Medical Nutrition Commons^™

Dub3 Inhibition Suppresses Breast Cancer Invasion And Metastasis By Promoting Snail1 Degradation, Yadi Wu, Yu Wang, Yiwei Lin, Yajuan Liu, Yifan Wang, Jianhang Jia, Puja Singh, Young-In Chi, Chi Wang, Chenfang Dong, Wei Li, Min Tao, Dana L. Napier, Qiuying Shi, Jiong Deng, B. Mark Evers, Binhua P. Zhou

Pharmacology and Nutritional Sciences Faculty Publications

Snail1, a key transcription factor of epithelial–mesenchymal transition (EMT), is subjected to ubiquitination and degradation, but the mechanism by which Snail1 is stabilized in tumours remains unclear. We identify Dub3 as a bona fide Snail1 deubiquitinase, which interacts with and stabilizes Snail1. Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis. These effects are rescued by ectopic Snail1 expression. IL-6 also stabilizes Snail1 by inducing Dub3 expression, the specific inhibitor WP1130 binds to Dub3 and inhibits the Dub3-mediating Snail1 stabilization in vitroand in vivo. …

M2 Polarization Of Macrophages Facilitates Arsenic-Induced Cell Transformation Of Lung Epithelial Cells, Jiajun Cui, Wenhua Xu, Jian Chen, Hui Li, Lu Dai, Jacqueline A. Frank, Shaojun Peng, Siying Wang, Gang Chen

Pharmacology and Nutritional Sciences Faculty Publications

The alterations in microenvironment upon chronic arsenic exposure may contribute to arsenic-induced lung carcinogenesis. Immune cells, such as macrophages, play an important role in mediating the microenvironment in the lungs. Macrophages carry out their functions after activation. There are two activation status for macrophages: classical (M1) or alternative (M2); the latter is associated with tumorigenesis. Our previous work showed that long-term arsenic exposure induces transformation of lung epithelial cells. However, the crosstalk between epithelial cells and macrophages upon arsenic exposure has not been investigated. In this study, using a co-culture system in which human lung epithelial cells are cultured with …

Use Of The Ketogenic Diet In The Neonatal Intensive Care Unit-Safety And Tolerability., Lindsey M. Thompson, Erin Day Fecske, Mohammad Salim, Ara Hall

Manuscripts, Articles, Book Chapters and Other Papers

Drug-resistant epilepsy poses a challenge in neonatal patients, especially those in the neonatal intensive care unit (NICU), who have various secondary comorbidities. We present results of four children with a history of drug-resistant epilepsy for whom a ketogenic diet was initiated and used in the NICU. A nonfasting induction into ketosis over 1-2 weeks was utilized, with gradual increases in the ketogenic ratio every 2-3 days. Data were collected retrospectively from a database, which included medical history, daily progress notes, relevant laboratory data, and imaging and diagnostic information. The ketogenic diet was well tolerated in all cases. The most common …

Inhibition Of The Integrin/Fak Signaling Axis And C-Myc Synergistically Disrupts Ovarian Cancer Malignancy, B. Xu, Jason R. Lefringhouse, Z. Liu, D. West, Lauren A. Baldwin, C. Ou, L. Chen, Dana L. Napier, Luksana Chaiswing, Lawrence D. Brewer, Daret K. St Clair, Olivier Thibault, John R. Van Nagell, Binhua P. Zhou, R. Drapkin, J.-A. Huang, M. L. Lu, Frederick R. Ueland, X. H. Yang

Pharmacology and Nutritional Sciences Faculty Publications

Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor. From this screening, JQ1, a potent inhibitor of Myc oncogenic network, emerged as the most robust collaborator. Treatment with a combination of VS-6063 …

Sodium-Myoinositol Cotransporter-1, Smit1, Mediates The Production Of Reactive Oxygen Species Induced By Hyperglycemia In The Heart, Anne Van Steenbergen, Magali Balteau, Audrey Ginion, Laura Ferté, Sylvain Battault, Christophe De Meester De Ravenstein, Jean-Luc Balligand, Evangelos-Panagiotis Daskalopoulos, Patrick Gilon, Florin Despa, Sanda Despa, Jean-Louis Vanoverschelde, Sandrine Horman, Hermann Koepsell, Gerard Berry, Louis Hue, Luc Bertrand, Christophe Beauloye

