nelson, Harald Hampel, Olivier Hanon, John Hardy, Annette M Hartmann, Lucrezia Hausner, Janet Harwood, Stefanie Heilmann-Heimbach, Seppo Helisalmi, Michael T Heneka, Isabel Hernández, Martin J Herrmann, Per Hoffmann, Clive Holmes, Henne Holstege, Raquel Huerto Vilas, Marc Hulsman, Jack Humphrey, Geert Jan Biessels, Xueqiu Jian, Charlotte Johansson, Gyungah R Jun, Yuriko Kastumata, John Kauwe, Patrick G Kehoe, Lena Kilander, Anne Kinhult Ståhlbom, Miia Kivipelto, Anne Koivisto, Johannes Kornhuber, Mary H Kosmidis, Walter A Kukull, Pavel P Kuksa, Brian W Kunkle, Amanda B Kuzma, Carmen Lage, Erika J Laukka, Lenore Launer, Alessandra Lauria, Chien-Yueh Lee, Jenni Lehtisalo, Ondrej Lerch, Alberto Lleó, William Longstreth, Oscar Lopez, Adolfo Lopez De Munain, Seth Love, Malin Löwemark, Lauren Luckcuck, Kathryn L Lunetta, Yiyi Ma, Juan Macías, Catherine A Macleod, Wolfgang Maier, Francesca Mangialasche, Marco Spallazzi, Marta Marquié, Rachel Marshall, Eden R Martin, Angel Martín Montes, Carmen Martínez Rodríguez, Carlo Masullo, Richard Mayeux, Simon Mead, Patrizia Mecocci, Miguel Medina, Alun Meggy, Shima Mehrabian, Silvia Mendoza, Manuel Menéndez-González, Pablo Mir, Susanne Moebus, Merel Mol, Laura Molina-Porcel, Laura Montrreal, Laura Morelli, Fermin Moreno, Kevin Morgan, Thomas Mosley, Markus M Nöthen, Carolina Muchnik, Shubhabrata Mukherjee, Benedetta Nacmias, Tiia Ngandu, Gael Nicolas, Børge G Nordestgaard, Robert Olaso, Adelina Orellana, Michela Orsini, Gemma Ortega, Alessandro Padovani, Caffarra Paolo, Goran Papenberg, Lucilla Parnetti, Florence Pasquier, Pau Pastor, Gina Peloso, Alba Pérez-Cordón, Jordi Pérez-Tur, Pierre Pericard, Oliver Peters, Yolande A L Pijnenburg, Juan A Pineda, Gerard Piñol-Ripoll, Claudia Pisanu, Thomas Polak, Julius Popp, Danielle Posthuma, Josef Priller, Raquel Puerta, Olivier Quenez, Inés Quintela, Jesper Qvist Thomassen, Alberto Rábano, Innocenzo Rainero, Farid Rajabli, Inez Ramakers, Luis M Real, Marcel J T Reinders, Christiane Reitz, Dolly Reyes-Dumeyer, Perry Ridge, Steffi Riedel-Heller, Peter Riederer, Natalia Roberto, Eloy Rodriguez-Rodriguez, Arvid Rongve, Irene Rosas Allende, Maitée Rosende-Roca, Jose Luis Royo, Elisa Rubino, Dan Rujescu, María Eugenia Sáez, Paraskevi Sakka, Ingvild Saltvedt, Ángela Sanabria, María Bernal Sánchez-Arjona, Florentino Sanchez-Garcia, Pascual Sánchez Juan, Raquel Sánchez-Valle, Sigrid B Sando, Chloé Sarnowski, Claudia L Satizabal, Michela Scamosci, Nikolaos Scarmeas, Elio Scarpini, Philip Scheltens, Norbert Scherbaum, Martin Scherer, Matthias Schmid, Anja Schneider, Jonathan M Schott, Geir Selbæk, Davide Seripa, Manuel Serrano, Jin Sha, Alexey A Shadrin, Olivia Skrobot, Susan Slifer, Gijsje J L Snijders, Hilkka Soininen, Vincenzo Solfrizzi, Alina Solomon, Yeunjoo Song, Sandro Sorbi, Oscar Sotolongo-Grau, Gianfranco Spalletta, Annika Spottke, Alessio Squassina, Eystein Stordal, Juan Pablo Tartan, Lluís Tárraga, Niccolo Tesí, Anbupalam Thalamuthu, Tegos Thomas, Giuseppe Tosto, Latchezar Traykov, Lucio Tremolizzo, Anne Tybjærg-Hansen, Andre Uitterlinden, Abbe Ullgren, Ingun Ulstein, Sergi Valero, Otto Valladares, Christine Van Broeckhoven, Jeffery Vance, Badri N Vardarajan, Aad Van Der Lugt, Jasper Van Dongen, Jeroen Van Rooij, John Van Swieten, Rik Vandenberghe, Frans Verhey, Jean-Sébastien Vidal, Jonathan Vogelgsang, Martin Vyhnalek, Michael Wagner, David Wallon, Li-San Wang, Ruiqi Wang, Leonie Weinhold, Jens Wiltfang, Gill Windle, Bob Woods, Mary Yannakoulia, Habil Zare, Yi Zhao, Xiaoling Zhang, Congcong Zhu, Miren Zulaica, Lindsay A Farrer, Bruce M Psaty, Mohsen Ghanbari, Towfique Raj, Perminder Sachdev, Karen Mather, Frank Jessen, M Arfan Ikram, Alexandre De Mendonça, Jakub Hort, Magda Tsolaki, Margaret A Pericak-Vance, Philippe Amouyel, Julie Williams, Ruth Frikke-Schmidt, Jordi Clarimon, Jean-François Deleuze, Giacomina Rossi, Sudha Seshadri, Ole A Andreassen, Martin Ingelsson, Mikko Hiltunen, Kristel Sleegers, Gerard D Schellenberg, Cornelia M Van Duijn, Rebecca Sims, Wiesje M Van Der Flier, Agustín Ruiz, Alfredo Ramirez, Jean-Charles Lambert

