Digital Commons Network^™

Computational Identification And Functional Validation Of Regulatory Motifs In Cartilage-Expressed Genes, Sherri R Davies, Li-Wei Chang, Debabrata Patra, Xiaoyun Xing, Karen Posey, Jacqueline Hecht, Gary D Stormo, Linda J Sandell

Journal Articles

Chondrocyte gene regulation is important for the generation and maintenance of cartilage tissues. Several regulatory factors have been identified that play a role in chondrogenesis, including the positive transacting factors of the SOX family such as SOX9, SOX5, and SOX6, as well as negative transacting factors such as C/EBP and delta EF1. However, a complete understanding of the intricate regulatory network that governs the tissue-specific expression of cartilage genes is not yet available. We have taken a computational approach to identify cis-regulatory, transcription factor (TF) binding motifs in a set of cartilage characteristic genes to better define the transcriptional regulatory …

Versatile Applications Of Transcriptional Pulsing To Study Mrna Turnover In Mammalian Cells, Chyi-Ying A Chen, Yukiko Yamashita, Tsung-Cheng Chang, Akio Yamashita, Wenmiao Zhu, Zhenping Zhong, Ann-Bin Shyu

Journal Articles

Development of transcriptional pulsing approaches using the c-fos and Tet-off promoter systems greatly facilitated studies of mRNA turnover in mammalian cells. However, optimal protocols for these approaches vary for different cell types and/or physiological conditions, limiting their widespread application. In this study, we have further optimized transcriptional pulsing systems for different cell lines and developed new protocols to facilitate investigation of various aspects of mRNA turnover. We apply the Tet-off transcriptional pulsing strategy to investigate ARE-mediated mRNA decay in human erythroleukemic K562 cells arrested at various phases of the cell cycle by pharmacological inhibitors. This application facilitates studies of the …

Selective Repression Of Retinoic Acid Target Genes By Rip140 During Induced Tumor Cell Differentiation Of Pluripotent Human Embryonal Carcinoma Cells, Kelly C. Heim, Kristina A. White, Dexin Deng, Craig R. Tomlinson, Jason Moore, Sarah Freemantle, Michael Spinella

Dartmouth Scholarship

The use of retinoids as anti-cancer agents has been limited due to resistance and low efficacy. The dynamics of nuclear receptor coregulation are incompletely understood. Cell-and context-specific activities of nuclear receptors may be in part due to distinct coregulator complexes recruited to distinct subsets of target genes. RIP140 (also called NRIP1) is a ligand-dependent corepressor that is inducible with retinoic acid (RA). We had previously shown that RIP140 limits RA induced tumor cell differentiation of embryonal carcinoma; the pluriopotent stem cells of testicular germ cell tumors. This implies that RIP140 represses key genes required for RA-mediated tumor cell differentiation. Identification …

Microvascular Endothelial Cells Express A Phosphatidylserine Receptor: A Functionally Active Receptor For Phosphatidylserine-Positive Erythrocytes, Yamaja Setty, Suhita Gayen Betal

Department of Pediatrics Faculty Papers

Phosphatidylserine (PS)-positive erythrocytes adhere to endothelium and subendothelial matrix components. While thrombospondin mediates these inter-actions, it is unknown whether PS-associated erythrocyte-endothelial adhesion occurs in the absence of plasma ligands. Using ionophore-treated PS-expressing control HbAA erythrocytes, we demonstrate that PS-positive erythrocytes adhered to human lung microendothelial cells in the absence of plasma ligands, that this adhesion was enhanced following endothelial activation with IL-1alpha, TNF-alpha, LPS, hypoxia, and heme, and that this adhesive interaction was selective to erythrocyte PS. We next explored whether microendothelial cells express an adhesion receptor that recognizes cell surface-expressed PS (PSR) similar to that expressed on activated macrophages. …

Recent Advances In Cancer Stem/Progenitor Cell Research: Therapeutic Implications For Overcoming Resistance To The Most Aggressive Cancers., M. Mimeault, Ralph Hauke, Parmender P. Mehta, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Overcoming intrinsic and acquired resistance of cancer stem/progenitor cells to current clinical treatments represents a major challenge in treating and curing the most aggressive and metastatic cancers. This review summarizes recent advances in our understanding of the cellular origin and molecular mechanisms at the basis of cancer initiation and progression as well as the heterogeneity of cancers arising from the malignant transformation of adult stem/progenitor cells. We describe the critical functions provided by several growth factor cascades, including epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF) receptor (KIT), hedgehog and Wnt/beta-catenin signalling pathways that …

