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Machine Learning For Predicting Risk Of Early Dropout In A Recovery Program For Opioid Use Disorder, Assaf Gottlieb, Andrea Yatsco, Christine Bakos-Block, James R Langabeer, Tiffany Champagne-Langabeer

Faculty, Staff and Student Publications

BACKGROUND: An increase in opioid use has led to an opioid crisis during the last decade, leading to declarations of a public health emergency. In response to this call, the Houston Emergency Opioid Engagement System (HEROES) was established and created an emergency access pathway into long-term recovery for individuals with an opioid use disorder. A major contributor to the success of the program is retention of the enrolled individuals in the program.

METHODS: We have identified an increase in dropout from the program after 90 and 120 days. Based on more than 700 program participants, we developed a machine learning …

Antibody Responses Of Healthy Adults To The P27 Peptide Of Respiratory Syncytial Virus Fusion Protein, Brittani N Blunck, Letisha Aideyan, Xunyan Ye, Vasanthi Avadhanula, Laura Ferlic-Stark, Lynn Zechiedrich, Brian E Gilbert, Pedro A Piedra

Faculty, Staff and Students Publications

The respiratory syncytial virus (RSV) fusion (F) protein undergoes two furin-cleavage events to become fusion competent, resulting in the release of a twenty-seven amino acid peptide (p27). Recent studies indicate that the p27 region of the F protein was an immunodominant antigen in young children. In this study, we evaluated the kinetics of the serum antibody response to the p27 peptide following natural RSV reinfection in adults. Nineteen healthy adults under sixty-five years of age were enrolled during the 2018-2019 RSV season in Houston, TX. Blood was collected at three study visits and RSV infection status was defined by changes …

Ms 079 Guide To Mylie E. Durham, Jr., Md Papers (1985), Mylie E. Durham Jr.

Manuscript Finding Aids

MS 079 the Mylie E. Durham Jr., MD papers consists primarily of an oral interview conducted circa 1985 in the form of a printed transcript and six (6) cassette tapes. Dr. Durham Jr. was a native Houstonian. He was a member of the Harris Country Medical Society, the Texas Medical Association, and the American Medical Association. See more at MS 079.

An Estrogen-Sensitive Hypothalamus-Midbrain Neural Circuit Controls Thermogenesis And Physical Activity, Hui Ye, Bing Feng, Chunmei Wang, Kenji Saito, Yongjie Yang, Lucas Ibrahimi, Sarah Schaul, Nirali Patel, Leslie Saenz, Pei Luo, Penghua Lai, Valeria Torres, Maya Kota, Devin Dixit, Xing Cai, Na Qu, Ilirjana Hyseni, Kaifan Yu, Yuwei Jiang, Qingchun Tong, Zheng Sun, Benjamin R Arenkiel, Yanlin He, Pingwen Xu, Yong Xu

Faculty, Staff and Students Publications

Estrogen receptor–α (ERα) expressed by neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (ERαvlVMH) regulates body weight in females, but the downstream neural circuits mediating this biology remain largely unknown. Here we identified a neural circuit mediating the metabolic effects of ERαvlVMH neurons. We found that selective activation of ERαvlVMH neurons stimulated brown adipose tissue (BAT) thermogenesis, physical activity, and core temperature and that ERαvlVMH neurons provide monosynaptic glutamatergic inputs to 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN). Notably, the ERαvlVMH → DRN circuit responds to changes in ambient temperature and nutritional states. We further showed …

Loss Of Irf2bpl Impairs Neuronal Maintenance Through Excess Wnt Signaling, Paul C Marcogliese, Debdeep Dutta, Shrestha Sinha Ray, Nghi D P Dang, Zhongyuan Zuo, Yuchun Wang, Di Lu, Fatima Fazal, Thomas A Ravenscroft, Hyunglok Chung, Oguz Kanca, Jijun Wan, Emilie D Douine, Undiagnosed Diseases Network, Loren D M Pena, Shinya Yamamoto, Stanley F Nelson, Matthew Might, Kathrin C Meyer, Nan Cher Yeo, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

