Digital Commons Network^™

Glucose 6-P Dehydrogenase Overexpression Improves Aging-Induced Endothelial Dysfunction In Aorta From Mice: Role Of Arginase Ii, Eva Serna, Maria D Mauricio, Teresa San-Miguel, Sol Guerra-Ojeda, David Verdú, Alicia Valls, Coralie Arc-Chagnaud, Adrián De La Rosa, José Viña

Faculty, Staff and Student Publications

The increase of vascular arginase activity during aging causes endothelial dysfunction. This enzyme competes with the endothelial nitric oxide synthase (eNOS) for L-arginine substrate. Our hypothesis is that glucose 6-P dehydrogenase (G6PD) overexpression could improve the endothelial function modulating the arginase pathway in aorta from mice. For this study, three groups of male mice were used: young wild type (WT) (6-9 months), old WT (21-22 months) and old G6PD-Tg (21-22 months) mice. Vascular reactivity results showed a reduced acetylcholine-dependent relaxation in the old WT but not old G6PD-Tg group. Endothelial dysfunction was reverted by nor-NOHA, an arginase inhibitor. Mice overexpressing …

Dual-Specificity Phosphatases 22-Deficient T Cells Contribute To The Pathogenesis Of Ankylosing Spondylitis, Ming-Han Chen, Huai-Chia Chuang, Yi-Chen Yeh, Chung-Tei Chou, Tse-Hua Tan

Children’s Nutrition Research Center Staff Publications

Background: Dual-specificity phosphatases (DUSPs) can dephosphorylate both tyrosine and serine/threonine residues of their substrates and regulate T cell-mediated immunity and autoimmunity. The aim of this study was to investigate the potential roles of DUSPs in ankylosing spondylitis (AS).

Methods: Sixty AS patients and 45 healthy controls were enrolled in this study. Associations of gene expression of 23 DUSPs in peripheral T cells with inflammatory cytokine gene expression and disease activity of AS were analyzed. Finally, we investigated whether the characteristics of AS are developed in DUSP-knockout mice.

Results: The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in peripheral …

Clinical Outcomes Of A Large-Scale, Partnership-Based Regional Food Prescription Program: Results Of A Quasi-Experimental Study, Nalini Ranjit, Jennifer N Aiyer, Jack D Toups, Esther Liew, Kenia Way, Henry Shelton Brown, John Wesley Mcwhorter, Shreela V Sharma

Faculty, Staff and Student Publications

BACKGROUND: Food prescription programs are gaining interest from funders, policy makers, and healthcare payers as a way to provide value-based care. A small body of research suggests that such programs effectively impact health outcomes; however, the quality of existing studies is variable, and most studies use small samples. This study attempts to address these gaps by utilizing a quasi-experimental design with non-equivalent controls, to evaluate clinical outcomes among participants enrolled in a food prescription program implemented at scale.

METHODS: We completed a secondary analysis of participant enrollment and utilization data collected between May 2018 and March 2021, by the Houston …

Management Of Patients With Refractory Cardiogenic Shock And Cardiointestinal Syndrome With Impella 5.5 As Bridge To Decision: Case Series, Ismael A. Salas De Armas, Bindu Akkanti, Amanda Bergeron, Anju Bhardwaj, Kha Dinh, Ali Shirafkan, Jayeshkumar A. Patel, Manish K. Patel, Carlos R. Manrique Neira, Igor D. Gregoric, Biswajit Kar, Mehmet H. Akay

Journal of Shock and Hemodynamics

Patients with advanced heart failure require multi-system management as a majority succumb to end-organ dysfunction, including gastrointestinal sequelae. Temporizing measures, such as early mechanical circulatory support, can assist in the recovery of patients with acute cardiogenic shock. The temporary support can improve patient characteristics to enable future definitive heart failure therapies such as durable left ventricular assist devices and orthotopic heart transplantation. We present two cases of cardiogenic shock that were successfully bridged with an Impella 5.5 (Abiomed). The management enabled the patients to recover from reversible cardiointestinal syndrome and undergo successful definitive therapies.

