Impact Of Sleep And Circadian Disruption On Energy Balance And Diabetes: A Summary Of Workshop Discussions, Deanna M. Arble, Joseph Bass, Cecilia Diniz Behn, Matthew P. Butler, Etienne Challet, Charles Czeisler, Christopher M. Depner, Joel Elmquist, Paul Franken, Michael A. Grandner, Erin C. Hanlon, Alex C. Keene, Michael J. Joyner, Ilia Karatsoreos, Philip A. Kern, Samuel Klein, Christopher J. Morris, Allan I. Pack, Satchidananda Panda, Louis J. Ptacek, Naresh M. Punjabi, Paolo Sassone-Corsi, Frank A. Scheer, Richa Saxena, Elizabeth R. Seaquest, Matthew S. Thimgan, Eve Van Cauter, Kenneth P. Wright

Clinical and Translational Science Faculty Publications

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact …

Mechanisms And Intervention Strategies For Alcohol And Hiv-Antiretroviral Therapy-Induced Liver Injury., Hridgandh Donde

Electronic Theses and Dissertations

Chronic alcohol consumption is a leading cause of liver disease and liver-related death worldwide. Alcoholic liver disease includes, hepatic steatosis, steatohepatitis and ultimately fibrosis and cirrhosis. Emerging evidence has established the important role of the “gut-liver” axis in the development of alcoholic liver disease (ALD). Our recent work indicated that chronic alcohol induced perturbations in the gut microbiome and consequent changes in fatty acids have a major impact on the development of intestinal barrier dysfunction and ALD. The aim of this study was to investigate whether treatment with tributyrin - a butyrate prodrug results in protection against ALD in terms …

Prediction Of Laser Ablation In Brain: Sensitivity, Calibration, And Validation, Samuel J. Fahrenholtz

Dissertations and Theses (Open Access)

The surgical planning of MR-guided laser induced thermal therapy (MRgLITT) stands to benefit from predictive computational modeling. The dearth of physical model parameter data leads to modeling uncertainty. This work implements a well-accepted framework with three key steps for model-building: model-parameter sensitivity analysis, model calibration, and model validation.

The sensitivity study is via generalized polynomial chaos (gPC) paired with a transient finite element (FEM) model. Uniform probability distribution functions (PDFs) capture the plausible range of values suggested by the literature for five model parameters. The five PDFs are input separately into the FEM model to gain a probabilistic sensitivity response …

Redirecting T Cells With Chimeric Antigen Receptors To Target Cd123+ Leukemia, Radhika Thokala

Dissertations and Theses (Open Access)

ABSTRAC

REDIRECTING T CELLS WITH CHIMERIC ANTIGEN RECEPTORS TO TARGET CD123+ LEUKEMIA

Radhika Thokala, Ph.D*

Advisory Professor: Dean Anthony Lee, M.D, Ph.D

CD123 or interleukin receptor alpha (IL-3Rα) is expressed on hematological malignancies such as acute myeloid leukemia (AML) and some acute lymphoblastic leukemia (ALL). Significantly, CD123 is over-expressed on leukemic stem cells (LSCs) compared to normal hematopoietic stem cells and thus targeting this tumor- associated antigen (TAA) provides the potential to prevent relapse. The prototyical chimeric antigen receptor (CAR) is fashioned by …

Fibronectin Signals Through Integrin Α5Β1 To Regulate Cardiovascular Development In A Cell Type-Specific Manner., Dongying Chen, Xia Wang, Dong Liang, Julie Gordon, Ashok Mittal, Nancy Manley, Karl Degenhardt, Sophie Astrof

Department of Medicine Faculty Papers

Fibronectin (Fn1) is an evolutionarily conserved extracellular matrix glycoprotein essential for embryonic development. Global deletion of Fn1 leads to mid-gestation lethality from cardiovascular defects. However, severe morphogenetic defects that occur early in embryogenesis in these embryos precluded assigning a direct role for Fn1 in cardiovascular development. We noticed that Fn1 is expressed in strikingly non-uniform patterns during mouse embryogenesis, and that its expression is particularly enriched in the pharyngeal region corresponding with the pharyngeal arches 3, 4, and 6. This region bears a special importance for the developing cardiovascular system, and we hypothesized that the localized enrichment of Fn1 in …

Extrapolating Evidence About Preventing Recurrent Cellulitis For An Individual Patient Concern, Christina L. Benkert D.O., Amrit K. Basi, Kristina L. Bahrou M.D., Catherine R. Cherri M.D., Suraiya K. Azom M.D., Nicholus H. Yee M.D.

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Thomas KS, Crook AM, Nunn AJ, et al. Penicillin to prevent recurrent leg cellulitis, N Engl J Med. 2013, May 2;368(18):1695-1703. doi: 10.1056/NEJMoa1206300

Interrater Variability In Identifying Ventilator Associated Pneumonia Using Six Different Definitions, Ahmad Nusair, Md, Balwinder Singh, Md, Ms., Shifang Ding, Md, Phd., Ognjen Gajic, Md, Guangxi Li, Md

Marshall Journal of Medicine

Objective

There is no widely accepted standard definition for Ventilator Associated Pneumonia (VAP). The reliability of the current definitions in use remains controversial. Our objective was to assess the reliability of six commonly used VAP definitions: The Loose, The Rigorous, The Modified Clinical Pulmonary Infection Score (CPIS), The Canadian Critical Care Trials Group (CCCTG), The International Sepsis Forum Consensus (ISFC) and The Center for Disease Control and Prevention (CDC).

