Digital Commons Network^™

Are Thyrotropin-Releasing Hormone (Trh) And Analog Taltirelin Viable Reversal Agents Of Opioid-Induced Respiratory Depression?, Marieke Hyke Algera, Joseph F Cotten, Monique Van Velzen, Marieke Niesters, Martijn Boon, Daniel S Shoham, Kaye E Dandrea, Rutger Van Der Schrier, Albert Dahan

Faculty, Staff and Student Publications

Opioid-induced respiratory depression (OIRD) is a potentially life-threatening complication of opioid consumption. Apart from naloxone, an opioid antagonist that has various disadvantages, a possible reversal strategy is treatment of OIRD with the hypothalamic hormone and neuromodulator thyrotropin-releasing hormone (TRH). In this review, we performed a search in electronic databases and retrieved 52 papers on the effect of TRH and TRH-analogs on respiration and their efficacy in the reversal of OIRD in awake and anesthetized mammals, including humans. Animal studies show that TRH and its analog taltirelin stimulate breathing via an effect at the preBötzinger complex, an important respiratory rhythm generator …

Outcomes After Definitive Surgery For Mandibular Osteoradionecrosis, Kevin J Contrera, Steven B Chinn, Randal S Weber, Dianna Roberts, Jeffery N Myers, Stephen Y Lai, Carol M Lewis, Amy C Hessel, Ann M Gillenwater, Collin F Mulcahy, Peirong Yu, Matthew M Hanasono, Clifton D Fuller, Mark S Chambers, Mark E Zafereo

Faculty, Staff and Student Publications

Objectives: To analyze charges, complications, survival, and functional outcomes for definitive surgery of mandibular osteoradionecrosis (ORN).

Materials and methods: Retrospective analysis of 76 patients who underwent segmental mandibulectomy with reconstruction from 2000 to 2009.

Results: Complications occurred in 49 (65%) patients and were associated with preoperative drainage (odds ratio [OR] 4.40, 95% confidence interval [CI] 1.01-19.27). The adjusted median charge was $343 000, and higher charges were associated with double flap reconstruction (OR 8.15, 95% CI 2.19-30.29) and smoking (OR 5.91, 95% CI 1.69-20.72). Improved swallow was associated with age <67 years (OR 3.76, 95% CI 1.16-12.17) and preoperative swallow (OR 3.42, 95% CI 1.23-9.51). Five-year ORN-recurrence-free survival was 93% while overall survival was 63% and associated with pulmonary disease (HR [hazard ratio] 3.57, 95% CI 1.43-8.94).

Conclusions: Although recurrence of ORN is rare, surgical complications are …

Cooking After Cancer: The Structure And Implementation Of A Community-Based Cooking Program For Cancer Survivors, Margaret Raber, Molly Costigan, Joya Chandra, Karen Basen-Engquist

Faculty, Staff and Student Publications

Cancer survivors are a growing population that may particularly benefit from nutrition and lifestyle interventions. Community-based programs teaching healthy cooking skills are increasingly popular and offer an opportunity to support survivors within communities. The objective of this study is to describe the curriculum and implementation of a cooking class program designed for cancer survivors, housed within an established community-based organization. First, we evaluated the class curriculum for specific constructs. An evidence-based measure of healthy cooking constructs, the Healthy Cooking Index (HCI), was used to analyze included recipes and revealed both summative cooking quality scores and individual constructs underlying the overall …

The Androgen Receptor Is A Therapeutic Target In Desmoplastic Small Round Cell Sarcoma, Salah-Eddine Lamhamedi-Cherradi, Mayinuer Maitituoheti, Brian A Menegaz, Sandhya Krishnan, Amelia M Vetter, Pamela Camacho, Chia-Chin Wu, Hannah C Beird, Robert W Porter, Davis R Ingram, Vandhana Ramamoorthy, Sana Mohiuddin, David Mccall, Danh D Truong, Branko Cuglievan, P Andrew Futreal, Alejandra Ruiz Velasco, Nazanin Esmaeili Anvar, Budi Utama, Mark Titus, Alexander J Lazar, Wei-Lien Wang, Cristian Rodriguez-Aguayo, Ravin Ratan, J Andrew Livingston, Kunal Rai, A Robert Macleod, Najat C Daw, Andrea Hayes-Jordan, Joseph A Ludwig