Splicing Factor Srsf1 Deficiency In The Liver Triggers Nash-Like Pathology And Cell Death, Waqar Arif, Bhoomika Mathur, Michael F Saikali, Ullas V Chembazhi, Katelyn Toohill, You Jin Song, Qinyu Hao, Saman Karimi, Steven M Blue, Brian A Yee, Eric L Van Nostrand, Sushant Bangru, Grace Guzman, Gene W Yeo, Kannanganattu V Prasanth, Sayeepriyadarshini Anakk, Carolyn L Cummins, Auinash Kalsotra

Faculty, Staff and Students Publications

Regulation of RNA processing contributes profoundly to tissue development and physiology. Here, we report that serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is associated with the excessive formation of deleterious RNA-DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA …

Hepatocytes Demarcated By Ephb2 Contribute To The Progression Of Nonalcoholic Steatohepatitis, Yang Xiao, Kirill Batmanov, Wenxiang Hu, Kun Zhu, Alexander Y Tom, Dongyin Guan, Chunjie Jiang, Lan Cheng, Sam J Mccright, Eric C Yang, Matthew R Lanza, Yifan Liu, David A Hill, Mitchell A Lazar

Faculty, Staff and Students Publications

Current therapeutic strategies for treating nonalcoholic steatohepatitis (NASH) have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. Here, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during NASH development in mice and humans. The bifurcation of hepatocyte trajectory with NASH progression was conserved between mice and humans. At the nonalcoholic fatty liver (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at the NASH stage, a subset of hepatocytes was enriched for the signatures of cell adhesion and migration, which were mainly demarcated by receptor tyrosine kinase ephrin type B receptor …

Bnt162b2 Mrna Vaccination Against Coronavirus Disease 2019 Is Associated With A Decreased Likelihood Of Multisystem Inflammatory Syndrome In Children Aged 5-18 Years-United States, July 2021 - April 2022, Laura D Zambrano, Margaret M Newhams, Samantha M Olson, Natasha B Halasa, Ashley M Price, Amber O Orzel, Cameron C Young, Julie A Boom, Leila C Sahni, Aline B Maddux, Katherine E Bline, Satoshi Kamidani, Keiko M Tarquinio, Kathleen Chiotos, Jennifer E Schuster, Melissa L Cullimore, Sabrina M Heidemann, Charlotte V Hobbs, Ryan A Nofziger, Pia S Pannaraj, Melissa A Cameron, Tracie C Walker, Stephanie P Schwartz, Kelly N Michelson, Bria M Coates, Heidi R Flori, Elizabeth H Mack, Laura Smallcomb, Shira J Gertz, Samina S Bhumbra, Tamara T Bradford, Emily R Levy, Michele Kong, Katherine Irby, Natalie Z Cvijanovich, Matt S Zinter, Cindy Bowens, Hillary Crandall, Janet R Hume, Manish M Patel, Angela P Campbell, Adrienne G Randolph, Overcoming Covid-19 Investigators

Faculty, Staff and Students Publications

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C), linked to antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is associated with considerable morbidity. Prevention of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) by vaccination might also decrease MIS-C likelihood.

METHODS: In a multicenter, case-control, public health investigation of children ages 5-18 years hospitalized from 1 July 2021 to 7 April 2022, we compared the odds of being fully vaccinated (2 doses of BNT162b2 vaccine ≥28 days before hospital admission) between MIS-C case-patients and hospital-based controls who tested negative for SARS-CoV-2. These associations were examined by age group, timing of vaccination, …

Neighborhood Deprivation And Residential Property Values Do Not Affect Weight Loss At 1 Or 3 Years After Bariatric Surgery, Adam Drewnowski, Benjamin D Hong, Ernest Shen, Ming Ji, Silvia R Paz, Bhumi B Bhakta, Mayra Macias, Cecelia L Crawford, Kristina H Lewis, Jialuo Liu, Darren D Moore, Sameer B Murali, Deborah R Young, Karen J Coleman

Faculty, Staff and Student Publications

OBJECTIVE: This study examined the association between individual- and neighborhood-level sociodemographic factors and surgical weight loss at 1 year (short term) and 3 years (long term).