Receiver Operating Characteristic And Location Analysis Of Simulated Near-Infrared Tomography Images, Xiaomei Song, Brian W. Pogue, Hamid Dehghani, Shudong Jiang, Keith D. Paulsen, Tor D. Tosteson

Dartmouth Scholarship

Receiver operating characteristic (ROC) analysis was performed on simulated near-infrared tomography images, using both human observer and contrast-to-noise ratio (CNR) computational assessment, for application in breast cancer imaging. In the analysis, a nonparametric approach was applied for estimating the ROC curves. Human observer detection of objects had superior capability to localize the presence of heterogeneities when the objects were small with high contrast, with a minimum detectable threshold of CNR near 3.0 to 3.3 in the images. Human observers were able to detect heterogeneities in the images below a size limit of 4 mm, yet could not accurately find the …

Funding Crisis In Title Vii Diversity Programs, Paula N O'Neill, Alvin H Strelnick

Journal Articles

No abstract provided.

Patient Involvement In Patient Safety: What Factors Influence Patient Participation And Engagement?, Rachel Davis, Rosamond Jacklin, Nick Sevdalis, Charles A. Vincent

Faculty Publications

BACKGROUND: Patients can play an important role in improving patient safety by becoming actively involved in their health care. However, there is a paucity of empirical data on the extent to which patients take on such a role. In order to encourage patient participation in patient safety we first need to assess the full range of factors that may be implicated in such involvement. OBJECTIVE: To delineate factors that could affect the participation of the patient in quality and safety issues in their health care. METHOD: Literature review of patient involvement in health care, drawing from direct evidence (specifically from …

Human Collagen Krox Up-Regulates Type I Collagen Expression In Normal And Scleroderma Fibroblasts Through Interaction With Sp1 And Sp3 Transcription Factors., Magdalini Kypriotou, Gallic Beauchef, Christos Chadjichristos, Russell Widom, Emmanuelle Renard, Sergio A. Jimenez, Joseph Korn, François-Xavier Maquart, Thierry Oddos, Otto Von Stetten, Jean-Pierre Pujol, Philippe Galéra

Department of Medicine Faculty Papers

Despite several investigations, the transcriptional mechanisms that regulate the expression of both type I collagen genes (COL1A1 and COL1A2) in either physiological or pathological situations, such as scleroderma, are not completely known. We have investigated the role of hc-Krox transcription factor on type I collagen expression by human dermal fibroblasts. hc-Krox exerted a stimulating effect on type I collagen protein synthesis and enhanced the corresponding mRNA steady-state levels of COL1A1 and COL1A2 in foreskin fibroblasts (FF), adult normal fibroblasts (ANF), and scleroderma fibroblasts (SF). Forced hc-Krox expression was found to up-regulate COL1A1 transcription through a -112/-61-bp sequence in FF, ANF, …

Human Muc4 Mucin Induces Ultra-Structural Changes And Tumorigenicity In Pancreatic Cancer Cells., N. Moniaux, P. Chaturvedi, G. C. Varshney, Jane L. Meza, J. F. Rodriguez-Sierra, J-P Aubert, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

MUC4 is a type-1 transmembrane glycoprotein and is overexpressed in many carcinomas. It is a heterodimeric protein of 930 kDa, composed of a mucin-type subunit, MUC4alpha, and a membrane-bound growth factor-like subunit, MUC4beta. MUC4 mRNA contains unique 5' and 3' coding sequences along with a large variable number of tandem repeat (VNTR) domain of 7-19 kb. A direct association of MUC4 overexpression has been established with the degree of invasiveness and poor prognosis of pancreatic cancer. To understand the precise role of MUC4 in pancreatic cancer, we engineered a MUC4 complementary DNA construct, mini-MUC4, whose deduced protein (320 kDa) is …

Molecular Determinants Of Mg2+ And Ca2+ Permeability And Ph Sensitivity In Trpm6 And Trpm7*S, Mingjiang Li, Jianyang Du, Jianmin Jiang, William J. Ratzan, Li-Ting Su, Loren W. Runnels, Lixia Yue

UCHC Articles - Research

The channel kinases TRPM6 and TRPM7 have recently been discovered to play important roles in Mg²⁺ and Ca²⁺ homeostasis, which is critical to both human health and cell viability. However, the molecular basis underlying these channels’ unique Mg²⁺ and Ca²⁺ permeability and pH sensitivity remains unknown. Here we have created a series of amino acid substitutions in the putative pore of TRPM7 to evaluate the origin of the permeability of the channel and its regulation by pH. Two mutants of TRPM7, E1047Q and E1052Q, produced dramatic changes in channel properties. The I–V relations of E1052Q and …