Faculty, Staff and Student Publications

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the …

Prognosticators Of Visual Acuity After Indirect Traumatic Optic Neuropathy, Alex J Wright, Joanna H Queen, Emilio P Supsupin, Alice Z Chuang, John J Chen, Rod Foroozan, Ore-Ofe O Adesina

Faculty, Staff and Student Publications

BACKGROUND: The purpose of this study is to determine whether there are radiographic and systemic clinical characteristics that can predict final visual outcomes in patients with indirect traumatic optic neuropathy (iTON).

METHODS: This study is a retrospective, multicenter case series of adult patients with iTON treated initially at large, urban, and/or academic trauma centers with follow-up at an affiliated ophthalmology clinic. In addition to detailed cranial computed tomography characteristics, demographics, systemic comorbidities, coinjuries, blood products administered, and intracranial pressure, along with other factors, were gathered. LogMAR visual acuity (VA) at the initial presentation to the hospital and up to 12 …

Association Study Between Mucin 4 (Muc4) Polymorphisms And Idiopathic Recurrent Pregnancy Loss In A Korean Population, Ji-Hyang Kim, Han-Sung Park, Jeong-Yong Lee, Eun-Ju Ko, Young-Ran Kim, Hee-Young Cho, Woo-Sik Lee, Eun-Hee Ahn, Nam-Keun Kim

Faculty, Staff and Student Publications

Recurrent pregnancy loss (RPL) is the loss of two or more consecutive pregnancies before 20 weeks of gestational age. Our study investigated whether mucin 4 (MUC4) polymorphisms are associated with RPL. MUC polymorphisms (rs882605 C>A, rs1104760 A>G, rs2688513 A>G, rs2258447 C>T, and rs2291652 A>G) were genotyped in 374 women with RPL and 239 controls of Korean ethnicity using polymerase chain reaction-restriction fragment length polymorphism analysis and the TaqMan probe SNP genotyping assay. Differences in genotype frequencies between cases of RPL and the controls were compared. MUC4 rs882605 C>A and rs1104760 A>G polymorphisms were …

Tissue-Specific Variations In Transcription Factors Elucidate Complex Immune System Regulation, Hengwei Lu, Yi-Ching Tang, Assaf Gottlieb

Faculty, Staff and Student Publications

Gene expression plays a key role in health and disease. Estimating the genetic components underlying gene expression can thus help understand disease etiology. Polygenic models termed "transcriptome imputation" are used to estimate the genetic component of gene expression, but these models typically consider only the cis regions of the gene. However, these cis-based models miss large variability in expression for multiple genes. Transcription factors (TFs) that regulate gene expression are natural candidates for looking for additional sources of the missing variability. We developed a hypothesis-driven approach to identify second-tier regulation by variability in TFs. Our approach tested two models …

A Crosstalk Between Gut And Brain In Sepsis-Induced Cognitive Decline\, Vijayasree V Giridharan, Jaqueline S Generoso, Leonardo Lence, Gabriela Candiotto, Emílio Streck, Fabricia Petronilho, Anilkumar Pillai, Tarek Sharshar, Felipe Dal-Pizzol, Tatiana Barichello

Faculty, Staff and Student Publications

BACKGROUND: Sepsis is a potentially fatal disease characterized by acute organ failure that affects more than 30 million people worldwide. Inflammation is strongly associated with sepsis, and patients can experience impairments in memory, concentration, verbal fluency, and executive functioning after being discharged from the hospital. We hypothesize that sepsis disrupts the microbiota-gut-brain axis homeostasis triggering cognitive impairment. This immune activation persists during treatment, causing neurological dysfunction in sepsis survivors.