METHODS: Data were obtained from the baseline survey of the BELONG (Bariatric Experience Long Term) prospective longitudinal cohort study. Individual-level self-reported data on sex, race and ethnicity, education, and household income were obtained by survey. Data from the 2010 US Census were used to calculate area Neighborhood Deprivation Index score and median value of owner-occupied housing units at the census tract level.

RESULTS: Patients (N = 1341) had a mean age of 43.4 (SD …

Biological Correlates Of The Effects Of Auricular Point Acupressure On Pain, Chao Hsing Yeh, Nada Lukkahatai, Xinran Huang, Hulin Wu, Hongyu Wang, Jingyu Zhang, Xinyi Sun, Thomas J Smith

Faculty, Staff and Student Publications

BACKGROUND: To identify candidate inflammatory biomarkers for the underlying mechanism of auricular point acupressure (APA) on pain relief and examine the correlations among pain intensity, interference, and inflammatory biomarkers.

DESIGN: This is a secondary data analysis.

METHODS: Data on inflammatory biomarkers collected via blood samples and patient self-reported pain intensity and interference from three pilot studies (chronic low back pain, n = 61; arthralgia related to aromatase inhibitors, n = 20; and chemotherapy-induced neuropathy, n = 15) were integrated and analyzed. This paper reports the results based on within-subject treatment effects (change in scores from pre- to post-APA intervention) for …

Spatial Molecular And Cellular Determinants Of Stat3 Activation In Liver Fibrosis Progression In Non-Alcoholic Fatty Liver Disease, Jingjing Jiao, Jessica I Sanchez, Omar A Saldarriaga, Luisa M Solis, David J Tweardy, Dipen M Maru, Heather L Stevenson, Laura Beretta

Faculty, Staff and Student Publications

BACKGROUND & AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), is increasing. Individuals with NASH often develop liver fibrosis and advanced liver fibrosis is the main determinant of mortality in individuals with NASH. We and others have reported that STAT3 contributes to liver fibrosis and hepatocellular carcinoma in mice.

METHODS: Here, we explored whether STAT3 activation in hepatocyte and non-hepatocyte areas, measured by phospho-STAT3 (pSTAT3), is associated with liver fibrosis progression in 133 patients with NAFLD. We further characterized the molecular and cellular determinants of STAT3 activation by integrating spatial distribution and …

Biosynthesis Of Chlorophyll And Other Isoprenoids In The Plastid Of Red Grape Berry Skins, António Teixeira, Henrique Noronha, Sarah Frusciante, Gianfranco Diretto, Hernâni Gerós

Faculty, Staff and Student Publications

Despite current knowledge showing that fruits like tomato and grape berries accumulate different components of the light reactions and Calvin cycle, the role of green tissues in fruits is not yet fully understood. In mature tomato fruits, chlorophylls are degraded and replaced by carotenoids through the conversion of chloroplasts in chromoplasts, while in red grape berries, chloroplasts persist at maturity and chlorophylls are masked by anthocyanins. To study isoprenoid and lipid metabolism in grape skin chloroplasts, metabolites of enriched organelle fractions were analyzed by high-performance liquid chromatography-high-resolution mass spectrometry (HPLC-HRMS) and the expression of key genes was evaluated by real-time …

How Much Did It Cost To Develop And Implement An Ehealth Intervention For A Minority Children Population That Overlapped With The Covid-19 Pandemic?, Alexandra Monashefsky, Dar Alon, Tom Baranowski, Tiago V Barreira, Kelly A Chiu, Amy Fleischman, Melanie C Green, Shirley Huang, Ronald C Samuels, Caio Victor Sousa, Debbe Thompson, Amy S Lu

Children’s Nutrition Research Center Staff Publications

Background: eHealth interventions using active video games (AVGs) offer an alternative method to help children exercise, especially during a pandemic where options are limited. There is limited data on costs associated with developing and implementing such interventions.

Objectives: We quantified the costs of delivering an eHealth RCT intervention among minority children during COVID-19.

Methods: We categorized the total trial cost into five subcategories: intervention material development, advertising and recruitment, intervention delivery, personnel salaries, and COVID-19-related equipment costs.