Inducible Caspase 9 Suicide Gene To Improve The Safety Of Allodepleted T Cells After Haploidentical Stem Cell Transplantation., Siok-Keen Tey, Gianpietro Dotti, Cliona M. Rooney, Helen E. Heslop, Malcolm K. Brenner

Faculty Publications

Addback of donor T cells following T cell-depleted stem cell transplantation (SCT) can accelerate immune reconstitution and be effective against relapsed malignancy. After haploidentical SCT, a high risk of graft-versus-host disease (GVHD) essentially precludes this option, unless the T cells are first depleted of alloreactive precursor cells. Even then, the risks of severe GVHD remain significant. To increase the safety of the approach and thereby permit administration of larger T cell doses, we used a suicide gene, inducible caspase 9 (iCasp9), to transduce allodepleted T cells, permitting their destruction should administration have adverse effects. We made a retroviral vector encoding …

Making Minimally Invasive Thr Safe: Conclusions From Biomechanical Simulation And Analysis., P C. Noble, J D. Johnston, J A. Alexander, M T. Thompson, M M. Usrey, E M. Heinrich, G C. Landon, K B. Mathis

Faculty Publications

The use of smaller surgical incisions has become popularized for total hip arthroplasty (THR) because of the potential benefits of shorter recovery and improved cosmetic appearance. However, an increased incidence of serious complications has been reported. To minimize the risks of minimally invasive approaches to THR, we have developed an experimental approach which enables us to evaluate risk factors in these procedures through cadaveric simulations performed within the laboratory. During cadaveric hip replacement procedures performed via posterior and antero-lateral mini-incisions, pressures developed between the wound edges and the retractors were approximately double those recorded during conventional hip replacement using Charnley …

Insights From The 2007 Disease Management Colloquium., David B Nash, Tine Hansen-Turton, Tracey Moorhead, Harry Leider, Donald F Wilson

College of Population Health Faculty Papers

No abstract provided.

Defective Dna Base Excision Repair In Brain From Individuals With Alzheimer's Disease And Amnestic Mild Cognitive Impairment, Lior Weissman, Dong-Gyu Jo, Martin M. Sørensen, Nadja C. De Souza-Pinto, William R. Markesbery, Mark P. Mattson, Vilhelm A. Bohr

Pathology and Laboratory Medicine Faculty Publications

Oxidative stress is thought to play a role in the pathogenesis of Alzheimer's disease (AD) and increased oxidative DNA damage has been observed in brain tissue from AD patients. Base excision repair (BER) is the primary DNA repair pathway for small base modifications such as alkylation, deamination and oxidation. In this study, we have investigated alterations in the BER capacity in brains of AD patients. We employed a set of functional assays to measure BER activities in brain tissue from short post-mortem interval autopsies of 10 sporadic AD patients and 10 age-matched controls. BER activities were also measured in brain …

Platelet Hyperreactivity: Predictive And Intrinsic Properties., Paul F. Bray

Cardeza Foundation for Hematologic Research

Platelet thrombi are central to the development of most vascular ischemic events. There is marked interindividual variation in platelet responsiveness, with some subjects displaying platelet hyperreactivity. An increasing number of reports indicate that there are laboratory measures of platelet function that predict clinical thrombotic events. Some, but not all, measures of platelet function are reproducible. Platelet hyperreactivity can be assessed with multiple stimuli in multiple assays and is more likely to be present in women and in subjects who have elevated fibrinogen levels.

Barriers To Recovery And Recommendations For Change: The Pennsylvania Consensus Conference On Psychiatry's Role., Joseph A. Rogers, Michael J. Vergare, Richard C. Baron, Mark S. Salzer

Department of Psychiatry and Human Behavior Faculty Papers

OBJECTIVE: Recovery has emerged over the past decade as a dominant theme in public mental health care.

METHODS: The 2006 Pennsylvania Consensus Conference brought together 24 community psychiatrists to explore the barriers they experienced in promoting recovery and their recommendations for change.

RESULTS: Twelve barriers were identified and classified into one of three categories: psychiatry knowledge, roles, and training; the need to transform public mental health systems and services; and environmental barriers to opportunity. Participants made 22 recommendations to address these barriers through changes in policies, programs, and psychiatric knowledge and practice.

