Effect Of Two-Year Caloric Restriction On Bone Metabolism And Bone Mineral Density In Non-Obese Younger Adults: A Randomized Clinical Trial, Dt Villareal, L Fontana, Sk Das, Et Al.

Faculty, Staff and Students Publications

Although caloric restriction (CR) could delay biologic aging in humans, it is unclear if this would occur at the cost of significant bone loss. We evaluated the effect of prolonged CR on bone metabolism and bone mineral density (BMD) in healthy younger adults. Two-hundred eighteen non-obese (body mass index [BMI] 25.1?±?1.7?kg/m(2) ), younger (age 37.9?±?7.2 years) adults were randomly assigned to 25% CR (CR group, n?=?143) or ad libitum (AL group, n?=?75) for 2 years. Main outcomes were BMD and markers of bone turnover. Other outcomes included body composition, bone-active hormones, nutrient intake, and physical activity. Body weight (-7.5?±?0.4 versus …

Cme/Cne Article: A Framework Of Care In Multiple Sclerosis, Part 1, Scott D Newsome, Philip J Aliotta, Jacquelyn Bainbridge, Susan E Bennett, Gary Cutter, Kaylan Fenton, Fred Lublin, Dorothy Northrop, David Rintell, Bryan D Walker, Megan Weigel, Kathleen Zackowski, David E Jones

Faculty, Staff and Student Publications

Activity Available Online: To access the article, post-test, and evaluation online, go to http://www.cmscscholar.org.

TARGET AUDIENCE: The target audience for this activity is physicians, physician assistants, nursing professionals, and other health-care providers involved in the management of patients with multiple sclerosis (MS).

LEARNING OBJECTIVES: Apply new information about MS to a comprehensive individualized treatment plan for patients with MSIntegrate the team approach into long-term planning in order to optimize rehabilitation care of patients with MSAccreditation Statement: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) …

Activation Of Signal Transduction Pathways During Hepatic Oncogenesis, W Chung, M Kim, S De La Monte, L Longato, R Carlson, B L. Slagle, X Dong, J R. Wands

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Understanding the molecular pathogenesis of hepatocellular carcinoma (HCC) is essential to identify therapeutic targets. A hepatitis B virus (HBV) related double transgenic murine model was developed. METHODS: Liver specific expression of HBV X protein (HBx) and insulin receptor substrate 1 (IRS1) was achieved and transgenic mice were followed from birth to age 21 months. Liver and tumor tissue were assessed for histologic changes as well as activation of signal transduction pathways by qRT-PCR and multiplex ELISA protein assays. RESULTS: Overexpression of HBx and IRS1 stimulates liver cell proliferation in the double transgenic mice. Only the male mice …

Identification Of A Novel Gene On 10q221 Causing Autosomal Dominant Retinitis Pigmentosa (Adrp), Stephen P Daiger, Lori S Sullivan, Sara J Bowne, Daniel C Koboldt, Susan H Blanton, Dianna K Wheaton, Cheryl E Avery, Elizabeth D Cadena, Robert K Koenekoop, Robert S Fulton, Richard K Wilson, George M Weinstock, Richard A Lewis, David G Birch

Faculty, Staff and Students Publications

Whole-genome linkage mapping identified a region on chromosome 10q21.3-q22.1 with a maximum LOD score of 3.0 at 0 % recombination in a six-generation family with autosomal dominant retinitis pigmentosa (adRP). All known adRP genes and X-linked RP genes were excluded in the family by a combination of methods. Whole-exome next-generation sequencing revealed a missense mutation in hexokinase 1, HK1 c.2539G > A, p.Glu847Lys, tracking with disease in all affected family members. One severely-affected male is homozygous for this region by linkage analysis and has two copies of the mutation. No other potential mutations were detected in the linkage region nor were …

Local Corticotropin Releasing Hormone (Crh) Signals To Its Receptor Crhr1 During Postnatal Development Of The Mouse Olfactory Bulb, Isabella Garcia, Paramjit K Bhullar, Burak Tepe, Joshua Ortiz-Guzman, Longwen Huang, Alexander M Herman, Lesley Chaboub, Benjamin Deneen, Nicholas J Justice, Benjamin R Arenkiel

Faculty, Staff and Students Publications

Neuropeptides play important physiological functions during distinct behaviors such as arousal, learning, memory, and reproduction. However, the role of local, extrahypothalamic neuropeptide signaling in shaping synapse formation and neuronal plasticity in the brain is not well understood. Here, we characterize the spatiotemporal expression profile of the neuropeptide corticotropin-releasing hormone (CRH) and its receptor CRHR1 in the mouse OB throughout development. We found that CRH-expressing interneurons are present in the external plexiform layer, that its cognate receptor is expressed by granule cells, and show that both CRH and CRHR1 expression enriches in the postnatal period when olfaction becomes important towards olfactory-related …