Pharmacology and Nutritional Sciences Faculty Publications

Hyperglycemia (HG) stimulates the production of reactive oxygen species in the heart through activation of NADPH oxidase 2 (NOX2). This production is independent of glucose metabolism but requires sodium/glucose cotransporters (SGLT). Seven SGLT isoforms (SGLT1 to 6 and sodium-myoinositol cotransporter-1, SMIT1) are known, although their expression and function in the heart remain elusive. We investigated these 7 isoforms and found that only SGLT1 and SMIT1 were expressed in mouse, rat and human hearts. In cardiomyocytes, galactose (transported through SGLT1) did not activate NOX2. Accordingly, SGLT1 deficiency did not prevent HG-induced NOX2 activation, ruling it out in the cellular response to …

Translational Models For Vascular Cognitive Impairment: A Review Including Larger Species, Atticus H. Hainsworth, Stuart M. Allan, Johannes Boltze, Catriona Cunningham, Chad Farris, Elizabeth Head, Masafumi Ihara, Jeremy D. Isaacs, Raj N. Kalaria, Saskia A. M. J. Lesnik Oberstein, Mark B. Moss, Björn Nitzsche, Gary A. Rosenberg, Julie W. Rutten, Melita Salkovic-Petrisic, Aron M. Troen

Pharmacology and Nutritional Sciences Faculty Publications

Background: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited.

Methods: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, …

Which Food Security Determinants Predict Adequate Vegetable Consumption Among Rural Western Australian Children?, Stephanie L. Godrich, Johnny Lo, Christina R. Davies, Jill Darby, Amanda Devine

Research outputs 2014 to 2021

Improving the suboptimal vegetable consumption among the majority of Australian children is imperative in reducing chronic disease risk. The objective of this research was to determine whether there was a relationship between food security determinants (FSD) (i.e., food availability, access, and utilisation dimensions) and adequate vegetable consumption among children living in regional and remote Western Australia (WA). Caregiver-child dyads (n = 256) living in non-metropolitan/rural WA completed cross-sectional surveys that included questions on FSD, demographics and usual vegetable intake. A total of 187 dyads were included in analyses, which included descriptive and logistic regression analyses via IBM SPSS (version 23). …

Combating Diabetes In Chittenden County: A Healthcare Provider Referral Campaign To Increase Patient Participation In The Vermont Diabetes Prevention Program, Samantha Magier

Family Medicine Clerkship Student Projects

As of 2016, diabetes affects more than 29 million people in the United States and is the 7th leading cause of death nationwide. In Vermont, 1/10 people are diagnosed with either diabetes or prediabetes, with 6% of Vermonters affected by prediabetes and 5% of Chittenden Country affected by prediabetes. The public health burden of this chronic disease is immense: diabetes costs Vermont an estimated $543 million each year and is the leading cause of kidney failure, lower limb amputations, and adult-onset blindness. Prediabetes occurs when blood sugar is higher than normal but not at the diagnostic threshold of diabetes. Prediabetes …

Motility And Adhesion Through Type Iv Pili In Gram-Positive Bacteria, Kurt H. Piepenbrink, Eric J. Sundberg

Food for Health Papers & Publications

Type IV pili are hair-like bacterial surface appendages that play a role in diverse processes such as cellular adhesion, colonization, twitching motility, biofilm formation, and horizontal gene transfer. These extracellular fibers are composed exclusively or primarily of many copies of one or more pilin proteins, tightly packed in a helix so that the highly hydrophobic amino-terminus of the pilin is buried in the pilus core. Type IV pili have been characterized extensively in Gram-negative bacteria, and recent advances in high-throughput genomic sequencing have revealed that they are also widespread in Gram-positive bacteria. Here, we review the current state of knowledge …

Oral Carbohydrate Administration Prior To Colorectal Surgery: Practice Change Outcomes And Economic Analysis, Joshua Kendrick Ezelle

Doctoral Projects

Difference in recovery times has been an interest of mine for many years. I observed that an open heart surgery routinely recovered and discharged on the third post-op day, while a colorectal patient often required a hospital stay of five to ten days. I began researching recovery methods of colorectal patients. I found enhanced recovery techniques like decreased narcotic, use of NSAID’s, early ambulation, and the use of medications that assist with bowel peristalsis are being employed nationally. Other techniques are now starting to be used with positive results. One of these is Carb-loading. Carb-loading is the oral intake of …