Design

We examined the electronic health records of all the consecutively admitted adult patients at our institution who received invasive mechanical ventilation (IMV) for ≥ 48 hours, from January 2006 through …

Rectal Indomethacin Reduces The Risk Of Post-Ercp Pancreatitis, John Dawdy

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical appraisal and clinical application of Elmunzer BJ, Scheiman JM, Lehman GA, Chak A, Mosler P, et al. A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med. 2012;366:1414–22. doi: 10.1056/NEJMoa1111103

Breast Cancer-Derived Extracellular Vesicles: Characterization And Contribution To The Metastatic Phenotype, Toni M. Green, Mary L. Alpaugh, Sanford H. Barsky, Germana Rappa, Aurelio Lorico

College of Science & Mathematics Departmental Research

The study of extracellular vesicles (EVs) in cancer progression is a complex and rapidly evolving field. Whole categories of cellular interactions in cancer which were originally presumed to be due solely to soluble secreted molecules have now evolved to include membrane-enclosed extracellular vesicles (EVs), which include both exosomes and shed microvesicles (MVs), and can contain many of the same molecules as those secreted in soluble form but many different molecules as well. EVs released by cancer cells can transfer mRNA, miRNA, and proteins to different recipient cells within the tumor microenvironment, in both an autocrine and paracrine manner, causing a …

Akt Kinase C-Terminal Modifications Control Activation Loop Dephosphorylation And Enhance Insulin Response., Tung O. Chan, Jin Zhang, Brian C. Tiegs, Brian Blumhof, Linda Yan, Nikhil Keny, Morgan Penny, Xue Li, John M. Pascal, Roger S. Armen, Ulrich Rodeck, Raymond B. Penn

Center for Translational Medicine Faculty Papers

The Akt protein kinase, also known as protein kinase B, plays key roles in insulin receptor signalling and regulates cell growth, survival and metabolism. Recently, we described a mechanism to enhance Akt phosphorylation that restricts access of cellular phosphatases to the Akt activation loop (Thr(308) in Akt1 or protein kinase B isoform alpha) in an ATP-dependent manner. In the present paper, we describe a distinct mechanism to control Thr(308) dephosphorylation and thus Akt deactivation that depends on intramolecular interactions of Akt C-terminal sequences with its kinase domain. Modifications of amino acids surrounding the Akt1 C-terminal mTORC2 (mammalian target of rapamycin …

Experiences With The Streptococcus Mutans In Lakota Sioux (Smiles) Study: Risk Factors For Caries In American Indian Children 0-3 Years, David R. Drake, Deborah Dawson, Katherine Kramer, Amy Schumacher, John Warren, Teresa Marshall, Delores Starr, Kathy Phipps

Journal of Health Disparities Research and Practice

Severe Early Childhood Caries (S-ECC) is a terribly aggressive and devastating disease that is all too common in lower socio-economic children, but none more so that what is encountered in American Indian Tribes. Nationwide, approximately 27% of 2-5 year olds have decay while 62% percent of American Indian/Alaska Native children in the same age group have a history of decay (IHS 2010, NHANES 1999-2002). We have conducted a study of children from birth to 36 months of age on Pine Reservation to gain a better understanding of the variables that come into play in the development of this disease, from …

Assessment Of The Perceived Role And Function Of A Community Advisory Board In A Nih Center Of Excellence: Lessons Learned, Margaret L. Walsh, Desiree Rivers, Maria Pinzon, Nina Entrekin, Emily M. Hite, Julie A. Baldwin

Journal of Health Disparities Research and Practice

Background: The Community Advisory Board (CAB) was a vital component of the Center for Equal Health. The center addressed health disparities through community-based research and educational outreach initiatives. Objectives: To evaluate the perceived relationship of the CAB and Center, explore members’ perceptions of the CAB’s role, and elicit feedback on how to enhance the relationship between the Center and the CAB. Methods: Ten in-depth, semi-structured interviews were conducted. All interviews were transcribed verbatim and analyzed with a focus on predetermined codes. Results: Main themes focused on perception of CAB roles and need for utilization of board members; overall center challenges; …

Implementation And Feasibility Of An Auricular Acupuncture Intervention For Smoking Cessation In A Residential Spiritual Recovery Program: A Pilot Study, Cynthia Johnson, Payam Sheikhattari, Lixing Lao, Yvonne Bronner, Fernando Wagner

Journal of Health Disparities Research and Practice

Abstract

This study examined the feasibility of recruiting of participants and retention to an auricular acupuncture intervention for smoking cessation at a residential spiritual recovery program for a chemically dependent population in the mid-Atlantic region. The association between beliefs about acupuncture and smoking cessation were also assessed. This was an intervention study guided by the principles of Community Based Participatory Research (CBPR).