A Rare Family: Exploring Genetic Literacy In An Online Support Group, Heather H. Goltz, Sandra Acosta

Journal of Family Strengths

Healthy People 2020 and the Institute of Medicine (IOM) define health literacy as the “degree to which individuals have the capacity to obtain, process and understand basic health information and services needed to make appropriate health decisions.” Essential components of health literacy include oral and print literacy, numeracy, and cultural and conceptual knowledge; the latter is influenced by sociodemographic factors and cultural understandings and approaches to concepts such as healthcare. Genetic literacy, a form of health literacy, may be defined as the knowledge, skills and attitudes necessary to individual understanding of genetic information, and genetic-based health, behavior, technology …

Literacy: A Continuously Evolving Concept, Angelo P. Giardino, Robert D. Sanborn, Elvon Christopher Lloyd, William V. Flores

Journal of Family Strengths

Angelo P. Giardino, Robert Sanborn, William V. Flores and E. Christopher Lloyd discuss the latest issue of the Journal of Family Strengths.

Promoting Health Literacy For People With Disabilities And Clinicians Through A Teamwork Model, David W. Hollar Jr., Jennifer Rowland

Journal of Family Strengths

Current health literacy programs for people with disabilities lack clear operational definitions, rely on inconsistent health literacy statistics, and tend to follow a medical model approach that often fallaciously assumes people with disabilities have limited health knowledge. The central issue in addressing and improving health literacy among people with disabilities is to focus on clear and effective health communication among health care team members, including people with disabilities, which can ultimately improve this population’s health outcomes. Our proposed teamwork model builds upon the World Health Organization’s International Classification of Functioning, Disability and Health (ICF) biopsychosocial model, decision-making theory, and health …

Engaging Children And Families In Culturally Relevant Literacies, Patricia Piña, Kindel T. Nash, Alicia Boardman, Bilal Polson, Leah Panther

Journal of Family Strengths

This article offers theoretical and practical strategies for engaging families, communities, and young children in culturally relevant and responsive early literacies. The authors highlight findings from data collected in their own classrooms and with families and communities for the Professional Dyads in Culturally Relevant (PDCRT) teaching project,[1] a collaborative research partnership (2013-2015) between teacher educator-teacher dads [2] aimed at generating, investigating, and documenting culturally relevant/responsive practices for early childhood contexts.

[1]The PDCRT was initiated by Affirmative Action Committee of the Early Childhood Education Assembly of the National Council of Teachers of English (NCTE).

[2]University-School Partners

Community-Based Participatory Research To Improve Early Detection And Treatment Of Hypertension In A Suburban Community In Thailand, Chuncharaporn Sinsiri

Dissertations and Theses (Open Access)

Communities have a significant role in working with health personnel to detect new and previously diagnosed cases of high blood pressure during community BP screening programs. In Thailand there are many people with elevated BP who do not access care. The purpose of this Community-Based Participatory Research (CBPR) was to build a community partnership following the CBPR approach to develop a health program to improve early detection and treatment of hypertension. Three specific aims were: Aim 1. Using CBPR principles, describe the process of building a community partnership to develop a community health program to improve early detection and treatment …

Trim28 Interacts With Ezh2 To Regulate Its Activity, Jing Li, Jing Li

Dissertations and Theses (Open Access)

In this dissertation, I discovered that TRIM28 interacts with EZH2 and regulates its activity in breast cancer cells. EZH2, the major H3K27 tri-methyltransferase, is over expressed in multiple subtypes of breast cancer; however, whether EZH2 plays an active role in breast cancer progression or treatment resistance is unknown. Here, we determined EZH2-interacting proteins in MCF7 cells by immunoprecipitation/mass spectrometry and detected TRIM28 with a high confidence score. TRIM28 is a transcription co-regulator with an N-terminal tri-partite RING finger, B-boxes and a coiled-coil domain (RBCC) and a C-terminal PHD/Bromo domain. Domain mapping revealed that the RBCC domain of TRIM28 interacts with …

Targeting Oncogenic Mirnas With Small Molecules For Breast Cancer Therapy, Paloma Del C. Monroig

Dissertations and Theses (Open Access)

The crucial role of microRNAs (miRNAs) in cancer pathobiology has driven the introduction of new drug development approaches such as miRNA inhibition. In order to advance miRNA-therapeutics, there is a need to develop screening strategies that can target tumors in a specific way. Small molecule inhibitors represent an attractive approach to pursue this. However, the absence of molecular structures for most of the miRNAs makes it very difficult to predict which inhibitors can bind to them. Herein we designed a strategy to screen for small molecules by assesing whether they could directly bind/ interact with miR-10b/miR-21. As part of our …

Plasmacytoid Dendritic Cell-Mediated Humoral Autoimmunity, Stephanie M. Dorta-Estremera Ph.D.