A Generalized Framework For Computational Design And Mutational Scanning Of T-Cell Receptor Binding Interfaces, Timothy P. Riley, Cory M. Ayres, Lance M. Hellman, Nishant K. Singh, Michael Cosiano, Jennifer M. Cimons, Michael J. Anderson, Kurt H. Piepenbrink, Brian G. Pierce, Zhiping Weng, Brian M. Baker

Food for Health Papers & Publications

T-cell receptors (TCRs) have emerged as a new class of therapeutics, most prominently for cancer where they are the key components of new cellular therapies as well as soluble biologics. Many studies have generated high affinity TCRs in order to enhance sensitivity. Recent outcomes, however, have suggested that fine manipulation of TCR binding, with an emphasis on specificity may be more valuable than large affinity increments. Structure-guided design is ideally suited for this role, and here we studied the generality of structure-guided design as applied to TCRs. We found that a previous approach, which successfully optimized the binding of a …

Current And Emerging Uses Of Statins In Clinical Therapeutics: A Review, Jonathan T. Davies, Spencer F. Delfino, Chad E. Feinberg, Meghan F. Johnson, Veronica L. Nappi, Joshua T. Olinger, Anthony P. Schwab, Hollie I. Swanson

Pharmacology and Nutritional Sciences Faculty Publications

Statins, a class of cholesterol-lowering medications that inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, are commonly administered to treat atherosclerotic cardiovascular disease. Statin use may expand considerably given its potential for treating an array of cholesterol-independent diseases. However, the lack of conclusive evidence supporting these emerging therapeutic uses of statins brings to the fore a number of unanswered questions including uncertainties regarding patient-to-patient variability in response to statins, the most appropriate statin to be used for the desired effect, and the efficacy of statins in treating cholesterol-independent diseases. In this review, the adverse effects, costs, and drug–drug and drug–food interactions associated with statin …

Vitamin K2 (Menaquinone) Supplementation And Its Benefits In Cardiovascular Disease, Osteoporosis, And Cancer, Grant S. Buchanan, Md, Thomas Melvin, Brandon Merritt, Charles Bishop, Md, Franklin D. Shuler, Md, Phd

Franklin D. Shuler

Vitamin K is known to play an essential role in the coagulation cascade; however, a growing body of research has found that a subtype of this vitamin, vitamin K2 (menaquinone) may have a beneficial effect in osteoporosis, cardiovascular disease, and cancer. This purpose of this article is to provide a comprehensive review of recent literature regarding menaquinone and its role in human health. This review discusses the physiology of menaquinone, its clinical benefits in cardiovascular disease, osteoporosis, and cancer, and how it may interact with certain medications. The authors conclude that menaquinone supplementation has been shown to improve carboxylation of …

Malnutrition In The Older Australian Rural Rehabilitation Community : Indentification, Patient Outcomes And The Role Of Informal Caregivers, Skye Marshall

Skye Marshall

Enhancing the effectiveness of nutritional care to improve the overall health of older adults will be key in reducing hospital and aged care facility demand, a priority target of current health service research and policy. Engaging informal caregivers as part of the nutrition care team presents an opportunity for improving the nutrition status of older Australians in rehabilitation and the community. This thesis provides evidence to improve malnutrition screening, assessment, diagnosis and resource allocation in rehabilitation facilities. It also makes recommendations to improve nutrition intervention in practice, and for how intervention studies should be designed in this setting. The thesis …

Process Evaluation Of A Patient-Centred, Patientdirected, Group-Based Education Program For The Management Of Type 2 Diabetes Mellitus, Kate Odgers-Jewell, Elisabeth Isenring, Rae Thomas, Dianne P Reidlinger

Rae Thomas

Aim: The present study developed and evaluated a patient-centred, patient-directed, group-based education program for the management of type 2 diabetes mellitus. Methods: Two frameworks, the Medical Research Council (MRC) framework for developing and evaluating complex interventions and the RE-AIM framework were followed. Data to develop the intervention were sourced from scoping of the literature and formative evaluation. Program evaluation comprised analysis of primary recruitment of participants through general practitioners, baseline and end-point measures of anthropometry, four validated questionnaires, contemporaneous facilitator notes and telephone interviews with participants. Results: A total of 16 participants enrolled in the intervention. Post-intervention results were obtained …

Process Evaluation Of A Patient-Centred, Patientdirected, Group-Based Education Program For The Management Of Type 2 Diabetes Mellitus, Kate Odgers-Jewell, Elisabeth Isenring, Rae Thomas, Dianne P Reidlinger