CONCLUSIONS: The recommendations identify areas for change that …

Left Ventricular Noncompaction Mimicking Peripartum Cardiomyopathy., Chetan Patel, Girish S. Shirali, Naveen Pereira

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Polymorphisms In Nucleotide Excision Repair Genes, Arsenic Exposure, And Non-Melanoma Skin Cancer In New Hampshire, Katie M. Applebaum, Margaret R. Karagas, David J. Hunter, Paul J. Catalano, Steven H. Byler, Steve Morris, Heather H. Nelson

Dartmouth Scholarship

Background:

Arsenic exposure may alter the efficiency of DNA repair. UV damage is specifically repaired by nucleotide excision repair (NER), and common genetic variants in NER may increase risk for non-melanoma skin cancer (NMSC).

Objective:

We tested whether polymorphisms in the NER genes XPA (A23G) and XPD (Asp312Asn and Lys751Gln) modify the association between arsenic and NMSC.

Methods:

Incident cases of basal and squamous cell carcinoma (BCC and SCC, respectively) were identified through a network of dermatologists and pathology laboratories across New Hampshire. Population-based controls were frequency matched to cases on age and sex. Arsenic exposure was assessed in toenail …

American Academy Of Allergy, Asthma & Immunology Work Group Report: Allergy Diagnosis In Clinical Practice, Dana V. Wallace, Sami L. Bahna, Stan Goldstein, Robert G. Hamilton, John R. Cohn

Department of Medicine Faculty Papers

No abstract provided.

Let-7 Expression Defines Two Differentiation Stages Of Cancer, Scott Shell, Sun-Mi Park, Amir Reza Radjabi, Robert Schickel, Emily Kistner, David Jewell

Dartmouth Scholarship

The early phases of carcinogenesis resemble embryonic development, often involving the reexpression of embryonic mesenchymal genes. The NCI60 panel of human tumor cell lines can genetically be subdivided into two superclusters (SCs) that correspond to CD95 Type I and II cells. SC1 cells are characterized by a mesenchymal and SC2 cells by an epithelial gene signature, suggesting that SC1 cells represent less differentiated, advanced stages of cancer. miRNAs are small 20- to 22-nucleotide-long noncoding RNAs that inhibit gene expression at the posttranscriptional level. By performing miRNA expression analysis on 10 Type I and 10 Type II cells, we have determined …

The Kentucky Plan Revisited: Lessons Learned From An Innovative Doctoral Education Program., Joel M. Lee, F. Douglas Scutchfield, Raymond Hill

Preventive Medicine and Environmental Health Faculty Publications

In the first doctoral education special issue of the Journal of Health Administration Education, the authors presented the University of Kentucky College of Public Health's plans for an innovative new Doctor of Public Health (Dr. P.H.) degree. The degree as designed, prepares graduates for professional practice, and included extensive supervised field experience as part of the academic training linking theory with practice. Based upon the interest that the Kentucky Dr.P.H. degree program received, the authors will share the experience of the degree's initial years of operation through a "lessons learned" paper. As the program evolved there have been many lessons …

Energizing Mirna Research: A Review Of The Role Of Mirnas In Lipid Metabolism, With A Prediction That Mir-103/107 Regulates Human Metabolic Pathways, Bernard R. Wilfred, Wang-Xia Wang, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

MicroRNAs (miRNAs) are powerful regulators of gene expression. Although first discovered in worm larvae, miRNAs play fundamental biological roles-including in humans-well beyond development. MiRNAs participate in the regulation of metabolism (including lipid metabolism) for all animal species studied. A review of the fascinating and fast-growing literature on miRNA regulation of metabolism can be parsed into three main categories: (1) adipocyte biochemistry and cell fate determination; (2) regulation of metabolic biochemistry in invertebrates; and (3) regulation of metabolic biochemistry in mammals. Most research into the 'function' of a given miRNA in metabolic pathways has concentrated on a given miRNA acting upon …

Walking Age Does Not Explain Term Versus Preterm Difference In Bone Geometry, Haifa Abou Samra, Bonny Specker

Ethel Austin Martin Program Publications

OBJECTIVE: To elucidate the relationship between bone geometry and onset of walking in former term and preterm children.
STUDY DESIGN: We conducted a cross-sectional study of 128 preschool children aged 3 to 5 years who underwent peripheral quantitative computerized tomography measures of bone size at the distal tibia. Linear models were developed, stratifying by sex, to determine whether bone differences between children born term and preterm were caused by differences in walking age.
RESULTS: Children with a history of preterm birth walked later than children born at term (12.4 +/- 0.5 versus 10.9 +/- 0.2 months; P = .004); however, …

Ethnic/Racial Diversity, Maternal Stress, Lactation And Very Low Birthweight Infants., C Lau, N M. Hurst, E O. Smith, R J. Schanler