Faculty, Staff and Student Publications

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly …

Estimation And Inference Of Predictive Discrimination For Survival Outcome Risk Prediction Models, Ruosha Li, Jing Ning, Ziding Feng

Faculty, Staff and Student Publications

Accurate risk prediction has been the central goal in many studies of survival outcomes. In the presence of multiple risk factors, a censored regression model can be employed to estimate a risk prediction rule. Before the prediction tool can be popularized for practical use, it is crucial to rigorously assess its prediction performance. In our motivating example, researchers are interested in developing and validating a risk prediction tool to identify future lung cancer cases by integrating demographic information, disease characteristics and smoking-related data. Considering the long latency period of cancer, it is desirable for a prediction tool to achieve discriminative …

Host Diversity And Behavior Determine Patterns Of Interspecies Transmission And Geographic Diffusion Of Avian Influenza A Subtypes Among North American Wild Reservoir Species, Joseph T Hicks, Kimberly Edwards, Xueting Qiu, Do-Kyun Kim, James E Hixson, Scott Krauss, Richard J Webby, Robert G Webster, Justin Bahl

Faculty, Staff and Student Publications

Wild birds can carry avian influenza viruses (AIV), including those with pandemic or panzootic potential, long distances. Even though AIV has a broad host range, few studies account for host diversity when estimating AIV spread. We analyzed AIV genomic sequences from North American wild birds, including 303 newly sequenced isolates, to estimate interspecies and geographic viral transition patterns among multiple co-circulating subtypes. Our results show high transition rates within Anseriformes and Charadriiformes, but limited transitions between these orders. Patterns of transition between species were positively associated with breeding habitat range overlap, and negatively associated with host genetic distance. Distance between …