Liz Isenring

Aim: The present study developed and evaluated a patient-centred, patient-directed, group-based education program for the management of type 2 diabetes mellitus. Methods: Two frameworks, the Medical Research Council (MRC) framework for developing and evaluating complex interventions and the RE-AIM framework were followed. Data to develop the intervention were sourced from scoping of the literature and formative evaluation. Program evaluation comprised analysis of primary recruitment of participants through general practitioners, baseline and end-point measures of anthropometry, four validated questionnaires, contemporaneous facilitator notes and telephone interviews with participants. Results: A total of 16 participants enrolled in the intervention. Post-intervention results were obtained …

Tgf-Β Signaling: New Insights Into Aortic Aneurysms, Sean E. Thatcher

Pharmacology and Nutritional Sciences Faculty Publications

No abstract provided.

Lifestyle And Other Factors Explain One-Half Of The Variability In The Serum 25-Hydroxyvitamin D Response To Cholecalciferol Supplementation In Healthy Adults, Judy R. Rees, Leila A. Mott, Elizabeth L. Barry, John A. Baron

Dartmouth Scholarship

Background: Many factors have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentrations in observational studies, with variable consistency. However, less information is available on factors affecting the magnitude of changes in serum 25(OH)D resulting from vitamin D supplementation. Objective: This study aimed to identify factors associated with the serum 25(OH)D response to supplementation with 1000 IU cholecalciferol/d during the first year of a large, multicenter, randomized, placebo-controlled colorectal adenoma chemoprevention trial. Methods: Eligible older adults who were not vitamin D–deficient [serum 25(OH)D12 ng/mL] were randomly assigned in a modified 2 3 2 factorial design to 1 of 4 groups: daily …

Structural Diversity In The Type Iv Pili Of Multidrug-Resistant Acinetobacter, Kurt H. Piepenbrink, Erik Lillehoj, Christian M. Harding, Jason W. Labonte, Xiaotong Zuo, Chelsea A. Rapp, Robert S. Munson Jr, Simeon E. Goldblum, Mario F. Feldman, Jeffrey J. Gray, Eric J. Sundberg

Food for Health Papers & Publications

Acinetobacter baumannii is a Gram-negative coccobacillus found primarily in hospital settings that has recently emerged as a source of hospital-acquired infections. A. baumannii expresses a variety of virulence factors, including type IV pili, bacterial extracellular appendages often essential for attachment to host cells. Here, we report the high resolution structures of the major pilin subunit, PilA, from three Acinetobacter strains, demonstrating thatA. baumannii subsets produce morphologically distinct type IV pilin glycoproteins. We examine the consequences of this heterogeneity for protein folding and assembly as well as host-cell adhesion by Acinetobacter. Comparisons of genomic and structural data with pilin proteins from …

The Neu1-Selective Sialidase Inhibitor, C9- Butyl-Amide-Dana, Blocks Sialidase Activity And Neu1-Mediated Bioactivities In Human Lung In Vitro And Murine Lung In Vivo, Sang W. Hyun, Anguo Liu, Zhenguo Liu, Alan S. Cross, Avelino C. Verceles, Sadagopan Magesh, Yadagiri Kommagalla, Chandrababunaidu Kona, Hiromune Ando, Irina G. Luzina, Sergei P. Atamas, Kurt H. Piepenbrink, Eric J. Sundberg, Wei Guang, Hideharu Ishida, Erik P. Lillehoj, Simeon E. Goldblum

Food for Health Papers & Publications

Neuraminidase-1 (NEU1) is the predominant sialidase expressed in human airway epithelia and lung microvascular endothelia where it mediates multiple biological processes. We tested whether the NEU1-selective sialidase inhibitor, C9-butyl-amide-2-deoxy-2,3-dehydro-Nacetylneuraminic acid (C9-BA-DANA), inhibits one or more established NEU1-mediated bioactivities in human lung cells. We established the IC50 values of C9-BA-DANA for total sialidase activity in human airway epithelia, lung microvascular endothelia and lung fibroblasts to be 3.74 µM, 13.0 µM and 4.82 µM, respectively. In human airway epithelia, C9-BA-DANA dose-dependently inhibited flagellin-induced, NEU1-mediated mucin-1 ectodomain desialylation, adhesiveness for Pseudomonas aeruginosa and shedding. In lung microvascular endothelia, C9-BA-DANA reversed NEU1-driven restraint of …