Dissertations and Theses (Open Access)

Humoral autoimmunity is characterized by the breakdown of B cell immune tolerance to self-antigens and consequent production of pathogenic autoantibodies. Plasmacytoid dendritic cells (pDCs), a potent type I interferon (IFN-I) producer, have been linked to the pathogenesis of systemic lupus erythematosus (SLE), a prototypic systemic humoral autoimmune disease. However, the cellular events that stimulate the development of humoral autoimmunity as a result of pDC activation have not been characterized. Moreover, the B cell subset(s) responsible for the generation of autoantibodies remains to be clearly identified.

The immunization of DNA-containing amyloids into non-autoimmune mice triggers the activation of pDCs and induction …

Preventing Thymus Involution In K5.Cyclin D1 Transgenic Mice Sustains The Naïve T Cell Compartment With Age, Michelle L. Bolner

Dissertations and Theses (Open Access)

The thymus maintains T cell receptor (TCR) repertoire diversity through perpetual release of self-MHC restricted naive T cells. However, thymus involution during the aging process reduces naïve T cell output, leading to defective immune responsiveness to newly encountered antigens. We have found that early thymus involution precipitates the age-associated shift favoring memory T cell dominancy in young control mice. Furthermore, we have shown that age-related thymus involution is prevented in mice expressing a keratin 5 promoter-driven Cyclin D1 (K5.D1) transgene in thymic epithelial cells (TECs). Thymopoiesis occurs normally in K5.D1 transgenic thymi and sustains T cell output to prevent the …

Investigation Of Quatitative Image Features From Pretreatment Ct And Fdg-Pet Scans In Stage Iii Nsclc Patients Undergoing Defintive Radiation Therapy, David Fried

Dissertations and Theses (Open Access)

The purpose of this work was to determine if quantitative image features (QIFs) extracted from computed tomography (CT) and flourodeoxyglucose (FDG) positron emission tomography (PET) could provide prognostic information to improve outcome models. Our goal for this work was to determine if it may one day be feasible to incorporate QIFs into personalized cancer care. QIFs were used to quantitatively characterize patient disease as seen on imaging. A leave-one-out cross-validation procedure was used to assess the prognostic ability of QIFs extracted from CT and PET in addition to conventional prognostic factors (CPFs). QIFs were found to improve model fit for …

Multivariate Criteria Most Accurately Distinguish Cardiac From Noncardiac Causes Of Dyspnea, Mirza Nubair Ahmad, Syed Hasan Yusuf, Rafath Ullah, Mirza Mujadil Ahmad, Mary K Ellis, Haroon Yousaf, Timothy E Paterick, Khawaja Afzal Ammar

The Texas Heart Institute Journal

Cardiopulmonary exercise testing provides oxygen pulse as a continuous measure of stroke volume, which is superior to other stress-testing methods in which systolic function is measured at baseline and at peak stress. However, the optimal peak oxygen pulse criterion for distinguishing cardiac from noncardiac causes of exercise limitation is unknown.

In comparing several peak oxygen pulse criteria against the clinical standard of cardiopulmonary exercise testing, we retrospectively studied 54 consecutive patients referred for cardiopulmonary exercise testing. These exercise tests included measurement of oxygen consumption, carbon dioxide production, breathing reserve, arterial blood gases at baseline and at peak stress, exercise electrocardiogram, …

Identifying Protein Kinase Tbk1 As A Novel Inhibitor Of Intestinal Tumorigenesis, Amber L. Mathews

Dissertations and Theses (Open Access)

Colorectal cancer (CRC) is the third most common cancer diagnosed in women and men， causing almost 600,000 annual deaths worldwide. There is a clear need to understand how CRC forms and progresses in order to improve the strategies of CRC prevention and therapy. A major factor that drives the development of CRC is genetic mutations that lead to activation of oncogenes and inactivation of tumor suppressor genes in intestinal epithelial cells (IECs). In addition, the initiation and progression of CRC involve environmental and immunological factors. In particular, chronic inflammatory conditions are known as an important risk factor for CRC. Intestinal …