METHODS: To test our hypothesis, adult Wistar rats were subjected to cecal-ligation and perforation (CLP) or sham (non-CLP) surgeries. The animals were subjected to the [

RESULTS: Compared to the control …

Mutational Activation Of The Nrf2 Pathway Upregulates Kynureninase Resulting In Tumor Immunosuppression And Poor Outcome In Lung Adenocarcinoma, Johannes F Fahrmann, Ichidai Tanaka, Ehsan Irajizad, Xiangying Mao, Jennifer B Dennison, Eunice Murage, Julian Casabar, Jeffrey Mayo, Qian Peng, Muge Celiktas, Jody V Vykoukal, Soyoung Park, Ayumu Taguchi, Oliver Delgado, Satyendra C Tripathi, Hiroyuki Katayama, Luisa Maren Solis Soto, Jaime Rodriguez-Canales, Carmen Behrens, Ignacio Wistuba, Samir Hanash, Edwin J Ostrin

Faculty, Staff and Student Publications

Activation of the NRF2 pathway through gain-of-function mutations or loss-of-function of its suppressor KEAP1 is a frequent finding in lung cancer. NRF2 activation has been reported to alter the tumor microenvironment. Here, we demonstrated that NRF2 alters tryptophan metabolism through the kynurenine pathway that is associated with a tumor-promoting, immune suppressed microenvironment. Specifically, proteomic profiles of 47 lung adenocarcinoma (LUAD) cell lines (11 KEAP1 mutant and 36 KEAP1 wild-type) revealed the tryptophan-kynurenine enzyme kynureninase (KYNU) as a top overexpressed protein associated with activated NRF2. The siRNA-mediated knockdown of NFE2L2, the gene encoding for NRF2, or activation of the NRF2 …

Impaired Gate16-Mediated Exocytosis In Exocrine Tissues Causes Sjögren’S Syndrome-Like Exocrinopathy, Akiko Suzuki, Chihiro Iwaya, Kenichi Ogata, Hiroki Yoshioka, Junbo Shim, Isei Tanida, Masaaki Komatsu, Norihiro Tada, Junichi Iwata

Faculty, Staff and Student Publications

Sjögren's syndrome (SjS) is a chronic autoimmune disease characterized by immune cell infiltration of the exocrine glands, mainly the salivary and lacrimal glands. Despite recent advances in the clinical and mechanistic characterization of the disease, its etiology remains largely unknown. Here, we report that mice with a deficiency for either Atg7 or Atg3, which are enzymes involved in the ubiquitin modification pathway, in the salivary glands exhibit a SjS-like phenotype, characterized by immune cell infiltration with autoantibody detection, acinar cell death, and dry mouth. Prior to the onset of the SjS-like phenotype in these null mice, we detected an accumulation …

Tite-Boin12: A Bayesian Phase I/Ii Trial Design To Find The Optimal Biological Dose With Late-Onset Toxicity And Efficacy, Yanhong Zhou, Ruitao Lin, J Jack Lee, Daniel Li, Li Wang, Ruobing Li, Ying Yuan

Faculty, Staff and Student Publications

In the era of immunotherapies and targeted therapies, the focus of early phase clinical trials has shifted from finding the maximum tolerated dose to identifying the optimal biological dose (OBD), which maximizes the toxicity-efficacy trade-off. One major impediment to using adaptive designs to find OBD is that efficacy or/and toxicity are often late-onset, hampering the designs’ real-time decision rules for treating new patients. To address this issue, we propose the model-assisted TITE-BOIN12 design to find OBD with late-onset toxicity and efficacy. As an extension of the BOIN12 design, the TITE-BOIN12 design also uses utility to quantify the toxicity-efficacy trade-off. We …