Results: The total RCT cost was $1,927,807 (Direct: $1,227,903; Indirect: $699,904) with three visits required for each participant. The average cost per participant …

Randomized Controlled Trial Of A Novel Lifestyle Intervention Used With Or Without Meal Replacements In Work Sites, Sai Krupa Das, Rachel E Silver, Taylor A Vail, Meghan K Chin, Caroline M Blanchard, Stephanie L Dickinson, Xiwei Chen, Lisa Ceglia, Edward Saltzman, David B Allison, Susan B Roberts

Children’s Nutrition Research Center Staff Publications

Objective: Lifestyle interventions have had limited effectiveness in work sites when evaluated in randomized trials. This study assessed the effectiveness of a novel lifestyle intervention for weight loss (Healthy Weight for Living [HWL]) implemented with or without meal replacements (MR) in work sites. HWL used a new behavioral approach emphasizing reducing hunger and building healthy food preferences, and, unlike traditional lifestyle interventions, it did not require calorie counting.

Methods: Twelve work sites were randomized to an 18-month intervention (n = 8; randomization within work sites to HWL, HWL + MR) or 6-month wait-listed control (n = 4). Participants were employees …

Diabetes Of Unclear Type In An Adolescent Boy With Multiple Islet-Cell Autoantibody Positivity Successfully Managed With Glucagon-Like Peptide-1 Receptor Agonist Alone: A Case Report, Olivia Z B Ginnard, Maria J Redondo, Sarah K Lyons

Children’s Nutrition Research Center Staff Publications

Diabetes classification has traditionally considered type 1 and type 2 diabetes as 2 separate entities with different pathogenic mechanisms. However, clinicians and researchers see increasingly more exceptions to this conventional paradigm, leading to a concept of mixed phenotypes in diabetes classification. Herein we report the case of an adolescent with unclear diabetes type due to the presence of obesity, robust endogenous insulin production, multiple islet autoantibody positivity and severe hyperglycemia at diabetes diagnosis that has been successfully treated with liraglutide therapy alone. Our case report highlights the difficulty of diabetes classification and subsequent need for personalized medicine with regard to …

How Much Did It Cost To Develop And Implement An Ehealth Intervention For A Minority Children Population That Overlapped With The Covid-19 Pandemic?, Alexandra Monashefsky, Dar Alon, Tom Baranowski, Tiago V Barreira, Kelly A Chiu, Amy Fleischman, Melanie C Green, Shirley Huang, Ronald C Samuels, Caio Victor Sousa, Debbe Thompson, Amy S Lu

Children’s Nutrition Research Center Staff Publications

Background: eHealth interventions using active video games (AVGs) offer an alternative method to help children exercise, especially during a pandemic where options are limited. There is limited data on costs associated with developing and implementing such interventions.

Objectives: We quantified the costs of delivering an eHealth RCT intervention among minority children during COVID-19.

Methods: We categorized the total trial cost into five subcategories: intervention material development, advertising and recruitment, intervention delivery, personnel salaries, and COVID-19-related equipment costs.

Results: The total RCT cost was $1,927,807 (Direct: $1,227,903; Indirect: $699,904) with three visits required for each participant. The average cost per participant …

Relationships Between Urinary Metals And Diabetes Traits Among Mexican Americans In Starr County, Texas, Usa, Margaret C Weiss, Yu-Hsuan Shih, Molly Scannell Bryan, Brian P Jackson, David Aguilar, Craig L Hanis, Maria Argos, Robert M Sargis

Faculty, Staff and Student Publications

Hispanics/Latinos have higher rates of type 2 diabetes (T2D), and the origins of these disparities are poorly understood. Environmental endocrine-disrupting chemicals (EDCs), including some metals and metalloids, are implicated as diabetes risk factors. Data indicate that Hispanics/Latinos may be disproportionately exposed to EDCs, yet they remain understudied with respect to environmental exposures and diabetes. The objective of this study is to determine how metal exposures contribute to T2D progression by evaluating the associations between 8 urinary metals and measures of glycemic status in 414 normoglycemic or prediabetic adults living in Starr County, Texas, a Hispanic/Latino community with high rates of …