The National Acupuncture Detoxification Association (NADA) protocol was used as part of the smoking cessation intervention (participants received auricular acupuncture for 40 minutes, 3 times per week for 1 month). Smoking cessation, adherence rate to the treatment plan, …

Isoform-Specific Dynamic Translocation Of Pkc By Α1-Adrenoceptor Stimulation In Live Cells., Jin O-Uchi, Jaime Sorenson, Bong Sook Jhun, Jyotsna Mishra, Stephen Hurst, Kaleef Williams, Shey-Shing Sheu, Coeli M.B. Lopes

Center for Translational Medicine Faculty Papers

Protein kinase C (PKC) plays key roles in the regulation of signal transduction and cellular function in various cell types. At least ten PKC isoforms have been identified and intracellular localization and trafficking of these individual isoforms are important for regulation of enzyme activity and substrate specificity. PKC can be activated downstream of Gq-protein coupled receptor (GqPCR) signaling and translocate to various cellular compartments including plasma membrane (PM). Recent reports suggested that different types of GqPCRs would activate different PKC isoforms (classic, novel and atypical PKCs) with different trafficking patterns. However, the knowledge of isoform-specific activation of PKC by each …

Research Design Creates Ambiguity Related To Efficacy Of Sickle Cell, Chronic Disease Specialty Clinic, Scott J. Dawsey

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Koch KL, Karafin MS, Simpson P, Field JJ. Intensive management of high-utilizing adults with sickle cell disease lowers admissions. Am J Hematol. 2015 Jan;90(3):215-219. doi:10.1002/ajh.23912

Use Of Smartphones To Capture Measures Of Functional Status In Frail And Non-Frail Community Dwelling Older Adults, Cassia R. Hanton

Theses & Dissertations

Numerous important health outcomes directly relate to one's ability to maintain normal gait speed. The purpose of this study is to employ ubiquitous smartphone technology, using algorithms developed and validated by our lab in a controlled setting, to continuously and noninvasively measure aspects of subject health status, including step counts, gait speed, and activity level, in a naturalistic community setting. A total of 33 ambulatory, independently dwelling older adults were recruited from Nebraska Medicine, including 22 healthy control and 11 frail individuals. Clinical performance measurements of frailty (4MW, TUG, F8W) and validated survey responses (LLFDI, SAFFE, PROMIS) were compared to …

Ex Vivo Expanded Cord Blood Natural Killer Cells As A Novel Therapeutic For Multiple Myeloma, Nina Shah

Dissertations and Theses (Open Access)

Multiple myeloma (MM) is the second most common hematologic malignancy in adults and, to date, is incurable. Allogeneic natural killer (NK) cells are active in various hematologic malignancies and may have a role against MM. Umbilical cord blood is a potential source for allogeneic NK cells and ex vivo expanded umbilical cord blood-derived NK (CB-NK) cells demonstrate activity comparable to that of peripheral blood-derived NK cells. However, large-scale expansion of these cells is required for clinical translation. Here we studied a potential method for ex vivo expansion of NK cells from fresh and cryopreserved CB. Using artificial antigen presenting cells …

Prophylactic Cranial Irradiation Reduces The Incidence Of Brain Metastasis In A Mouse Model Of Metastatic Breast Cancer, Daniel L. Smith

Dissertations and Theses (Open Access)

Prophylactic cranial irradiation (PCI) is a preventative whole-brain irradiation technique used to reduce the incidence of brain metastasis and improve overall survival in select patients with small cell lung cancer and acute lymphoblastic leukemia. A population of breast cancer patients – stage IV, HER2+ or triple-negative – has emerged as having a high risk of developing brain metastases. Because only 10-20% of breast cancer patients diagnosed with brain metastases survive longer than one year, in this high-risk population the benefit of PCI – potential for reduced incidence of brain metastasis and improved overall survival – may outweigh the risks – …

Ankyrin-B And Mtor Complex 1 In The Regulation Of Electrical Activities In The Heart, Henry C. Wu, Henry C. Wu

Dissertations and Theses (Open Access)

The mammalian target of rapamycin complex 1 (mTORC1) activity is paramount in the regulation of electrical activities in the brain and the heart. In the brain, the tumor suppressor gene TSC2 encodes the protein product tuberin that interacts with hamartin to form a heterodimer Tuberous Sclerosis Complex (TSC) that regulates mTORC1. When TSC2 is disrupted, mTORC1 activity becomes dysregulated resulting in abnormal electrical activities in the brain manifesting in the form of epileptic seizures. In the heart, mTORC1 activity is triggered by a sustained increase in hemodynamic pressure causing the heart to electrically remodel. A likely candidate serving as the …

New Evidence Prompts Rethinking The Clinical Management Of Community Acquired Pneumonia In Patients Admitted To General Medical Services., J. Timothy Caldwell

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Postma DF, van Werkhoven CH, van Elden LJR, et al. Antibiotic treatment strategies for community-acquired pneumonia in adults. N Engl J Med. 2015;372(14):1312-1323. doi:10.1056/NEJMoa1406330