Definition Of Germ Layer Cell Lineage Alternative Splicing Programs Reveals A Critical Role For Quaking In Specifying Cardiac Cell Fate, W Samuel Fagg, Naiyou Liu, Ulrich Braunschweig, Karen Larissa Pereira De Castro, Xiaoting Chen, Frederick S Ditmars, Steven G Widen, John Paul Donohue, Katalin Modis, William K Russell, Jeffrey H Fair, Matthew T Weirauch, Benjamin J Blencowe, Mariano A Garcia-Blanco

Faculty, Staff and Student Publications

Alternative splicing is critical for development; however, its role in the specification of the three embryonic germ layers is poorly understood. By performing RNA-Seq on human embryonic stem cells (hESCs) and derived definitive endoderm, cardiac mesoderm, and ectoderm cell lineages, we detect distinct alternative splicing programs associated with each lineage. The most prominent splicing program differences are observed between definitive endoderm and cardiac mesoderm. Integrative multi-omics analyses link each program with lineage-enriched RNA binding protein regulators, and further suggest a widespread role for Quaking (QKI) in the specification of cardiac mesoderm. Remarkably, knockout of QKI disrupts the cardiac mesoderm-associated alternative …

One-Pot, One-Step Synthesis Of Drug-Loaded Magnetic Multimicelle Aggregates, Chang Soo Kim, Dmitry Nevozhay, Rebeca Romero Aburto, Ashok Pehere, Lan Pang, Rebecca Dillard, Ziqiu Wang, Clayton Smith, Kelsey Boitnott Mathieu, Marie Zhang, John D Hazle, Robert C Bast, Konstantin Sokolov

Faculty, Staff and Student Publications

Lipid-based formulations provide a nanotechnology platform that is widely used in a variety of biomedical applications because it has several advantageous properties including biocompatibility, reduced toxicity, relative ease of surface modifications, and the possibility for efficient loading of drugs, biologics, and nanoparticles. A combination of lipid-based formulations with magnetic nanoparticles such as iron oxide was shown to be highly advantageous in a growing number of applications including magnet-mediated drug delivery and image-guided therapy. Currently, lipid-based formulations are prepared by multistep protocols. Simplification of the current multistep procedures can lead to a number of important technological advantages including significantly decreased processing …

Micro-Computed Tomography Assessment Of Bone Structure In Aging Mice, Junbo Shim, Chihiro Iwaya, Catherine G Ambrose, Akiko Suzuki, Junichi Iwata

Faculty, Staff and Student Publications

High-resolution computed tomography (CT) is widely used to assess bone structure under physiological and pathological conditions. Although the analytic protocols and parameters for micro-CT (μCT) analyses in mice are standardized for long bones, vertebrae, and the palms in aging mice, they have not yet been established for craniofacial bones. In this study, we conducted a morphometric assessment of craniofacial bones, in comparison with long bones, in aging mice. Although age-related changes were observed in the microarchitecture of the femur, tibia, vertebra, and basisphenoid bone, and were more pronounced in females than in males, the microarchitecture of both the interparietal bone …

An Evidence-Based Lexical Pattern Approach For Quality Assurance Of Gene Ontology Relations, Rashmie Abeysinghe, Yuntao Yang, Mason Bartels, W Jim Zheng, Licong Cui

Faculty, Staff and Student Publications

Gene Ontology (GO) is widely used in the biological domain. It is the most comprehensive ontology providing formal representation of gene functions (GO concepts) and relations between them. However, unintentional quality defects (e.g. missing or erroneous relations) in GO may exist due to the large size of GO concepts and complexity of GO structures. Such quality defects would impact the results of GO-based analyses and applications. In this work, we introduce a novel evidence-based lexical pattern approach for quality assurance of GO relations. We leverage two layers of evidence to suggest potentially missing relations in GO as follows. We first …