De novo truncations in Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of IRF2BPL causes neural dysfunction, we examined its function in Drosophila and zebrafish. Overexpression of either IRF2BPL or Pits, the Drosophila ortholog, represses Wnt transcription in flies. In contrast, neuronal depletion of Pits leads to increased wingless (wg) levels in the brain and is associated with axonal loss, whereas inhibition of Wg signaling is neuroprotective. Moreover, increased neuronal expression of wg in flies is sufficient to cause age-dependent axonal loss, similar to reduction …

Common Genetic Variants Contribute To Risk Of Transposition Of The Great Arteries, Doris Škorić-Milosavljević, Rafik Tadros, Fernanda M Bosada, Federico Tessadori, Jan Hendrik Van Weerd, Odilia I Woudstra, Fleur V Y Tjong, Najim Lahrouchi, Fanny Bajolle, Heather J Cordell, A J Agopian, Gillian M Blue, Daniela Q C M Barge-Schaapveld, Marc Gewillig, Christoph Preuss, Elisabeth M Lodder, Phil Barnett, Aho Ilgun, Leander Beekman, Karel Van Duijvenboden, Regina Bokenkamp, Martina Müller-Nurasyid, Hubert W Vliegen, Thelma C Konings, Joost P Van Melle, Arie P J Van Dijk, Roland R J Van Kimmenade, Jolien W Roos-Hesselink, Gertjan T Sieswerda, Folkert Meijboom, Hashim Abdul-Khaliq, Felix Berger, Sven Dittrich, Marc-Phillip Hitz, Julia Moosmann, Frank-Thomas Riede, Stephan Schubert, Pilar Galan, Mark Lathrop, Hans M Munter, Ammar Al-Chalabi, Christopher E Shaw, Pamela J Shaw, Karen E Morrison, Jan H Veldink, Leonard H Van Den Berg, Sylvia Evans, Marcelo A Nobrega, Ivy Aneas, Milena Radivojkov-Blagojević, Thomas Meitinger, Erwin Oechslin, Tapas Mondal, Lynn Bergin, John F Smythe, Luis Altamirano-Diaz, Jane Lougheed, Berto J Bouma, Marie-A Chaix, Jennie Kline, Anne S Bassett, Gregor Andelfinger, Roel L F Van Der Palen, Patrice Bouvagnet, Sally-Ann B Clur, Jeroen Breckpot, Wilhelmina S Kerstjens-Frederikse, David S Winlaw, Ulrike M M Bauer, Seema Mital, Elizabeth Goldmuntz, Bernard Keavney, Damien Bonnet, Barbara J Mulder, Michael W T Tanck, Jeroen Bakkers, Vincent M Christoffels, Cornelis J Boogerd, Alex V Postma, Connie R Bezzina

Faculty, Staff and Student Publications

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored.

OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA.

METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients …

Sensory Processing Phenotypes In Phelan-Mcdermid Syndrome And Syngap1-Related Intellectual Disability, Ariel M Lyons-Warren, Maria C Mccormack, Jimmy L Holder

Duncan NRI Faculty and Staff Publications

Sensory processing differences are an established feature of both syndromic and non-syndromic Autism Spectrum Disorders (ASDs). Significant work has been carried out to characterize and classify specific sensory profiles in non-syndromic autism. However, it is not known if syndromic autism disorders, such as Phelan-McDermid Syndrome (PMD) or SYNGAP1-related Intellectual Disability (SYNGAP1-ID), have unique sensory phenotypes. Understanding the sensory features of these disorders is important for providing appropriate care and for understanding their underlying mechanisms. Our objective in this work was to determine the sensory processing abnormalities present in two syndromic ASDs: Phelan-McDermid Syndrome and SYNGAP1-related Intellectual …