Cross-Sectional And Prospective Associations Of Rest-Activity Rhythms With Body Mass Index In Older Men: A Novel Analysis Using Harmonic Hidden Markov Models, Brian Heckler, Miryoung Lee, Katie Stone, Cici Bauer, Qian Xiao

Faculty, Staff and Student Publications

Growing evidence supports a role for rest-activity rhythms (RARs) in metabolic health. Epidemiological studies in adolescents and young adults showed that RAR characteristics consistent with weakened rhythmicity were associated with obesity. However, studies in older adults are lacking. The objective of this study was to examine the cross-sectional and prospective associations between RAR and obesity in older men using the Harmonic Hidden Markov Model (HHMM), a novel analytical approach with several advantages over conventional methods for characterizing RAR. The analysis included nearly 3,000 participants in the Osteoporotic Fractures in Men study with 5-day 24-h actigraphy data. The strength of RAR …

Acculturation, Dietary Behaviors, And Macronutrient Intake Among Mexican Americans With Prediabetes: The Starr County Diabetes Prevention Initiative, Sharon A Brown, Heather A Becker, Alexandra A García, Mary M Velasquez, Hirofumi Tanaka, Mary A Winter, William B Perkison, Eric L Brown, David Aguilar, Craig L Hanis

Faculty, Staff and Student Publications

PURPOSE: The purpose of the study was to examine the influences of sex and acculturation on dietary behaviors, macronutrient intake, and dietary quality in participants enrolled in a diabetes prevention initiative in Starr County, Texas.

METHODS: Baseline data from the Starr County diabetes prevention study (N = 300) were analyzed-acculturation (country of origin, years in Starr County, language and food preferences), depressive symptoms (Patient Health Questionnaire-9), healthy eating self-efficacy (Weight Efficacy Lifestyle Questionnaire-Short Form), diet quality (USDA Healthy Eating Index), fat avoidance (Fat Avoidance Scale, Spanish version), and macronutrients. Descriptive statistics and univariate analysis of covariance were used to examine …

Pyridoxamine Treatment Ameliorates Large Artery Stiffening And Cerebral Artery Endothelial Dysfunction In Old Mice, Emily H Reeve, Elise K Kronquist, Julia R Wolf, Byron Lee, Aleena Khurana, Hanson Pham, Abigail E Cullen, Jessica A Peterson, Antonio Meza, R Colton Bramwell, Laura Villasana, Daniel R Machin, Grant D Henson, Ashley E Walker

Faculty, Staff and Student Publications

Age-related increases in large artery stiffness are associated with cerebrovascular dysfunction and cognitive impairment. Pyridoxamine treatment prevents large artery stiffening with advancing age, but the effects of pyridoxamine treatment on the cerebral vasculature or cognition is unknown. The purpose of this study was to investigate the effects of pyridoxamine on blood pressure, large artery stiffness, cerebral artery function, and cognitive function in old mice. Old male C57BL/6 mice consumed either pyridoxamine (2 g/L) or vehicle control in drinking water for ∼7.5 months and were compared with young male C57BL/6 mice. From pre- to post-treatment, systolic blood pressure increased in old …

Telehealth Trials To Address Health Equity In Stroke Survivors, Anjail Z Sharrief, Amy K Guzik, Erica Jones, Munachi Okpala, Mary F Love, Tamra Ishan Jayenda Ranasinghe, Cheryl Bushnell

Faculty, Staff and Student Publications

Telehealth has seen rapid expansion into chronic care management in the past 3 years because of the COVID-19 pandemic. Telehealth for acute care management has expanded access to equitable stroke care to many patients over the past two decades, but there is limited evidence for its benefit for addressing disparities in the chronic care of patients living with stroke. In this review, we discuss advantages and disadvantages of telehealth use for the outpatient management of stroke survivors. Further, we explore opportunities and potential barriers for telehealth in addressing disparities in stroke outcomes related to various social determinants of health. We …