Rapid Acceleration Of Kras-Mutant Pancreatic Carcinogenesis Via Remodeling Of Tumor Immune Microenvironment By Pparδ, Yi Liu, Yasunori Deguchi, Daoyan Wei, Fuyao Liu, Micheline J Moussalli, Eriko Deguchi, Donghui Li, Huamin Wang, Lovie Ann Valentin, Jennifer K Colby, Jing Wang, Xiaofeng Zheng, Haoqiang Ying, Mihai Gagea, Baoan Ji, Jiaqi Shi, James C Yao, Xiangsheng Zuo, Imad Shureiqi

Faculty, Staff and Student Publications

Pancreatic intraepithelial neoplasia (PanIN) is a precursor of pancreatic ductal adenocarcinoma (PDAC), which commonly occurs in the general populations with aging. Although most PanIN lesions (PanINs) harbor oncogenic KRAS mutations that initiate pancreatic tumorigenesis; PanINs rarely progress to PDAC. Critical factors that promote this progression, especially targetable ones, remain poorly defined. We show that peroxisome proliferator-activated receptor-delta (PPARδ), a lipid nuclear receptor, is upregulated in PanINs in humans and mice. Furthermore, PPARδ ligand activation by a high-fat diet or GW501516 (a highly selective, synthetic PPARδ ligand) in mutant KRASG12D (KRASmu) pancreatic epithelial cells strongly accelerates PanIN progression to PDAC. This …

Factors Associated With Covid-19 Death In The United States: Cohort Study, Uan-I Chen, Hua Xu, Trudy Millard Krause, Raymond Greenberg, Xiao Dong, Xiaoqian Jiang

Faculty, Staff and Student Publications

BACKGROUND: Since the initial COVID-19 cases were identified in the United States in February 2020, the United States has experienced a high incidence of the disease. Understanding the risk factors for severe outcomes identifies the most vulnerable populations and helps in decision-making.

OBJECTIVE: This study aims to assess the factors associated with COVID-19-related deaths from a large, national, individual-level data set.

METHODS: A cohort study was conducted using data from the Optum de-identified COVID-19 electronic health record (EHR) data set; 1,271,033 adult participants were observed from February 1, 2020, to August 31, 2020, until their deaths due to COVID-19, deaths …

Factors Associated With Covid-19 Death In The United States: Cohort Study, Uan-I Chen, Hua Xu, Trudy Millard Krause, Raymond Greenberg, Xiao Dong, Xiaoqian Jiang

Faculty, Staff and Student Publications

Background: Since the initial COVID-19 cases were identified in the United States in February 2020, the United States has experienced a high incidence of the disease. Understanding the risk factors for severe outcomes identifies the most vulnerable populations and helps in decision-making.

Objective: This study aims to assess the factors associated with COVID-19-related deaths from a large, national, individual-level data set.

Methods: A cohort study was conducted using data from the Optum de-identified COVID-19 electronic health record (EHR) data set; 1,271,033 adult participants were observed from February 1, 2020, to August 31, 2020, until their deaths due to COVID-19, deaths …

Prioritization Of Risk Genes In Multiple Sclerosis By A Refined Bayesian Framework Followed By Tissue-Specificity And Cell Type Feature Assessment, Andi Liu, Astrid M Manuel, Yulin Dai, Zhongming Zhao

Faculty, Staff and Student Publications

BACKGROUND: Multiple sclerosis (MS) is a debilitating immune-mediated disease of the central nervous system that affects over 2 million people worldwide, resulting in a heavy burden to families and entire communities. Understanding the genetic basis underlying MS could help decipher the pathogenesis and shed light on MS treatment. We refined a recently developed Bayesian framework, Integrative Risk Gene Selector (iRIGS), to prioritize risk genes associated with MS by integrating the summary statistics from the largest GWAS to date (n = 115,803), various genomic features, and gene-gene closeness.