Using Cryo-Et To Distinguish Platelets During Pre-Acute Myeloid Leukemia From Steady State Hematopoiesis, Yuewei Wang, Tong Huo, Yu-Jung Tseng, Lan Dang, Zhili Yu, Wenjuan Yu, Zachary Foulks, Rebecca L Murdaugh, Steven J Ludtke, Daisuke Nakada, Zhao Wang

Faculty, Staff and Students Publications

Early diagnosis of acute myeloid leukemia (AML) in the pre-leukemic stage remains a clinical challenge, as pre-leukemic patients show no symptoms, lacking any known morphological or numerical abnormalities in blood cells. Here, we demonstrate that platelets with structurally abnormal mitochondria emerge at the pre-leukemic phase of AML, preceding detectable changes in blood cell counts or detection of leukemic blasts in blood. We visualized frozen-hydrated platelets from mice at different time points during AML development in situ using electron cryo-tomography (cryo-ET) and identified intracellular organelles through an unbiased semi-automatic process followed by quantitative measurement. A large proportion of platelets exhibited changes …

Comprehensive Structure And Functional Adaptations Of The Yeast Nuclear Pore Complex, Christopher W Akey, Digvijay Singh, Christna Ouch, Ignacia Echeverria, Ilona Nudelman, Joseph M Varberg, Zulin Yu, Fei Fang, Yi Shi, Junjie Wang, Daniel Salzberg, Kangkang Song, Chen Xu, James C Gumbart, Sergey Suslov, Jay Unruh, Sue L Jaspersen, Brian T Chait, Andrej Sali, Javier Fernandez-Martinez, Steven J Ludtke, Elizabeth Villa, Michael P Rout

Faculty, Staff and Students Publications

Nuclear pore complexes (NPCs) mediate the nucleocytoplasmic transport of macromolecules. Here we provide a structure of the isolated yeast NPC in which the inner ring is resolved by cryo-EM at sub-nanometer resolution to show how flexible connectors tie together different structural and functional layers. These connectors may be targets for phosphorylation and regulated disassembly in cells with an open mitosis. Moreover, some nucleoporin pairs and transport factors have similar interaction motifs, which suggests an evolutionary and mechanistic link between assembly and transport. We provide evidence for three major NPC variants that may foreshadow functional specializations at the nuclear periphery. Cryo-electron …

Effects Of Road Traffic On The Accuracy And Bias Of Low-Cost Particulate Matter Sensor Measurements In Houston, Texas, Temitope Oluwadairo, Lawrence Whitehead, Elaine Symanski, Cici Bauer, Arch Carson, Inkyu Han

Faculty, Staff and Student Publications

Although PM2.5 measurements of low-cost particulate matter sensors (LCPMS) generally show moderate and strong correlations with those from research-grade air monitors, the data quality of LCPMS has not been fully assessed in urban environments with different road traffic conditions. We examined the linear relationships between PM2.5 measurements taken by an LCPMS (Dylos DC1700) and two research grade monitors, a personal environmental monitor (PEM) and the GRIMM 11R, in three different urban environments, and compared the accuracy (slope) and bias of these environments. PM2.5 measurements were carried out at three locations in Houston, Texas (Clinton Drive largely with diesel trucks, US-59 …

The Power And Challenge Of Lipid (A)Symmetry Across The Membrane And Cell, Heather E Webber, Joy M Schmitz

Faculty, Staff and Student Publications

Current treatments for substance use disorders (SUDs) are far from ideal, with no U.S. Food and Drug Administration-approved pharmacotherapies to treat stimulant and other use disorders. New approaches are urgently needed to combat the increasing prevalence of SUDs and overdose deaths. It is widely accepted that addiction is a chronic disease of the brain involving changes in neural circuitry associated with cognitive and reward functioning. Brain stimulation techniques are novel methods that can modulate these circuits directly and thus hold considerable promise for treating SUDs.

