Medicine and Health Sciences Commons^™

Acetate Causes Alcohol Hangover Headache In Rats., Christina R Maxwell, Rebecca Jay Spangenberg, Jan B Hoek, Stephen D Silberstein, Michael L Oshinsky

Department of Neurology Faculty Papers

BACKGROUND: The mechanism of veisalgia cephalgia or hangover headache is unknown. Despite a lack of mechanistic studies, there are a number of theories positing congeners, dehydration, or the ethanol metabolite acetaldehyde as causes of hangover headache.

METHODS: We used a chronic headache model to examine how pure ethanol produces increased sensitivity for nociceptive behaviors in normally hydrated rats.

RESULTS: Ethanol initially decreased sensitivity to mechanical stimuli on the face (analgesia), followed 4 to 6 hours later by inflammatory pain. Inhibiting alcohol dehydrogenase extended the analgesia whereas inhibiting aldehyde dehydrogenase decreased analgesia. Neither treatment had nociceptive effects. Direct administration of acetate …

C-Jun Inhibits Mammary Apoptosis In Vivo., Sanjay Katiyar, Mathew C Casimiro, Luis Dettin, Xiaoming Ju, Erwin F Wagner, Hirokazu Tanaka, Richard Pestell

Department of Cancer Biology Faculty Papers

c-jun, which is overexpressed in a number of human cancers encodes a critical component of the AP-1 complex. c-jun has been shown to either induce or inhibit cellular apoptosis. Germ line deletion of both c-jun alleles is embryonically lethal. To determine the role of the endogenous c-jun gene in apoptosis, we performed mammary epithelial cell-targeted somatic deletion using floxed c-jun (c-jun(f/f)) conditional knockout mice. Laser capture microdissection demonstrated endogenous c-jun inhibits expression of apoptosis inducing genes and reactive oxygen species (ROS)-reducing genes (MnSOD, catalase). ROS have been implicated in apoptosis and undergo enzymatic elimination via MnSOD and CuZnSOD with further …

Biological Rationale For The Use Of Dna Methyltransferase Inhibitors As New Strategy For Modulation Of Tumor Response To Chemotherapy And Radiation., Giovanni L Gravina, Claudio Festuccia, Francesco Marampon, Vladimir M Popov, Richard G Pestell, Bianca M Zani, Vincenzo Tombolini

Kimmel Cancer Center Faculty Papers

Epigenetic modifications play a key role in the patho-physiology of many tumors and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research. DNA methyltransferase (DNMT) inhibitors represent a promising class of epigenetic modulators. Research performed yielded promising anti-tumorigenic activity for these agents in vitro and in vivo against a variety of hematologic and solid tumors. These epigenetic modulators cause cell cycle and growth arrest, differentiation and apoptosis. Rationale for combining these agents with cytotoxic therapy or radiation is straightforward since the use of DNMT inhibitor offers greatly improved access for cytotoxic …

Calcium Regulates Vesicle Replenishment At The Cone Ribbon Synapse., Norbert Babai, Theodore M. Bartoletti, Wallace B. Thoreson

Journal Articles: Ophthalmology

Cones release glutamate-filled vesicles continuously in darkness, and changing illumination modulates this release. Because sustained release in darkness is governed by vesicle replenishment rates, we analyzed how cone membrane potential regulates replenishment. Synaptic release from cones was measured by recording postsynaptic currents in Ambystoma tigrinum horizontal or OFF bipolar cells evoked by depolarization of simultaneously voltage-clamped cones. We measured replenishment after attaining a steady state between vesicle release and replenishment using trains of test pulses. Increasing Ca(2+) currents (I(Ca)) by changing the test step from -30 to -10 mV increased replenishment. Lengthening -30 mV test pulses to match the Ca(2+) …

The Endogenous Soluble Vegf Receptor-2 Isoform Suppresses Lymph Node Metastasis In A Mouse Immunocompetent Mammary Cancer Model, Masa-Aki Shibata, Jayakrishna Ambati, Eiko Shibata, Romulo J. C. Albuquerque, Junji Morimoto, Yuko Ito, Yoshinori Otsuki

Ophthalmology and Visual Science Faculty Publications

BACKGROUND: Cancer metastasis contributes significantly to cancer mortality and is facilitated by lymphangiogenesis and angiogenesis. A new splicing variant, endogenous soluble vascular endothelial growth factor receptor-2 (esVEGFR-2) that we recently identified is an endogenous selective inhibitor of lymphangiogenesis. To evaluate the antimetastatic potential of esVEGFR-2, gene therapy with vector expressing esVEGFR-2 (pesVEGFR-2) or endostatin (pEndo) as a positive control was conducted on murine metastatic mammary cancer.