RESULTS: We identified 163 MS-associated prioritized risk genes (MS-PRGenes) through the Bayesian framework. …

Identification Of Biomarkers Of Response To Preoperative Talazoparib Monotherapy In Treatment Naïve Gbrca+ Breast Cancers, Xuan Liu, Zhongqi Ge, Fei Yang, Alejandro Contreras, Sanghoon Lee, Jason B White, Yiling Lu, Marilyne Labrie, Banu K Arun, Stacy L Moulder, Gordon B Mills, Helen Piwnica-Worms, Jennifer K Litton, Jeffrey T Chang

Faculty, Staff and Student Publications

Germline mutations in BRCA1 or BRCA2 exist in ~2-7% of breast cancer patients, which has led to the approval of PARP inhibitors in the advanced setting. We have previously reported a phase II neoadjuvant trial of single agent talazoparib for patients with germline BRCA pathogenic variants with a pathologic complete response (pCR) rate of 53%. As nearly half of the patients treated did not have pCR, better strategies are needed to overcome treatment resistance. To this end, we conducted multi-omic analysis of 13 treatment naïve breast cancer tumors from patients that went on to receive single-agent neoadjuvant talazoparib. We looked …

Racial And Ethnic Differences In Genomic Profiling Of Early Onset Colorectal Cancer, David M Hein, Weiye Deng, Marylena Bleile, Syed Ali Kazmi, Brooke Rhead, Francisco M De La Vega, Amy L Jones, Radhika Kainthla, Wen Jiang, Brandi Cantarel, Nina N Sanford

Faculty, Staff and Student Publications

The incidence and mortality of early onset colorectal cancer (EOCRC) is rising; outcomes appear to differ by race and ethnicity. We aimed to assess differences in mutational landscape and gene expression of EOCRC by racial and ethnic groups (non-Hispanic Asian, non-Hispanic Black, non-Hispanic White, White Hispanic) using data from the American Association for Cancer Research Project GENIE (10.2) and University of Texas Southwestern, the latter enriched in Hispanic patients. All statistical tests were 2-sided. Of 1752 EOCRC patients, non-Hispanic Black patients had higher rates of KRAS mutations (60.9%; P = .001, q = 0.015), and non-Hispanic White and non-Hispanic Black …

Bi-Order Multimodal Integration Of Single-Cell Data, Jinzhuang Dou, Shaoheng Liang, Vakul Mohanty, Qi Miao, Yuefan Huang, Qingnan Liang, Xuesen Cheng, Sangbae Kim, Jongsu Choi, Yumei Li, Li Li, May Daher, Rafet Basar, Katayoun Rezvani, Rui Chen, Ken Chen

Faculty, Staff and Student Publications

Integration of single-cell multiomics profiles generated by different single-cell technologies from the same biological sample is still challenging. Previous approaches based on shared features have only provided approximate solutions. Here, we present a novel mathematical solution named bi-order canonical correlation analysis (bi-CCA), which extends the widely used CCA approach to iteratively align the rows and the columns between data matrices. Bi-CCA is generally applicable to combinations of any two single-cell modalities. Validations using co-assayed ground truth data and application to a CAR-NK study and a fetal muscle atlas demonstrate its capability in generating accurate multimodal co-embeddings and discovering cellular identity.

Pattern Differentiation And Tuning Shift In Human Sensory Cortex Underlie Long-Term Threat Memory, Yuqi You, Lucas R Novak, Kevin J Clancy, Wen Li

Faculty, Staff and Student Publications

The amygdala-prefrontal-cortex circuit has long occupied the center of the threat system 1, but new evidence has rapidly amassed to implicate threat processing outside this canonical circuit 2-4. Through non-human research, the sensory cortex has emerged as a critical substrate for long-term threat memory 5-9, underpinned by sensory cortical pattern separation/completion 10,11 and tuning shift 12,13. In humans, research has begun to associate the human sensory cortex with long-term threat memory 14,15, but the lack of mechanistic insights obscures a direct linkage. Towards that end, …