Effect Of P2y12 Inhibitors On Survival Free Of Organ Support Among Non-Critically Ill Hospitalized Patients With Covid-19: A Randomized Clinical Trial, Jeffrey S Berger, Lucy Z Kornblith, Michelle N Gong, Harmony R Reynolds, Mary Cushman, Yu Cheng, Bryan J Mcverry, Keri S Kim, Renato D Lopes, Bassel Atassi, Scott Berry, Grant Bochicchio, Murillo De Oliveira Antunes, Michael E Farkouh, Yonatan Greenstein, Erinn M Hade, Kristin Hudock, Robert Hyzy, Pooja Khatri, Andrei Kindzelski, Bridget-Anne Kirwan, Lisa Baumann Kreuziger, Patrick R Lawler, Eric Leifer, Jose Lopez-Sendon Moreno, Jose Lopez-Sendon, James F Luther, Lilia Nigro Maia, John Quigley, Robert Sherwin, Lana Wahid, Jennifer Wilson, Judith S Hochman, Matthew D Neal, Activ-4a Investigators

Faculty, Staff and Students Publications

IMPORTANCE: Platelets represent a potential therapeutic target for improved clinical outcomes in patients with COVID-19.

OBJECTIVE: To evaluate the benefits and risks of adding a P2Y12 inhibitor to anticoagulant therapy among non-critically ill patients hospitalized for COVID-19.

DESIGN, SETTING, AND PARTICIPANTS: An open-label, bayesian, adaptive randomized clinical trial including 562 non-critically ill patients hospitalized for COVID-19 was conducted between February 2021 and June 2021 at 60 hospitals in Brazil, Italy, Spain, and the US. The date of final 90-day follow-up was September 15, 2021.

INTERVENTIONS: Patients were randomized to a therapeutic dose of heparin plus a P2Y12 inhibitor (n = …

Rspo2 And Rankl Signal Through Lgr4 To Regulate Osteoclastic Premetastatic Niche Formation And Bone Metastasis, Zhiying Yue, Xin Niu, Zengjin Yuan, Qin Qin, Wenhao Jiang, Liang He, Jingduo Gao, Yi Ding, Yanxi Liu, Ziwei Xu, Zhenxi Li, Zhengfeng Yang, Rong Li, Xiwen Xue, Yankun Gao, Fei Yue, Xiang H-F Zhang, Guohong Hu, Yi Wang, Yi Li, Geng Chen, Stefan Siwko, Alison Gartland, Ning Wang, Jianru Xiao, Mingyao Liu, Jian Luo

Faculty, Staff and Students Publications

Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate premetastatic niche and bone tropism are largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through Gαq and β-catenin signaling. …

Sociodemographic And Clinical Characteristics Associated With Improvements In Quality Of Life For Participants With Opioid Use Disorder, Assaf Gottlieb, Christine Bakos-Block, James R Langabeer, Tiffany Champagne-Langabeer

Faculty, Staff and Student Publications

Background: The Houston Emergency Opioid Engagement System was established to create an access pathway into long-term recovery for individuals with opioid use disorder. The program determines effectiveness across multiple dimensions, one of which is by measuring the participant's reported quality of life (QoL) at the beginning of the program and at successive intervals.

Methods: A visual analog scale was used to measure the change in QoL among participants after joining the program. We then identified sociodemographic and clinical characteristics associated with changes in QoL.

Results: 71% of the participants (n = 494) experienced an increase in their QoL scores, …

Clonal Hematopoiesis Mutations In Patients With Lung Cancer Are Associated With Lung Cancer Risk Factors, Wei Hong, Ang Li, Yanhong Liu, Xiangjun Xiao, David C Christiani, Rayjean J Hung, James Mckay, John Field, Christopher I Amos, Chao Cheng

Faculty, Staff and Students Publications

Clonal hematopoiesis (CH) is a phenomenon caused by expansion of white blood cells descended from a single hematopoietic stem cell. While CH can be associated with leukemia and some solid tumors, the relationship between CH and lung cancer remains largely unknown. To help clarify this relationship, we analyzed whole-exome sequencing (WES) data from 1,958 lung cancer cases and controls. Potential CH mutations were identified by a set of hierarchical filtering criteria in different exonic regions, and the associations between the number of CH mutations and clinical traits were investigated. Family history of lung cancer (FHLC) may exert diverse influences on …