METHODS: Syngeneic inoculated metastatic mammary cancers received direct intratumoral injection of pesVEGFR-2, pEndo or pVec as control, once a week for six weeks. In vivo gene electrotransfer was performed on the tumors after each …

Ms4a4b, A Cd20 Homologue In T Cells, Inhibits T Cell Propagation By Modulation Of Cell Cycle., Hui Xu, Yaping Yan, Mark S Williams, Gregory B Carey, Jingxian Yang, Hongmei Li, Guang-Xian Zhang, Abdolmohamad Rostami

Department of Neurology Faculty Papers

MS4a4B, a CD20 homologue in T cells, is a novel member of the MS4A gene family in mice. The MS4A family includes CD20, FcεRIβ, HTm4 and at least 26 novel members that are characterized by their structural features: with four membrane-spanning domains, two extracellular domains and two cytoplasmic regions. CD20, FcεRIβ and HTm4 have been found to function in B cells, mast cells and hematopoietic cells respectively. However, little is known about the function of MS4a4B in T cell regulation. We demonstrate here that MS4a4B negatively regulates mouse T cell proliferation. MS4a4B is highly expressed in primary T cells, natural …

Endothelial Cell Capture Of Heparin-Binding Growth Factors Under Flow, Bing Zhao, Changjiang Zhang, Kimberly Forsten-Williams, Jun Zhang, Michael Fannon

Ophthalmology and Visual Science Faculty Publications

Circulation is an important delivery method for both natural and synthetic molecules, but microenvironment interactions, regulated by endothelial cells and critical to the molecule's fate, are difficult to interpret using traditional approaches. In this work, we analyzed and predicted growth factor capture under flow using computer modeling and a three-dimensional experimental approach that includes pertinent circulation characteristics such as pulsatile flow, competing binding interactions, and limited bioavailability. An understanding of the controlling features of this process was desired. The experimental module consisted of a bioreactor with synthetic endothelial-lined hollow fibers under flow. The physical design of the system was incorporated …

Differential Regulation Of P53 Function By The N-Terminal Δnp53 And Δ113p53 Isoforms In Zebrafish Embryos., William R Davidson, Csaba Kari, Qing Ren, Borbala Daroczi, Adam P Dicker, Ulrich Rodeck

Department of Radiation Oncology Faculty Papers

BACKGROUND: The p53 protein family coordinates stress responses of cells and organisms. Alternative promoter usage and/or splicing of p53 mRNA gives rise to at least nine mammalian p53 proteins with distinct N- and C-termini which are differentially expressed in normal and malignant cells. The human N-terminal p53 variants contain either the full-length (FL), or a truncated (ΔN/Δ40) or no transactivation domain (Δ133) altogether. The functional consequences of coexpression of the different p53 isoforms are poorly defined. Here we investigated functional aspects of the zebrafish ΔNp53 ortholog in the context of FLp53 and the zebrafish Δ133p53 ortholog (Δ113p53) coexpressed in the …

The Mir-15/107 Group Of Microrna Genes: Evolutionary Biology, Cellular Functions, And Roles In Human Diseases, John R. Finnerty, Wang-Xia Wang, Sébastien S. Hébert, Bernard R. Wilfred, Guogen Mao, Peter T. Nelson

Pathology and Laboratory Medicine Faculty Publications

The miR-15/107 group of microRNA (miRNA) gene is increasingly appreciated to serve key functions in humans. These miRNAs regulate gene expression involved in cell division, metabolism, stress response, and angiogenesis in vertebrate species. The miR-15/107 group has also been implicated in human cancers, cardiovascular disease and neurodegenerative disease, including Alzheimer's disease. Here we provide an overview of the following: (1) the evolution of miR-15/107 group member genes; (2) the expression levels of miRNAs in mammalian tissues; (3) evidence for overlapping gene-regulatory functions by different miRNAs; (4) the normal biochemical pathways regulated by miR-15/107 group miRNAs; and (5) the roles played …