Faculty Publications

OBJECTIVE: (1) To compare maternal characteristics and psychological stress profile among African-American, Caucasian and Hispanic mothers who delivered very low birthweight infants. (2) To investigate associations between psychosocial factors, frequency of milk expression, skin-to-skin holding (STS), and lactation performance, defined as maternal drive to express milk and milk volume. STUDY DESIGN: Self-reported psychological questionnaires were given every 2 weeks after delivery over 10 weeks. Milk expression frequency, STS, and socioeconomic variables were collected. RESULT: Infant birthweight, education, and milk expression frequency differed between groups. Trait anxiety, depression and parental stress in a neonatal intensive care unit (PSS:NICU) were similar. African-American …

Epstein-Barr Virus Infection Of Langerhans Cell Precursors As A Mechanism Of Oral Epithelial Entry, Persistence, And Reactivation, Dennis M. Walling, Autumn J. Ray, Joan E. Nichols, Catherine M. Flaitz, C. Mark Nichols

Journal Articles

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus associated with many malignant and nonmalignant human diseases. Life-long latent EBV persistence occurs in blood-borne B lymphocytes, while EBV intermittently productively replicates in mucosal epithelia. Although several models have previously been proposed, the mechanism of EBV transition between these two reservoirs of infection has not been determined. In this study, we present the first evidence demonstrating that EBV latently infects a unique subset of blood-borne mononuclear cells that are direct precursors to Langerhans cells and that EBV both latently and productively infects oral epithelium-resident cells that are likely Langerhans cells. These data …

A Larger Sense Of Purpose: Dentistry And Society, David A. Nash

Oral Health Science Faculty Publications

Dentistry is undergoing a subtle shift away from being a profession to becoming a business. The two cultures of professionalism and business are contrasted. Among the forces driving this change are the emphasis on esthetics in dentistry and the increasing inability of a large class of patients to access dentistry on a business basis. The shift toward dentistry as a business entails the unhealthy transition toward regarding patients as means to satisfy the dentist's ends rather than patients' health being an end in itself. Dentists run the risk of "objectivifying" rather than "humanizing" patients. This trend must be overcome with …

Spontaneous Low-Frequency Fluctuations In The Bold Signal In Schizophrenic Patients: Anomalies In The Default Network, Robyn L Bluhm, Jodi Miller, Ruth A Lanius, Elizabeth A Osuch, Kristine Boksman, R W J Neufeld, Jean Theberge, Betsy Schaefer, Peter Williamson

Department of Medicine Publications

Spontaneous low-frequency fluctuations in the blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (MRI) signal have been shown to reflect neural synchrony between brain regions. A "default network" of spontaneous low-frequency fluctuations has been described in healthy volunteers during stimulus-independent thought. Negatively correlated with this network are regions activated during attention-demanding tasks. Both these networks involve brain regions and functions that have been linked with schizophrenia in previous research. The present study examined spontaneous slow fluctuations in the BOLD signal at rest, as measured by correlation with low-frequency oscillations in the posterior cingulate, in 17 schizophrenic patients, and 17 comparable …

Gangliocytic Paraganglioma: Case Report And Review Of The Literature, Agnes Witkiewicz, Avi Galler, Charles Yeo

Department of Surgery Faculty Papers

Gangliocytic paraganglioma is a rare tumor, which occurs nearly exclusively in the second portion of the duodenum. Generally, this tumor has a benign clinical course, although rarely, it may recur or metastasize to regional lymph nodes. Only one case with distant metastasis has been reported. We present a case of duodenal gangliocytic paraganglioma treated first by local resection followed by pylorus-preserving pancreaticoduodenectomy. Examination of the first specimen revealed focal nuclear pleomorphism and mitotic activity, in addition to the presence of three characteristic histologic components: epithelioid, ganglion, and spindle cell. In the subsequent pancreaticoduodenectomy specimen, there was no residual tumor identified …

Quality Of Weight Loss Advice On Internet Forums., Kevin O Hwang, Kiran Farheen, Craig W Johnson, Eric J Thomas, Ann S Barnes, Elmer V Bernstam

Journal Articles

BACKGROUND: Adults use the Internet for weight loss information, sometimes by participating in discussion forums. Our purpose was to analyze the quality of advice exchanged on these forums. METHODS: This was a retrospective analysis of messages posted to 18 Internet weight loss forums during 1 month in 2006. Advice was evaluated for congruence with clinical guidelines; potential for causing harm; and subsequent correction when it was contradictory to guidelines (erroneous) or potentially harmful. Message- and forum-specific characteristics were evaluated as predictors of advice quality and self-correction. RESULTS: Of 3368 initial messages, 266 (7.9%) were requests for advice. Of 654 provisions …