The Role Of Dna Methylation And Hydroxymethylation In Smooth Muscle Cell Phenotypic Change During Atherogenesis, Jason Williams

Dissertations and Theses (Open Access)

Atherosclerosis is a chronic arterial disease which impacts systemically the function of organs and tissues by causing inflammation and disruption of blood supply. During atherogenesis, lipid deposits, inflammation, and cells accumulate within the walls of arteries, ultimately leading to a buildup of fatty plaques and occlusion of the arterial lumen. In a multifactorial disease like atherosclerosis there are complex interplays between environmental, genetic and epigenetic risk factors. The epigenetics of atherosclerosis involving DNA methylation has been progressing from single gene to genome wide analyses. Although these epistudies have provided evidence that DNA methylation exists within certain genes during atherogenesis, the …

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 …

Characterization Of Erbb4 Expression In Osteosarcoma, Nupur Lala

Dissertations and Theses (Open Access)

ERBB4 (Her-4) is a member of the ERBB family of Class I receptor tyrosine kinases. ERBB4 is unique within the ERBB family for alternate splicing in its juxtamembrane and cytoplasmic regions, which produces four juxtamembrane isoforms and two cytoplasmic isoforms. The cleavable juxtamembrane isoforms, Jm-a and Jm-d, can undergo proteolytic cleavage and produce an 80-kDa cytoplasmic fragment referred to as “p80,” which has been demonstrated to enhance cellular survival and malignant behavior in many solid tumors [44]. ERBB4 was almost exclusively 80 kDa in size and localized to the nucleus in primary tumors and metastases in studies characterizing ERBB4 expression …

Regulation Of The Oxidative Stress Response By Arid1a, Suet Yan Kwan

Dissertations and Theses (Open Access)

SWI/SNF is mutated in about 20% of all human cancers; in particular ARID1A is the most frequently mutated SWI/SNF subunit. ARID1A is a tumor suppressor gene, inactivating mutations in ARID1A are most frequently found in ovarian and endometrial cancers, specifically uterine corpus endometrioid carcinomas (UCEC), ovarian clear cell carcinomas (OCCC) and ovarian endometrioid carcinomas (OEC). The functional roles of ARID1A are not completely understood and there are limited therapeutic strategies that specifically target ARID1A-mutant cancers. Given that ARID1A expression is lost in cancer, ARID1A mutations cannot be targeted directly and novel therapeutic strategies are required to target ARID1A-mutant …

In Vivo Functional Significance Of Ccat2 Long Non-Coding Rna In Myelodysplastic Syndrome, Maitri Y. Shah

Dissertations and Theses (Open Access)

Long non-coding RNAs form the largest part of the mammalian non-coding transcriptome and control gene expression at various levels including chromatin modification, transcriptional and post-transcriptional processing. Although the underlying molecular mechanisms are not yet entirely understood, lncRNAs are implicated in initiation and progression of several cancers. CCAT2 is a lncRNA that spans the highly conserved 8q24 region associated with increased risk for various cancers. CCAT2 has been shown to play an important role in inducing chromosomal instability and supporting cell proliferation and cell cycle arrest. However, a causal role of CCAT2 in initiation of tumorigenesis and the importance of G/T …

Role Of Stat3 In Human Nk Cell Functions, Prasad V. Phatarpekar

Dissertations and Theses (Open Access)

Natural Killer (NK) cells are cytotoxic lymphocytes, which play a critical role in the immune response against malignant cells and microbial infections. NK cells are equipped with activating receptors, which upon detecting ligands expressed on stressed cells induce cytolytic activity of NK cells. Stimulation of NK cell proliferation and priming of NK cytolytic capability are accomplished by cytokines, which mediate their signals mainly through JAK-STAT signaling pathway. Previously, we found that K562 cells genetically modified to express membrane bound IL-21 (mbIL-21), which predominantly activates STAT3, induce robust expansion and activation of human NK cells. Further investigations revealed role of STAT3 …

Mobilization Of Adipose Stromal Cells In Obesity And Cancer By Sparc And Its Proteolytic Isoforms, Chieh Tseng

Dissertations and Theses (Open Access)

Obesity increases cancer risk and progression as shown by epidemiologic studies. However, the underlying pathophysiology remained unclear. Adipose stromal cells (ASC) are adipose tissue-derived mesenchymal progenitors, abundant in white adipose tissue (WAT). In this study, we show that the ASC pool is expanded in obesity and is associated with promoted tumor growth. Next, by using a chimeric GFP-RFP bone marrow transplant model, we observed higher tumor infiltrating cells with ASC phenotype in obese mice compared to lean. Consistently, systemic circulating ASC frequency is six fold higher in tumor-bearing obese mice compared to lean. The tumor infiltrating cells with ASC phenotype …