Expression And Functions Of Transient Receptor Potential Channels In Liver Diseases, Wenhui Wang, Pengyu Liu, Yalin Zhang, Li Yan, Michael X Zhu, Jin Wang, Ye Yu

Faculty, Staff and Student Publications

Liver diseases constitute a major healthcare burden globally, including acute hepatic injury resulted from acetaminophen overdose, ischemia-reperfusion or hepatotropic viral infection and chronic hepatitis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). Attainable treatment strategies for most liver diseases remain inadequate, highlighting the importance of substantial pathogenesis. The transient receptor potential (TRP) channels represent a versatile signalling mechanism regulating fundamental physiological processes in the liver. It is not surprising that liver diseases become a newly explored field to enrich our knowledge of TRP channels. Here, we discuss recent findings revealing TRP functions across the fundamental …

Association Of Frailty And The Expanded Operative Stress Score With Preoperative Acute Serious Conditions, Complications, And Mortality In Males Compared To Females: A Retrospective Observational Study, Qi Yan, Jeongsoo Kim, Daniel E Hall, Myrick C Shinall, Katherine Moll Reitz, Karyn B Stitzenberg, Lillian S Kao, Elizabeth L George, Ada Youk, Chen-Pin Wang, Jonathan C Silverstein, Elmer V Bernstam, Paula K Shireman

Faculty, Staff and Student Publications

OBJECTIVE: The aim of this study was to expand Operative Stress Score (OSS) increasing procedural coverage and assessing OSS and frailty association with Preoperative Acute Serious Conditions (PASC), complications and mortality in females versus males.

SUMMARY BACKGROUND DATA: Veterans Affairs male-dominated study showed high mortality in frail veterans even after very low stress surgeries (OSS1).

METHODS: Retrospective cohort using NSQIP data (2013-2019) merged with 180-day postoperative mortality from multiple hospitals to evaluate PASC, 30-day complications and 30-, 90-, and 180-day mortality.

RESULTS: OSS expansion resulted in 98.2% case coverage versus 87.0% using the original. Of 82,269 patients (43.8% male), 7.9% …

Prospective Evaluation Of The Fungitell® (1-->3) Beta-D-Glucan Assay As A Diagnostic Tool For Invasive Fungal Disease In Pediatric Allogeneic Hematopoietic Cell Transplantation: A Report From The Children’S Oncology Group, William R Otto, Christopher C Dvorak, Craig L K Boge, Luis Ostrosky-Zeichner, Adam J Esbenshade, Michael L Nieder, Sarah Alexander, William J Steinbach, Ha Dang, Doojduen Villaluna, Lu Chen, Micah Skeens, Theoklis E Zaoutis, Lillian Sung, Brian T Fisher

Faculty, Staff and Student Publications

BACKGROUND: Invasive fungal disease (IFD) is a major source of morbidity and mortality for hematopoietic cell transplant (HCT) recipients. Non-invasive biomarkers, such as the beta-D-glucan assay, may improve the diagnosis of IFD. The objective was to define the utility of surveillance testing using Fungitell® beta-D-glucan (BDG) assay in children receiving antifungal prophylaxis in the immediate post-HCT period.

METHODS: Weekly surveillance blood testing with the Fungitell® BDG assay was performed during the early post-HCT period in the context of a randomized trial of children, adolescents, and young adults undergoing allogeneic HCT allocated to triazole or caspofungin prophylaxis. Positivity was defined at …

Profiling Human Pathogenic Repeat Expansion Regions By Synergistic And Multi-Level Impacts On Molecular Connections, Cong Fan, Ken Chen, Yukai Wang, Edward V Ball, Peter D Stenson, Matthew Mort, Albino Bacolla, Hildegard Kehrer-Sawatzki, John A Tainer, David N Cooper, Huiying Zhao

Faculty, Staff and Student Publications

Whilst DNA repeat expansions cause numerous heritable human disorders, their origins and underlying pathological mechanisms are often unclear. We collated a dataset comprising 224 human repeat expansions encompassing 203 different genes, and performed a systematic analysis with respect to key topological features at the DNA, RNA and protein levels. Comparison with controls without known pathogenicity and genomic regions lacking repeats, allowed the construction of the first tool to discriminate repeat regions harboring pathogenic repeat expansions (DPREx). At the DNA level, pathogenic repeat expansions exhibited stronger signals for DNA regulatory factors (e.g. H3K4me3, transcription factor-binding sites) in exons, promoters, 5'UTRs and …