Development Of A Macromolecular Prodrug For The Treatment Of Inflammatory Arthritis: Mechanisms Involved In Arthrotropism And Sustained Therapeutic Efficacy., Ling-Dong Quan, P. Edward Purdue, Xin-Ming Liu, Michael D. Boska, Subodh M. Lele, Geoffrey M. Thiele, Ted R. Mikuls, Huanyu Dou, Steven R. Goldring, Dong Wang

Journal Articles: Radiology

INTRODUCTION: The purpose of the present manuscript is to test the hypothesis that arthrotropic localization and synovial cell internalization account for the unique capacity of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex, a macromolecular prodrug of dexamethasone) to induce sustained amelioration of joint inflammation and inhibition of tissue damage in an animal model of inflammatory arthritis.

METHODS: Rats with adjuvant-induced arthritis (AA) were treated with P-Dex, free dexamethasone, saline or HPMA homopolymer. To define the biodistribution of P-Dex, conjugates with different imaging labels were given to AA rats and analyzed. Isolated joint tissues were evaluated by fluorescence-activated cell sorting (FACS) and immunohistochemical …

Association Between Chronic Liver And Colon Inflammation During The Development Of Murine Syngeneic Graft-Versus-Host Disease, Jason Anthony Brandon, Jacqueline Perez-Rodriguez, C. Darrell Jennings, Donald A. Cohen, Vishal J. Sindhava, Subbarao Bondada, Alan M. Kaplan, J. Scott Bryson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The murine model of cyclosporine A (CsA)-induced syngeneic graft-versus-host disease (SGVHD) is a bone marrow (BM) transplantation model that develops chronic colon inflammation identical to other murine models of CD4⁺ T cell-mediated colitis. Interestingly, SGVHD animals develop chronic liver lesions that are similar to the early peribiliary inflammatory stages of clinical chronic liver disease, which is frequently associated with inflammatory bowel disease (IBD). Therefore, studies were initiated to investigate the chronic liver inflammation that develops in the SGVHD model. To induce SGVHD, mice were lethally irradiated, reconstituted with syngeneic BM, and treated with CsA. All of the SGVHD animals …

Methylglyoxal Increases Cardiomyocyte Ischemia-Reperfusion Injury Via Glycative Inhibition Of Thioredoxin Activity., Xiaoliang Wang, Wayne B. Lau, Yue-Xing Yuan, Ya-Jing Wang, Wei Yi, Theodore A. Christopher, Bernard L. Lopez, Hui-Rong Liu, Xin-Liang Ma

Department of Emergency Medicine Faculty Papers

Diabetes mellitus (DM) is closely related to cardiovascular morbidity and mortality, but the specific molecular basis linking DM with increased vulnerability to cardiovascular injury remains incompletely understood. Methylglyoxal (MG), a precursor to advanced glycation end products (AGEs), is increased in diabetic patient plasma, but its role in diabetic cardiovascular complications is unclear. Thioredoxin (Trx), a cytoprotective molecule with antiapoptotic function, has been demonstrated to be vulnerable to glycative inhibition, but whether Trx is glycatively inhibited by MG, thus contributing to increased cardiac injury, has never been investigated. Cultured H9c2 cardiomyocytes were treated with MG (200 muM) for 6 days. The …

Gsk-3alpha Directly Regulates Beta-Adrenergic Signaling And The Response Of The Heart To Hemodynamic Stress In Mice., Jibin Zhou, Hind Lal, Xiongwen Chen, Xiying Shang, Jianliang Song, Yingxin Li, Risto Kerkela, Bradley W Doble, Katrina Macaulay, Morgan Decaul, Walter J Koch, John Farber, James Woodgett, Erhe Gao, Thomas Force