Active Living After Cancer: Adaptation And Evaluation Of A Community-Based Physical Activity Program For Minority And Medically Underserved Breast Cancer Survivors, Irene M Tami-Maury, Yue Liao, Maria L Rangel, Leticia A Gatus, Eileen H Shinn, Ashley Alexander, Karen Basen-Engquist

Faculty, Staff and Student Publications

BACKGROUND: An expanding body of research documents the benefits of physical activity for cancer survivors' physical functioning and quality of life, but few successful models provide community-based physical activity programs to cancer survivors. This report presents an evaluation of Active Living After Cancer, an evidence-based physical activity program for breast cancer survivors, adapted for community delivery to minority and medically underserved survivors.

METHODS: Survivors were recruited from health care and community settings. The program consisted of 12 weekly group sessions providing training in cognitive and behavioral skills for behavior change, brief physical activity, and cancer survivorship-related content. At the baseline …

Glynac (Glycine And N-Acetylcysteine) Supplementation Improves Impaired Mitochondrial Fuel Oxidation And Lowers Insulin Resistance In Patients With Type 2 Diabetes: Results Of A Pilot Study, Rajagopal V Sekhar

Faculty, Staff and Students Publications

Patients with type 2 diabetes (T2D) are known to have mitochondrial dysfunction and increased insulin resistance (IR), but the underlying mechanisms are not well understood. We reported previously that (a) adequacy of the antioxidant glutathione (GSH) is necessary for optimal mitochondrial fatty-acid oxidation (MFO); (b) supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC) in mice corrected GSH deficiency, reversed impaired MFO, and lowered oxidative stress (OxS) and IR; and (c) supplementing GlyNAC in patients with T2D improved GSH synthesis and concentrations, and lowered OxS. However, the effect of GlyNAC on MFO, MGO (mitochondrial glucose oxidation), IR and plasma FFA …

New Approaches For Testing Non-Inferiority For Three-Arm Trials With Poisson Distributed Outcomes, Samiran Ghosh, Erina Paul, Shrabanti Chowdhury, Ram C Tiwari

Faculty, Staff and Student Publications

With the availability of limited resources, innovation for improved statistical method for the design and analysis of randomized controlled trials (RCTs) is of paramount importance for newer and better treatment discovery for any therapeutic area. Although clinical efficacy is almost always the primary evaluating criteria to measure any beneficial effect of a treatment, there are several important other factors (e.g., side effects, cost burden, less debilitating, less intensive, etc.), which can permit some less efficacious treatment options favorable to a subgroup of patients. This leads to non-inferiority (NI) testing. The objective of NI trial is to show that an experimental …

Determining The Theoretical Quality Of The Strengths Perspective: A Critical Analysis, Rigaud Joseph, Imelda Duran Herrera, Kaelyn Doyle

Journal of Family Strengths

This paper asks a relevant question that previous work has not yet answered empirically: what is the theoretical quality of the Strengths Perspective (SP)? This paper answers this question, using the Theory Evaluation Scale (TES) and peer-reviewed materials from the existing literature. The findings indicate that, as a theoretical framework, the SP is a high-quality practice model that aligns itself with the values of the social work profession. As a practice model, however, this perspective has room for improvement in the areas of falsifiability, empiricism, boundaries, and client context. This paper concludes with a discussion of these findings and their …

Ms 105 Guide To Jane H. Preston, Md Papers (1950-2000s), Jane H. Preston (1920-2001)

Manuscript Finding Aids

The Jane H. Preston, MD papers contains tapes, interview transcripts, questionnaires, correspondence, patient information, publications, and other various papers related to the work and research of Jane Preston in psychiatry and telemedicine. See more at MS 105.