Energy Intake At The Intersection Of The Clock And Ageing, Kristin Eckel-Mahan

Faculty, Staff and Student Publications

Calorie restriction and timed dietary intake are two approaches known to increase lifespan or delay age-associated diseases. New studies reveal the importance of the ‘how much’ and ‘when’ of dietary intake in ageing modulation and collectively demonstrate how protection of the internal clock by diet can delay the ageing process.

Phase Ii Trial Of Weekly Erlotinib Dosing To Reduce Duodenal Polyp Burden Associated With Familial Adenomatous Polyposis, N Jewel Samadder, Nathan Foster, Ryan P Mcmurray, Carol A Burke, Elena Stoffel, Priyanka Kanth, Rohit Das, Marcia Cruz-Correa, E Vilar, Gautam Mankaney, Navtej Buttar, Selvi Thirumurthi, Danielle K Turgeon, Michael Sossenheimer, Michelle Westover, Ellen Richmond, Asad Umar, Gary Della'zanna, Luz M Rodriguez, Eva Szabo, David Zahrieh, Paul J Limburg

Faculty, Staff and Student Publications

Importance: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate.

Objective: To evaluate if a once weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP.

Design, setting and participants: Single-arm trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in eight academic cancer centres.

Exposures: Participants self-administered 350 mg of erlotinib …

Serum Biomarkers Correlated With Liver Stiffness Assessed In A Multicenter Study Of Pediatric Cholestatic Liver Disease, Daniel H Leung, Sridevi Devaraj, Nathan P Goodrich, Xinpu Chen, Deepthi Rajapakshe, Wen Ye, Victor Andreev, Charles G Minard, Danielle Guffey, Jean P Molleston, Lee M Bass, Saul J Karpen, Binita M Kamath, Kasper S Wang, Shikha S Sundaram, Philip Rosenthal, Patrick Mckiernan, Kathleen M Loomes, M Kyle Jensen, Simon P Horslen, Jorge A Bezerra, John C Magee, Robert M Merion, Ronald J Sokol, Benjamin L Shneider, Estella Alonso, Lee Bass, Susan Kelly, Mary Riordan, Hector Melin-Aldana, Jorge Bezerra, Kevin Bove, James Heubi, Alexander Miethke, Greg Tiao, Julie Denlinger, Erin Chapman, Ronald Sokol, Amy Feldman, Cara Mack, Michael Narkewicz, Frederick Suchy, Shikha S Sundaram, Johan Van Hove, Benigno Garcia, Mikaela Kauma, Kendra Kocher, Matthew Steinbeiss, Mark Lovell, Kathleen M Loomes, David Piccoli, Elizabeth Rand, Pierre Russo, Nancy Spinner, Jessi Erlichman, Samantha Stalford, Dina Pakstis, Sakya King, Robert Squires, Rakesh Sindhi, Veena Venkat, Kathy Bukauskas, Patrick Mckiernan, Lori Haberstroh, James Squires, Philip Rosenthal, Laura Bull, Joanna Curry, Camille Langlois, Grace Kim, Jeffery Teckman, Vikki Kociela, Rosemary Nagy, Shraddha Patel, Jacqueline Cerkoski, Jean P Molleston, Molly Bozic, Girish Subbarao, Ann Klipsch, Cindy Sawyers, Oscar Cummings, Simon P Horslen, Karen Murray, Evelyn Hsu, Kara Cooper, Melissa Young, Laura Finn, Binita M Kamath, Vicky Ng, Claudia Quammie, Juan Putra, Deepika Sharma, Aishwarya Parmar, Stephen Guthery, Kyle Jensen, Ann Rutherford, Amy Lowichik, Linda Book, Rebecka Meyers, Tyler Hall, Kasper S Wang, Sonia Michail, Danny Thomas, Catherine Goodhue, Rohit Kohli, Larry Wang, Nisreen Soufi, Daniel Thomas, Saul Karpen, Nitika Gupta, Rene Romero, Miriam B Vos, Rita Tory, John-Paul Berauer, Carlos Abramowsky, Jeanette Mcfall, Benjamin L Shneider, Sanjiv Harpavat, Paula Hertel, Daniel Leung, Mary Tessier, Deborah Schady, Laurel Cavallo, Diego Olvera, Christina Banks, Cynthia Tsai, Richard Thompson, Edward Doo, Jay Hoofnagle, Averell Sherker, Rebecca Torrance, Sherry Hall, John Magee, Robert Merion, Cathie Spino, Wen Ye