The Tumor Suppressor Notch Inhibits Head And Neck Squamous Cell Carcinoma (Hnscc) Tumor Growth And Progression By Modulating Proto-Oncogenes Axl And Ctnnal1 (Α-Catulin), Shhyam Moorthy, Shhyam Moorthy

Dissertations and Theses (Open Access)

Background: Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common malignancy worldwide, with roughly 300,000 cancer related deaths occurring globally each year. The survival of patients with HNSCC has not changed significantly over the past decade, leading investigators to search for promising molecular targets. To identify new treatment targets and biomarkers that could better guide therapy, we previously characterized the genomic alterations from primary HNSCC patient samples. We were among the first to discover that NOTCH1 is one of the most frequently mutated genes in this cancer type. The spectrum of inactivating NOTCH1 mutations in HNSCC suggested …

Voxel-Level Absorbed Dose Calculations With A Deterministic Grid-Based Boltzmann Solver For Nuclear Medicine And The Clinical Value Of Voxel-Level Calculations, Justin Mikell

Dissertations and Theses (Open Access)

Voxel-level absorbed dose (VLAD) is rarely calculated for nuclear medicine (NM) procedures involving unsealed sources or 90Y microspheres (YM). The current standard of practice for absorbed dose calculations in NM utilizes MIRD S-values, which 1) assume a uniform distribution in organs, 2) do not use patient specific geometry, and 3) lack a tumor model. VLADs overcome these limitations. One reason VLADs are not routinely performed is the difficulty in obtaining accurate absorbed doses in a clinically acceptable time. The deterministic grid-based Boltzmann solver (GBBS) was recently applied to radiation oncology where it was reported as fast and accurate for both …

Normal Glycolytic Enzyme Activity Is Critical For Hypoxia Inducible Factor-1a Activity And Provides Novel Targets For Inhibiting Tumor Growth, Geoffrey Grandjean Phd

Dissertations and Theses (Open Access)

Normal Glycolytic Enzyme Activity is Critical for Hypoxia Inducible Factor-1α Activity and Provides Novel Targets for Inhibiting Tumor Growth

By Geoffrey Grandjean

Advisory Professor: Garth Powis, D. Phil

Unique to proliferating cancer cells is the observation that their increased need for energy is provided by a high rate of glycolysis followed by lactic acid fermentation in a process known as the Warburg Effect, a process many times less efficient than oxidative phosphorylation employed by normal cells to satisfy a similar energy demand ^[1]. This high rate of glycolysis occurs regardless of the concentration of oxygen in the cell and …

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 …

Molecular Regulation Of Vascular Calcification In Murine Models Of Atherosclerosis, Shanshan Gao

Dissertations and Theses (Open Access)

Background: Calcification occurs often in the atherosclerotic lesions of patients with coronary heart disease and animals with hypercholesterolemia, such as apolipoprotein-E deficient (ApoE-/-) mice. However, the mechanism(s) underlying the development of calcification in atherosclerosis remains unclear. ApoE acts as a lipid transporter, but also has been recognized as a potential regulator of osteogenesis. Little information is available as to whether ApoE has any direct impact on osteogenesis and calcification in vascular smooth muscle cells (VSMC). Several signal transduction pathways play a role in regulation of calcification, including the Wnt/β-catenin system and potentially GTAP, an ubiquitin-conjugating enzyme responsible for protein …

Effects Of Pharmacological And Genetic Disruption Of Chemokine Receptor Cxcr4 In B-Cell Acute Lymphoblastic Leukemia, Shubhchintan Randhawa

Dissertations and Theses (Open Access)

The CXCR4 chemokine receptor plays a pivotal role in homing and retention of B-cell Acute Lymphoblastic Leukemia cells to bone marrow niches. The bone marrow stromal cells (BMSCs) constitutively secrete the CXCR4 ligand CXCL12, thus attracting leukemia cells and protecting them from cytotoxic drugs, a mechanism that might be responsible for minimal residual disease after conventional chemotherapy against B-ALL. Indeed, in this study we observed that B-ALL cells that had migrated beneath the BMSCs were highly resistant to chemotherapeutic drugs. Inhibition of CXCR4 to disrupt this interaction presents itself as an attractive target to overcome bone marrow derived drug resistance …