Bhlhe40 Regulates The T-Cell Effector Function Required For Tumor Microenvironment Remodeling And Immune Checkpoint Therapy Efficacy, Avery J Salmon, Alexander S Shavkunov, Qi Miao, Nicholas N Jarjour, Sunita Keshari, Ekaterina Esaulova, Charmelle D Williams, Jeffrey P Ward, Anna M Highsmith, Josué E Pineda, Reshma Taneja, Ken Chen, Brian T Edelson, Matthew M Gubin

Faculty, Staff and Student Publications

Immune checkpoint therapy (ICT) using antibody blockade of programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can provoke T cell-dependent antitumor activity that generates durable clinical responses in some patients. The epigenetic and transcriptional features that T cells require for efficacious ICT remain to be fully elucidated. Herein, we report that anti-PD-1 and anti-CTLA-4 ICT induce upregulation of the transcription factor BHLHE40 in tumor antigen-specific CD8+ and CD4+ T cells and that T cells require BHLHE40 for effective ICT in mice bearing immune-edited tumors. Single-cell RNA sequencing of intratumoral immune cells in BHLHE40-deficient mice revealed differential …

Iv Sotalol Use In Pediatric And Congenital Heart Patients: A Multicenter Registry Study, Lindsey E Malloy-Walton, Nicholas H Von Bergen, Seshadri Balaji, Peter S Fischbach, Jason M Garnreiter, S Yukiko Asaki, Jeffrey P Moak, Luis A Ochoa, Philip M Chang, Hoang H Nguyen, Akash R Patel, Christa Kirk, Ashley K Sherman, Jennifer N Avari Silva, J Philip Saul

Faculty, Staff and Student Publications

Background There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease, including those with severe myocardial dysfunction. A multicenter registry study was designed to evaluate the safety, efficacy, and dosing of IV sotalol. Methods and Results A total of 85 patients (age 1 day-36 years) received IV sotalol, of whom 45 (53%) had additional congenital cardiac diagnoses and 4 (5%) were greater than 18 years of age. In 79 patients (93%), IV sotalol was used to treat supraventricular tachycardia and 4 (5%) received it to treat ventricular arrhythmias. …

Genomic Correlates Of Outcome In Tumor-Infiltrating Lymphocyte Therapy For Metastatic Melanoma, Caitlin A Creasy, Yuzhong Jeff Meng, Marie-Andrée Forget, Tatiana Karpinets, Katarzyna Tomczak, Chip Stewart, Carlos A Torres-Cabala, Shari Pilon-Thomas, Amod A Sarnaik, James J Mulé, Levi Garraway, Matias Bustos, Jianhua Zhang, Sapna P Patel, Adi Diab, Isabella C Glitza, Cassian Yee, Hussein Tawbi, Michael K Wong, Jennifer Mcquade, Dave S B Hoon, Michael A Davies, Patrick Hwu, Rodabe N Amaria, Cara Haymaker, Rameen Beroukhim, Chantale Bernatchez

Faculty, Staff and Student Publications

Purpose: Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL) historically yields a 40%-50% response rate in metastatic melanoma. However, the determinants of outcome are largely unknown.

Experimental design: We investigated tumor-based genomic correlates of overall survival (OS), progression-free survival (PFS), and response to therapy by interrogating tumor samples initially collected to generate TIL infusion products.

Results: Whole-exome sequencing (WES) data from 64 samples indicated a positive correlation between neoantigen load and OS, but not PFS or response to therapy. RNA sequencing analysis of 34 samples showed that expression of PDE1C, RTKN2, and NGFR was enriched in responders who had improved …

Plasma Proteome Analyses In Individuals Of European And African Ancestry Identify Cis-Pqtls And Models For Proteome-Wide Association Studies, Jingning Zhang, Diptavo Dutta, Anna Köttgen, Adrienne Tin, Pascal Schlosser, Morgan E Grams, Benjamin Harvey, Ckdgen Consortium, Bing Yu, Eric Boerwinkle, Josef Coresh, Nilanjan Chatterjee