Center for Translational Medicine Faculty Papers

The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases consists of 2 highly related isoforms, alpha and beta. Although GSK-3beta has an important role in cardiac development, much remains unknown about the function of either GSK-3 isoform in the postnatal heart. Herein, we present what we believe to be the first studies defining the role of GSK-3alpha in the mouse heart using gene targeting. Gsk3a(-/-) mice over 2 months of age developed progressive cardiomyocyte and cardiac hypertrophy and contractile dysfunction. Following thoracic aortic constriction in young mice, we observed enhanced hypertrophy that rapidly transitioned to ventricular dilatation and contractile dysfunction. …

Histamine Reduces Flash Sensitivity Of On Ganglion Cells In The Primate Retina, Nikolay P Akimov, David W Marshak, Laura J Frishman, Randolph D Glickman, Rafail G Yusupov

Journal Articles

PURPOSE. In Old World primates, the retina receives input from histaminergic neurons in the posterior hypothalamus. They are a subset of the neurons that project throughout the central nervous system and fire maximally during the day. The contribution of these neurons to vision, was examined by applying histamine to a dark-adapted, superfused baboon eye cup preparation while making extracellular recordings from peripheral retinal ganglion cells. METHODS. The stimuli were 5-ms, 560-nm, weak, full-field flashes in the low scotopic range. Ganglion cells with sustained and transient ON responses and two cell types with OFF responses were distinguished; their responses were recorded …

High-Throughput Experimental Studies To Identify Mirna Targets Directly, With Special Focus On The Mammalian Brain, Peter T. Nelson, Marianthi Kiriakidou, Zissimos Mourelatos, Grace S. Tan, Mary H. Jennings, Kevin Xie, Wang-Xia Wang

Pathology and Laboratory Medicine Faculty Publications

We review the pertinent literature on methods used in high-throughput experimental identification of microRNA (miRNA) "targets" with emphasis on neurochemical studies. miRNAs are short regulatory noncoding RNAs that play important roles in the mammalian brain. The functions of miRNAs are related to their binding of RNAs including mRNAs. Since mammalian miRNAs tend to bind to target mRNAs via imperfect complementarity, understanding exactly which target mRNAs are recognized by which specific miRNAs is a challenge. Based on early experimental evidence, a set of "binding rules" for miRNAs has been described. These have focused on the 5' "seed" region of miRNAs binding …

Notch1 Functions As A Tumor Suppressor In A Model Of K-Ras–Induced Pancreatic Ductal Adenocarcinoma, Linda Hanlon, Jacqueline L Avila, Renée M Demarest, Scott Troutman, Megan Allen, Francesca Ratti, Anil K Rustgi, Ben Z Stanger, Fred Radtke, Volkan Adsay, Fenella Long, Anthony J Capobianco, Joseph L Kissil

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

K-ras is the most commonly mutated oncogene in pancreatic cancer and its activation in murine models is sufficient to recapitulate the spectrum of lesions seen in human pancreatic ductal adenocarcinoma (PDAC). Recent studies suggest that Notch receptor signaling becomes reactivated in a subset of PDACs, leading to the hypothesis that Notch1 functions as an oncogene in this setting. To determine whether Notch1 is required for K-ras-induced tumorigenesis, we used a mouse model in which an oncogenic allele of K-ras is activated and Notch1 is deleted simultaneously in the pancreas. Unexpectedly, the loss of Notch1 in this model resulted in increased …

Physiologically Based Pharmacokinetics Of Molecular Imaging Nanoparticles For Mrna Detection Determined In Tumor-Bearing Mice., Armin W Opitz, Eric Wickstrom, Mathew L Thakur, Norman J Wagner

Kimmel Cancer Center Faculty Papers

Disease detection and management might benefit from external imaging of disease gene mRNAs. Previously we designed molecular imaging nanoparticles (MINs) based on peptide nucleic acids complementary to cancer gene mRNAs. The MINs included contrast agents and analogs of insulin-like growth factor 1 (IGF-1). Analysis of MIN tumor uptake data showed stronger binding in tumors than in surrounding tissues. We hypothesized that MINs with an IGF-1 analog stay in circulation by binding to IGF-binding proteins. To test that hypothesis, we fit the tissue distribution results of several MINs in xenograft-bearing mice to a physiological pharmacokinetics model. Fitting experimental tissue distribution data …

A Direct Role For Secretory Phospholipase A2 And Lysophosphatidylcholine In The Mediation Of Lps-Induced Gastric Injury, Elizabeth J Dial, Duy M Tran, Jimmy J Romero, Mayssa Zayat, Lenard M Lichtenberger