Genetic Determinants Of Telomere Length From 109,122 Ancestrally Diverse Whole-Genome Sequences In Topmed, Margaret A Taub, Matthew P Conomos, Rebecca Keener, Kruthika R Iyer, Joshua S Weinstock, Lisa R Yanek, John Lane, Tyne W Miller-Fleming, Jennifer A Brody, Laura M Raffield, Caitlin P Mchugh, Deepti Jain, Stephanie M Gogarten, Cecelia A Laurie, Ali Keramati, Marios Arvanitis, Albert V Smith, Benjamin Heavner, Lucas Barwick, Lewis C Becker, Joshua C Bis, John Blangero, Eugene R Bleecker, Esteban G Burchard, Juan C Celedón, Yen Pei C Chang, Brian Custer, Dawood Darbar, Lisa De Las Fuentes, Dawn L Demeo, Barry I Freedman, Melanie E Garrett, Mark T Gladwin, Susan R Heckbert, Bertha A Hidalgo, Marguerite R Irvin, Talat Islam, W Craig Johnson, Stefan Kaab, Lenore Launer, Jiwon Lee, Simin Liu, Arden Moscati, Kari E North, Patricia A Peyser, Nicholas Rafaels, Christine Seidman, Daniel E Weeks, Fayun Wen, Marsha M Wheeler, L Keoki Williams, Ivana V Yang, Wei Zhao, Stella Aslibekyan, Paul L Auer, Donald W Bowden, Brian E Cade, Zhanghua Chen, Michael H Cho, L Adrienne Cupples, Joanne E Curran, Michelle Daya, Ranjan Deka, Celeste Eng, Tasha E Fingerlin, Xiuqing Guo, Lifang Hou, Shih-Jen Hwang, Jill M Johnsen, Eimear E Kenny, Albert M Levin, Chunyu Liu, Ryan L Minster, Take Naseri, Mehdi Nouraie, Muagututi'a Sefuiva Reupena, Ester C Sabino, Jennifer A Smith, Nicholas L Smith, Jessica Lasky Su, James G Taylor, Marilyn J Telen, Hemant K Tiwari, Russell P Tracy, Marquitta J White, Yingze Zhang, Kerri L Wiggins, Scott T Weiss, Ramachandran S Vasan, Kent D Taylor, Moritz F Sinner, Edwin K Silverman, M Benjamin Shoemaker, Wayne H-H Sheu, Frank Sciurba, David A Schwartz, Jerome I Rotter, Daniel Roden, Susan Redline, Benjamin A Raby, Bruce M Psaty, Juan M Peralta, Nicholette D Palmer, Sergei Nekhai, Courtney G Montgomery, Braxton D Mitchell, Deborah A Meyers, Stephen T Mcgarvey, Nhlbi Care Network, Angel Cy Mak, Ruth Jf Loos, Rajesh Kumar, Charles Kooperberg, Barbara A Konkle, Shannon Kelly, Sharon Lr Kardia, Robert Kaplan, Jiang He, Hongsheng Gui, Frank D Gilliland, Bruce D Gelb, Myriam Fornage, Patrick T Ellinor, Mariza De Andrade, Adolfo Correa, Yii-Der Ida Chen, Eric Boerwinkle, Kathleen C Barnes, Allison E Ashley-Koch, Donna K Arnett, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Hematology And Hemostasis Working Group, Topmed Structural Variation Working Group, Cathy C Laurie, Goncalo Abecasis, Deborah A Nickerson, James G Wilson, Stephen S Rich, Daniel Levy, Ingo Ruczinski, Abraham Aviv, Thomas W Blackwell, Timothy Thornton, Jeff O'Connell, Nancy J Cox, James A Perry, Mary Armanios, Alexis Battle, Nathan Pankratz, Alexander P Reiner, Rasika A Mathias

Faculty, Staff and Student Publications

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value <5×10-9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, …

Mapk4 Promotes Triple Negative Breast Cancer Growth And Reduces Tumor Sensitivity To Pi3k Blockade, Wei Wang, Dong Han, Qinbo Cai, Tao Shen, Bingning Dong, Michael T Lewis, Runsheng Wang, Yanling Meng, Wolong Zhou, Ping Yi, Chad J Creighton, David D Moore, Feng Yang