Faculty, Staff and Student Publications

Improved understanding of genetic regulation of the proteome can facilitate identification of the causal mechanisms for complex traits. We analyzed data on 4,657 plasma proteins from 7,213 European American (EA) and 1,871 African American (AA) individuals from the Atherosclerosis Risk in Communities study, and further replicated findings on 467 AA individuals from the African American Study of Kidney Disease and Hypertension study. Here, we identified 2,004 proteins in EA and 1,618 in AA, with most overlapping, which showed associations with common variants in cis-regions. Availability of AA samples led to smaller credible sets and notable number of population-specific cis-protein quantitative …

Multi-Ancestry Genetic Study Of Type 2 Diabetes Highlights The Power Of Diverse Populations For Discovery And Translation, Anubha Mahajan, Cassandra N Spracklen, Weihua Zhang, Maggie C Y Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro Della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor J Y Lim, Claudia H T Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Cécile Lecoeur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond K Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Jack Flanagan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Chad M Brummett, Thomas A Buchanan, Mickaël Canouil, Juliana C N Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H Janaka De Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jørgensen, Torben Jørgensen, Yoichiro Kamatani, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian'an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N Nadkarni, Jerry L Nadler, Michael A Nalls, Uma Nayak, Suraj S Nongmaithem, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Kathryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schönherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A Smith, Wing Yee So, Alena Stančáková, Adrienne M Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M Van Dam, Jan B Van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Eleanor Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Ko Willems Van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loïc Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, Finngen, Emerge Consortium, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne H H Sheu, Sharon L R Kardia, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald C W Ma, Tien-Yin Wong, Leif Groop, Dennis O Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Roberta Mckean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P Bottinger, Abbas Dehghan, E-Shyong Tai, Josée Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Colin N A Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth J F Loos, Kari E North, Christopher A Haiman, Jose C Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Mägi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y Millwood, Robin G Walters, Kari Stefansson, Simon R Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L Mohlke, Anna L Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I Rotter, Mark I Mccarthy, Andrew P Morris

Faculty, Staff and Student Publications

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10-9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS …

Rhoa-Rock Competes With Yap To Regulate Amoeboid Breast Cancer Cell Migration In Response To Lymphatic-Like Flow, Amina Mohammadalipour, Miguel F Diaz, Megan Livingston, Adesuwa Ewere, Allen Zhou, Paulina D Horton, Loretta T Olamigoke, John M Lamar, John P Hagan, Hyun J Lee, Pamela L Wenzel

Faculty, Staff and Student Publications

Lymphatic drainage generates force that induces prostate cancer cell motility via activation of Yes-associated protein (YAP), but whether this response to fluid force is conserved across cancer types is unclear. Here, we show that shear stress corresponding to fluid flow in the initial lymphatics modifies taxis in breast cancer, whereas some cell lines use rapid amoeboid migration behavior in response to fluid flow, a separate subset decrease movement. Positive responders displayed transcriptional profiles characteristic of an amoeboid cell state, which is typical of cells advancing at the edges of neoplastic tumors. Regulation of the HIPPO tumor suppressor pathway and YAP …

Home Cooking Quality Assessment Tool Validation Using Community Science And Crowdsourcing Approaches, Margaret Raber, Nalini Ranjit, Larkin L Strong, Karen Basen-Engquist

Faculty, Staff and Student Publications

Objective: To refine a measure of home cooking quality (defined as the usage level of practices with the potential to influence the nutrient content of prepared foods) and conduct a construct validation of the revised tool, the Healthy Cooking Questionnaire 2 (HCQ2).

Design: Two validation approaches are described: (1) a community science approach used to refine and validate Healthy Cooking Questionnaire (HCQ) constructs, and (2) responses to the revised HCQ (HCQ2) in a sample of Amazon Mechanical Turk (MTurk) workers to determine questionnaire comprehension.

Setting: The Community Scientist Program at the University of Texas MD Anderson Cancer Center facilitated discussion …