Journal Articles

Endotoxemia from sepsis can injure the gastrointestinal tract through mechanisms that have not been fully elucidated. We have shown that LPS induces an increase in gastric permeability in parallel with the luminal appearance of secretory phospholipase A2 (sPLA2) and its product, lysophosphatidylcholine (lyso-PC). We proposed that sPLA2 acted on the gastric hydrophobic barrier, composed primarily of phosphatidylcholine (PC), to degrade it and produce lyso-PC, an agent that is damaging to the mucosa. In the present study, we have tested whether lyso-PC and/or sPLA2 have direct damaging effects on the hydrophobic barriers of synthetic and mucosal surfaces. Rats were administered LPS …

Thoracic Aortic Disease In Tuberous Sclerosis Complex: Molecular Pathogenesis And Potential Therapies In Tsc2+/- Mice, Jiumei Cao, Limin Gong, Dong-Chuan Guo, Ulrike Mietzsch, Shao-Qing Kuang, Callie S Kwartler, Hazim Safi, Anthony Estrera, Michael J Gambello, Dianna M Milewicz

Journal Articles

Tuberous sclerosis complex (TSC) is a genetic disorder with pleiotropic manifestations caused by heterozygous mutations in either TSC1 or TSC2. One of the less investigated complications of TSC is the formation of aneurysms of the descending aorta, which are characterized on pathologic examination by smooth muscle cell (SMC) proliferation in the aortic media. SMCs were explanted from Tsc2(+/-) mice to investigate the pathogenesis of aortic aneurysms caused by TSC2 mutations. Tsc2(+/-) SMCs demonstrated increased phosphorylation of mammalian target of rapamycin (mTOR), S6 and p70S6K and increased proliferation rates compared with wild-type (WT) SMCs. Tsc2(+/-) SMCs also had reduced expression of …

Individual Micrornas (Mirnas) Display Distinct Mrna Targeting "Rules", Wang-Xia Wang, Bernard R. Wilfred, Kevin Xie, Mary H. Jennings, Yanling Hu, Arnold J. Stromberg, Peter T. Nelson

Pathology and Laboratory Medicine Faculty Publications

MicroRNAs (miRNAs) guide Argonaute (AGO)-containing microribonucleoprotein (miRNP) complexes to target mRNAs.It has been assumed that miRNAs behave similarly to each other with regard to mRNA target recognition. The usual assumptions, which are based on prior studies, are that miRNAs target preferentially sequences in the 3'UTR of mRNAs,guided by the 5' "seed" portion of the miRNAs. Here we isolated AGO- and miRNA-containing miRNPs from human H4 tumor cells by co-immunoprecipitation (co-IP) with anti-AGO antibody. Cells were transfected with miR-107, miR-124,miR-128, miR-320, or a negative control miRNA. Co-IPed RNAs were subjected to downstream high-density Affymetrix Human Gene 1.0 ST microarray analyses using …

Perfusion In Rat Brain At 7 T With Arterial Spin Labeling Using Fair-Truefisp And Quipss, Emilio Esparza-Coss, Jarek Wosik, Ponnada A Narayana

Journal Articles

Measurement of perfusion in longitudinal studies allows for the assessment of tissue integrity and the detection of subtle pathologies. In this work, the feasibility of measuring brain perfusion in rats with high spatial resolution using arterial spin labeling is reported. A flow-sensitive alternating recovery sequence, coupled with a balanced gradient fast imaging with steady-state precession readout section was used to minimize ghosting and geometric distortions, while achieving high signal-to-noise ratio. The quantitative imaging of perfusion using a single subtraction method was implemented to address the effects of variable transit delays between the labeling of spins and their arrival at the …

Optimal Bone Strength And Mineralization Requires The Type 2 Iodothyronine Deiodinase In Osteoblasts, J. H. D. Bassett, Alan Boyde, Peter G. T. Howell, Richard H. Bassett, Thomas M. Galliford, Marta Archanco, Holly Evans, Michelle A. Lawson, Peter Croucher, Donald L. St. Germain, Valerie A. Galton, Graham R. Williams