Faculty, Staff and Students Publications

About 15-20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity …

Pressure-Mediated Reflection Spectroscopy Criterion Validity As A Biomarker Of Fruit And Vegetable Intake: A 2-Site Cross-Sectional Study Of 4 Racial Or Ethnic Groups, Stephanie B Jilcott Pitts, Nancy E Moran, Qiang Wu, Lisa Harnack, Neal E Craft, Neil Hanchard, Ronny Bell, Stacey G Moe, Nevin Johnson, Justice Obasohan, Pamela L Carr-Manthe, Melissa N Laska

Children’s Nutrition Research Center Staff Publications

Background: Valid biomarkers of fruit and vegetable (FV) intake are needed for field-based nutrition research.

Objectives: To examine criterion-related validity of pressure-mediated reflection spectroscopy as a proxy measure of FV intake, using plasma carotenoids and self-reported FV and carotenoid intake as primary and secondary criterion measures, respectively.

Methods: Healthy adults 18-65 y of age, self-identifying as African American/black (n = 61), Asian (n = 53), white (n = 70), or Hispanic (n = 29), in North Carolina and Minnesota were recruited. Skin carotenoids were assessed via pressure-mediated reflection spectroscopy (Veggie Meter), skin melanin via spectrophotometer, and total plasma carotenoid concentration …

Association Between Perceived Health Risks Of E-Cigarettes And Actual E-Cigarette Use, Based On Cigarette Smoking Status And Sexual And Gender Minority Status Among Us Adults, David Adzrago, Yue Shi, Kayo Fujimoto

Faculty, Staff and Student Publications

BACKGROUND: There is a lack of consensus in the literature about the association between the perceived health risks of e-cigarettes and their actual use, an association that may be based on cigarette smoking status or sexual and gender minority status. This study examined the moderating effect of these variables as well as differences in e-cigarette use between and within perceived harmfulness of e-cigarettes and cigarette smoking among U.S. adults.

METHODS: The data were drawn from the 2020 and 2019 Health Information National Trends Survey (HINTS 5), Cycles 4 and 3, on adults (

RESULTS: Of the study population, 30.75% currently …

Accuracy And Practical Considerations For Doubly Labeled Water Analysis In Nutrition Studies Using A Laser-Based Isotope Instrument (Off-Axis Integrated Cavity Output Spectroscopy), Linda M Reynard, William W Wong, Noreen Tuross

Children’s Nutrition Research Center Staff Publications

Background: Given the utility of the doubly labeled water (DLW) method for determination of energy expenditure, additional techniques for isotope analysis of the samples are welcome. Laser-based instruments are one such new analytical tool, but their accuracy and feasibility for DLW studies are grossly understudied.

Objectives: We assessed the accuracy of laser-based isotope ratio measurements as part of the DLW method for estimation of carbon dioxide production rate (rCO2) and total energy expenditure (TEE), in between-group comparison study designs.

Methods: Urine samples from a previous study were analyzed with a laser-based instrument [off-axis integrated cavity output spectroscopy (OA-ICOS)]. In that …

The Allergy Mediator Histamine Confers Resistance To Immunotherapy In Cancer Patients Via Activation Of The Macrophage Histamine Receptor H1, Hongzhong Li, Yi Xiao, Qin Li, Jun Yao, Xiangliang Yuan, Yuan Zhang, Xuedong Yin, Yohei Saito, Huihui Fan, Ping Li, Wen-Ling Kuo, Angela Halpin, Don L Gibbons, Hideo Yagita, Zhongming Zhao, Da Pang, Guosheng Ren, Cassian Yee, J Jack Lee, Dihua Yu

Duncan NRI Faculty and Staff Publications

Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. …

Mutations In Hcfc1 And Ronin Result In An Inborn Error Of Cobalamin Metabolism And Ribosomopathy, Tiffany Chern, Annita Achilleos, Xuefei Tong, Matthew C Hill, Alexander B Saltzman, Lucas C Reineke, Arindam Chaudhury, Swapan K Dasgupta, Yushi Redhead, David Watkins, Joel R Neilson, Perumal Thiagarajan, Jeremy B A Green, Anna Malovannaya, James F Martin, David S Rosenblatt, Ross A Poché