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.

APPROACH AND RESULTS: A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM …

Structure Of The Lysosomal Mtorc1-Tfeb-Rag-Ragulator Megacomplex, Zhicheng Cui, Gennaro Napolitano, Mariana E G De Araujo, Alessandra Esposito, Jlenia Monfregola, Lukas A Huber, Andrea Ballabio, James H Hurley

Duncan NRI Faculty and Staff Publications

The transcription factor TFEB is a master regulator of lysosomal biogenesis and autophagy1. The phosphorylation of TFEB by the mechanistic target of rapamycin complex 1 (mTORC1)2–5 is unique in its mTORC1 substrate recruitment mechanism, which is strictly dependent on the amino acid-mediated activation of the RagC GTPase activating protein FLCN6,7. TFEB lacks the TOR signalling motif responsible for the recruitment of other mTORC1 substrates. We used cryogenic-electron microscopy to determine the structure of TFEB as presented to mTORC1 for phosphorylation, which we refer to as the ‘megacomplex’. Two full Rag–Ragulator complexes …

The Roles Of Cyp1a2 And Cyp2d In Pharmacokinetic Profiles Of Serotonin And Norepinephrine Reuptake Inhibitor Duloxetine And Its Metabolites In Mice, Xuan Qin, Cen Xie, John M Hakenjos, Kevin R Mackenzie, Shelton R Boyd, Mercedes Barzi, Karl-Dimiter Bissig, Damian W Young, Feng Li

Faculty, Staff and Students Publications

Duloxetine (DLX) is widely used to treat major depressive disorder. Little is known about the mechanistic basis for DLX-related adverse effects (e.g., liver injury). Human CYP1A2 and CYP2D6 mainly contributes to DLX metabolism, which was proposed to be involved in its adverse effects. Here, we investigated the roles of Cyp1a2 and Cyp2d on DLX pharmacokinetic profile and tissue distribution using a Cyp1a2 knockout (Cyp1a2-KO) mouse model together with a Cyp2d inhibitor (propranolol). Cyp1a2-KO has the few effects on the systematic exposure (area under the plasma concentration-time curve, AUC) and tissue disposition of DLX and its primary metabolites. Propranolol dramatically increased …

Effect Of Liquid And Solid Test Meals On Symptoms And Gastric Myoelectrical Activity In Patients With Gastroparesis And Functional Dyspepsia, Kenneth L Koch, Mark Van Natta, Henry P Parkman, Madhusudan Grover, Thomas L Abell, Richard W Mccallum, Hossam A Shaltout, Irene Sarosiek, Gianrico Farrugia, Robert J Shulman, James Tonascia, Laura Miriel, Frank Hamilton, Pankaj J Pasricha, Gastroparesis Clinical Research Consortium

Faculty, Staff and Students Publications

BACKGROUND: Patients with gastroparesis (GP) and functional dyspepsia (FD) have similar symptoms, but the pathophysiology of postprandial symptoms remains uncertain.

AIMS: To compare symptoms and gastric myoelectrical activity (GMA) after liquid and solid test meals in patients with GP and FD.

METHODS: Patients enrolled in the Gastroparesis Clinical Research Consortium Registry were studied. Clinical characteristics were measured with standard questionnaires. GP was determined by 4-h solid-phase gastric scintigraphy. GMA was measured using electrogastrography before and after ingestion of a water load or nutrient bar on separate days. Symptoms were measured on visual analog scales. GMA responses to the water load …