Dartmouth Scholarship

Hypothyroidism and thyrotoxicosis are each associated with an increased risk of fracture. Although thyroxine (T4) is the predominant circulating thyroid hormone, target cell responses are determined by local intracellular availability of the active hormone 3,5,3'-L-triiodothyronine (T3), which is generated from T4 by the type 2 deiodinase enzyme (D2). To investigate the role of locally produced T3 in bone, we characterized mice deficient in D2 (D2KO) in which the serum T3 level is normal. Bones from adult D2KO mice have reduced toughness and are brittle, displaying an increased susceptibility to fracture. This phenotype is characterized by a 50% reduction in bone …

Syntaxin 3b Is Essential For The Exocytosis Of Synaptic Vesicles In Ribbon Synapses Of The Retina, L Curtis, P Datta, X Liu, N Bogdanova, R Heidelberger, R Janz

Journal Articles

Ribbon synapses of the vertebrate retina are specialized synapses that release neurotransmitter by synaptic vesicle exocytosis in a manner that is proportional to the level of depolarization of the cell. This release property is different from conventional neurons, in which the release of neurotransmitter occurs as a short-lived burst triggered by an action potential. Synaptic vesicle exocytosis is a calcium regulated process that is dependent on a set of interacting synaptic proteins that form the so-called SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) complex. Syntaxin 3B has been identified as a specialized SNARE molecule in ribbon synapses of the …

Cardiomyocyte-Derived Adiponectin Is Biologically Active In Protecting Against Myocardial Ischemia-Reperfusion Injury., Yajing Wang, Wayne Bond Lau, Erhe Gao, Ling Tao, Yuexing Yuan, Rong Li, Xiaoliang Wang, Walter J. Koch, Xin-Liang Ma

Department of Emergency Medicine Faculty Papers

Adiponectin (APN) has traditionally been viewed as an adipocyte-specific endocrine molecule with cardioprotective effects. Recent studies suggest that APN is also expressed in cardiomyocytes. However, biological significances of this locally produced APN remain completely unknown. The aim of this study was to investigate the pathological and pharmacological significance of cardiac-derived APN in cardiomyocyte pathology. Adult cardiomyocytes from wild-type littermates (WT) or gene-deficient mice were pretreated with vehicle (V) or rosiglitazone (RSG) for 6 h followed by simulated ischemia-reperfusion (SI/R, 3 h/12 h). Compared with WT cardiomyocytes, myocytes from APN knockout (APN-KO) mice sustained greater SI/R injury, evidenced by greater oxidative/nitrative …

Cardioprotection By Regular Ethanol Consumption: Potential Mechanisms And Clinical Application., Masami Miyamae, Kazuhiro Kaneda, Naochika Domae, Vincent M. Figueredo, M.D.

Division of Cardiology Faculty Papers

Epidemiological studies demonstrate that excessive drinking is associated with hypertension, cerebral bleeding and loss of cardiac contractility. Conversely, studies have shown that mortality rates for people who regularly drink ethanol in moderation are lower than in abstainers, primarily due to decreased fatal ischemic heart disease. Further, moderate ethanol consumers have lower rates of myocardial infarction compared with abstainers. These beneficial cardiac effects may be due to pleiotropic effects of ethanol on lipids, platelets, and fibrinolytic activity. During the past decade, studies conducted in several animal models have revealed that light to moderate regular ethanol consumption renders hearts more tolerant to …

Anti-Argonaute Rip-Chip Shows That Mirna Transfections Alter Global Patterns Of Mrna Recruitment To Microribonucleoprotein Complexes, Wang-Xia Wang, Bernard R. Wilfred, Yanling Hu, Arnold J. Stromberg, Peter T. Nelson

Pathology and Laboratory Medicine Faculty Publications

MicroRNAs (miRNAs) play key roles in gene expression regulation by guiding Argonaute (AGO)-containing microribonucleoprotein (miRNP) effector complexes to target polynucleotides. There are still uncertainties about how miRNAs interact with mRNAs. Here we employed a biochemical approach to isolate AGO-containing miRNPs from human H4 tumor cells by co-immunoprecipitation (co-IP) with a previously described anti-AGO antibody. Co-immunoprecipitated (co-IPed) RNAs were subjected to downstream Affymetrix Human Gene 1.0 ST microarray analysis. During rigorous validation, the "RIP-Chip" assay identified target mRNAs specifically associated with AGO complexes. RIP-Chip was performed after transfecting brain-enriched miRNAs (miR-107, miR-124, miR-128, and miR-320) and nonphysiologic control miRNA to identify …