Faculty, Staff and Students Publications

Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously …

Secretogranin Iii Stringently Regulates Pathological But Not Physiological Angiogenesis In Oxygen-Induced Retinopathy, Chang Dai, Prabuddha Waduge, Liyang Ji, Chengchi Huang, Ye He, Hong Tian, Elizabeth Zuniga-Sanchez, Amit Bhatt, Iok-Hou Pang, Guanfang Su, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized …

Total Energy Expenditure Is Repeatable In Adults But Not Associated With Short-Term Changes In Body Composition, Rebecca Rimbach, Yosuke Yamada, Hiroyuki Sagayama, Philip N Ainslie, Lene F Anderson, Liam J Anderson, Lenore Arab, Issaad Baddou, Kweku Bedu-Addo, Ellen E Blaak, Stephane Blanc, Alberto G Bonomi, Carlijn V C Bouten, Pascal Bovet, Maciej S Buchowski, Nancy F Butte, Stefan G J A Camps, Graeme L Close, Jamie A Cooper, Sai Krupa Das, Lara R Dugas, Ulf Ekelund, Sonja Entringer, Terrence Forrester, Barry W Fudge, Annelies H Goris, Michael Gurven, Catherine Hambly, Asmaa El Hamdouchi, Marije B Hoos, Sumei Hu, Noorjehan Joonas, Annemiek M Joosen, Peter Katzmarzyk, Kitty P Kempen, Misaka Kimura, William E Kraus, Robert F Kushner, Estelle V Lambert, William R Leonard, Nader Lessan, Corby K Martin, Anine C Medin, Erwin P Meijer, James C Morehen, James P Morton, Marian L Neuhouser, Theresa A Nicklas, Robert M Ojiambo, Kirsi H Pietiläinen, Yannis P Pitsiladis, Jacob Plange-Rhule, Guy Plasqui, Ross L Prentice, Roberto A Rabinovich, Susan B Racette, David A Raichlen, Eric Ravussin, Rebecca M Reynolds, Susan B Roberts, Albertine J Schuit, Anders M Sjödin, Eric Stice, Samuel S Urlacher, Giulio Valenti, Ludo M Van Etten, Edgar A Van Mil, Jonathan C K Wells, George Wilson, Brian M Wood, Jack Yanovski, Tsukasa Yoshida, Xueying Zhang, Alexia J Murphy-Alford, Cornelia U Loechl, Amy H Luke, Jennifer Rood, Dale A Schoeller, Klaas R Westerterp, William W Wong, John R Speakman, Herman Pontzer

Children’s Nutrition Research Center Staff Publications

Low total energy expenditure (TEE, MJ/d) has been a hypothesized risk factor for weight gain, but repeatability of TEE, a critical variable in longitudinal studies of energy balance, is understudied. We examine repeated doubly labeled water (DLW) measurements of TEE in 348 adults and 47 children from the IAEA DLW Database (mean ± SD time interval: 1.9 ± 2.9 y) to assess repeatability of TEE, and to examine if TEE adjusted for age, sex, fat-free mass, and fat mass is associated with changes in weight or body composition. Here, we report that repeatability of TEE is high for adults, but …

The Allergy Mediator Histamine Confers Resistance To Immunotherapy In Cancer Patients Via Activation Of The Macrophage Histamine Receptor H1, Hongzhong Li, Yi Xiao, Qin Li, Jun Yao, Xiangliang Yuan, Yuan Zhang, Xuedong Yin, Yohei Saito, Huihui Fan, Ping Li, Wen-Ling Kuo, Angela Halpin, Don L Gibbons, Hideo Yagita, Zhongming Zhao, Da Pang, Guosheng Ren, Cassian Yee, J Jack Lee, Dihua Yu

Faculty, Staff and Student Publications

Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. …