Cardiomyocyte Pdgfr-Beta Signaling Is An Essential Component Of The Mouse Cardiac Response To Load-Induced Stress, Vishnu Chintalgattu, Di Ai, Robert R Langley, Jianhu Zhang, James A Bankson, Tiffany L Shih, Anilkumar K Reddy, Kevin R Coombes, Iyad N Daher, Shibani Pati, Shalin S Patel, Jennifer S Pocius, George E Taffet, L Maximillian Buja, Mark L Entman, Aarif Y Khakoo

Journal Articles

PDGFR is an important target for novel anticancer therapeutics because it is overexpressed in a wide variety of malignancies. Recently, however, several anticancer drugs that inhibit PDGFR signaling have been associated with clinical heart failure. Understanding this effect of PDGFR inhibitors has been difficult because the role of PDGFR signaling in the heart remains largely unexplored. As described herein, we have found that PDGFR-beta expression and activation increase dramatically in the hearts of mice exposed to load-induced cardiac stress. In mice in which Pdgfrb was knocked out in the heart in development or in adulthood, exposure to load-induced stress resulted …

Elevated Albumin In Retinas Of Monkeys With Experimental Glaucoma, Louvenia Carter-Dawson, Yujin Zhang, Ronald S Harwerth, Ricky Rojas, Pramod Dash, Xinping C Zhao, Elizabeth Woldemussie, Guadalupe Ruiz, Alice Chuang, William P Dubinsky, John B Redell

Journal Articles

PURPOSE: To establish the identity of a prominent protein, approximately 70 kDa, that is markedly increased in the retina of monkeys with experimental glaucoma compared with the fellow control retina, the relationship to glaucoma severity, and its localization in the retina.

METHODS: Retinal extracts were subjected to 2-D gel electrophoresis to identify differentially expressed proteins. Purified peptides from the abundant 70 kDa protein were analyzed and identified by liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) separation, and collision-induced dissociation sequencing. Protein identity was performed on MASCOT (Matrix Science, Boston, MA) and confirmed by Western blot. The relationship between the increase in this …

Progressive Changes In Microglia And Macrophages In Spinal Cord And Peripheral Nerve In The Transgenic Rat Model Of Amyotrophic Lateral Sclerosis, David J. Graber, William F. Hickey, Brent T. Harris

Dartmouth Scholarship

The role of neuroinflammation in motor neuron death of amyotrophic lateral sclerosis (ALS) is unclear. The human mutant superoxide dismutase-1 (hmSOD1)-expressing murine transgenic model of ALS has provided some insight into changes in microglia activity during disease progression. The purpose of this study was to gain further knowledge by characterizing the immunological changes during disease progression in the spinal cord and peripheral nerve using the more recently developed hmSOD1 rat transgenic model of ALS. Using immunohistochemistry, the extent and intensity of tissue CD11b expression in spinal cord, lumbar nerve roots, and sciatic nerve were evaluated in hmSOD1 rats that were …

Imaging Spontaneous Mmtvneu Transgenic Murine Mammary Tumors: Targeting Metabolic Activity Versus Genetic Products., Mathew L Thakur, Devakumar Devadhas, Kaijun Zhang, Richard G Pestell, Chenguang Wang, Peter Mccue, Eric Wickstrom

Department of Radiology Faculty Papers

INTRODUCTION: Despite the great strides made in imaging breast cancer (BC) in humans, the current imaging modalities miss up to 30% of BC, do not distinguish malignant lesions from benign ones, and require histologic examinations for which invasive biopsy must be performed. Annually in the United States, approximately 5.6 million biopsies find benign lesions. More than 50% of human BCs overexpress cyclin D1, and all BCs exhibit VPAC1 oncogene products. Together, these gene products may provide an excellent biomarker for the early and accurate detection of BC. We have evaluated 4 biologically active peptide analogs that have high affinity for …