Digital Commons Network^™

Normal Acquisition Of Expertise With Greebles In Two Cases Of Acquired Prosopagnosia, Constantin Rezlescu, Jason J. S. Barton, David Pitcher, Bradley Duchaine

Dartmouth Scholarship

Face recognition is generally thought to rely on different neurocognitive mechanisms than most types of objects, but the specificity of these mechanisms is debated. One account suggests the mechanisms are specific to upright faces, whereas the expertise view proposes the mechanisms operate on objects of high within-class similarity with which an observer has become proficient at rapid individuation. Much of the evidence cited in support of the expertise view comes from laboratory-based training experiments involving computer-generated objects called greebles that are designed to place face-like demands on recognition mechanisms. A fundamental prediction of the expertise hypothesis is that recognition deficits …

Diagnosis Of Pancreatic Neoplasms Using A Novel Method Of Dna Methylation Analysis Of Mucin Expression In Pancreatic Juice., Seiya Yokoyama, Sho Kitamoto, Michiyo Higashi, Yuko Goto, Taro Hara, Dai Ikebe, Taketo Yamaguchi, Yoshifumi Arisaka, Toru Niihara, Hiroto Nishimata, Sadao Tanaka, Kyoichi Takaori, Surinder K. Batra, Suguru Yonezawa

Journal Articles: Biochemistry & Molecular Biology

Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMNs). Our immunohistochemistry (IHC) studies have shown a consensus position on mucin expression profiles in pancreatic neoplasms as follows: MUC1-positive but MUC2-negative expression in PDACs; MUC1-negative but MUC2-positive expression in intestinal-type IPMNs (dangerous type); MUC1-negative and MUC2-negative expression in gastric-type IPMNs (safe type); High MUC4 expression in PDAC patients with a poor outcome; and MUC4-positive expression in intestinal-type IPMNs. We also showed that three mucin genes (MUC1, MUC2 and MUC4) expression in cancer cell line was regulated by DNA methylation. …

The Impact Of Salsalate Treatment On Serum Levels Of Advanced Glycation End Products In Type 2 Diabetes., Joshua I Barzilay, Kathleen A. Jablonski, Vivian Fonseca, Steven E Shoelson, Allison B Goldfine, Christopher Strauch, Vincent M Monnier, Tinsal-T2d Research Consortium.

GW Biostatistics Center

OBJECTIVE Salsalate is a nonacetylated salicylate that lowers glucose levels in people with type 2 diabetes (T2D). Here we examined whether salsalate also lowered serum-protein-bound levels of early and advanced glycation end products (AGEs) that have been implicated in diabetic vascular complications. RESEARCH DESIGN AND METHODS Participants were from the Targeting Inflammation Using Salsalate for Type 2 Diabetes (TINSAL-T2D) study, which examined the impact of salsalate treatment on hemoglobin A1c (HbA1c) and a wide variety of other parameters. One hundred eighteen participants received salsalate, 3.5 g/day for 48 weeks, and 109 received placebo. Early glycation product levels (HbA1c and fructoselysine …

Sudemycin E Influences Alternative Splicing And Changes Chromatin Modifications, Paolo Convertini, Manli Shen, Philip M. Potter, Gustavo Palacios, Chandraiah Lagisetti, Pierre De La Grange, Craig Horbinski, Yvonne N. Fondufe-Mittendorf, Thomas R. Webb, Stefan Stamm

Molecular and Cellular Biochemistry Faculty Publications

Sudemycin E is an analog of the pre-messenger RNA splicing modulator FR901464 and its derivative spliceostatin A. Sudemycin E causes the death of cancer cells through an unknown mechanism. We found that similar to spliceostatin A, sudemycin E binds to the U2 small nuclear ribonucleoprotein (snRNP) component SF3B1. Native chromatin immunoprecipitations showed that U2 snRNPs physically interact with nucleosomes. Sudemycin E induces a dissociation of the U2 snRNPs and decreases their interaction with nucleosomes. To determine the effect on gene expression, we performed genome-wide array analysis. Sudemycin E first causes a rapid change in alternative pre-messenger RNA splicing, which is …

Metformin Inhibits Androgen-Induced Igf-Ir Up-Regulation In Prostate Cancer Cells By Disrupting Membrane-Initiated Androgen Signaling., Roberta Malaguarnera, Antonella Sacco, Alaide Morcavallo, Sebastiano Squatrito, Antimo Migliaccio, Andrea Morrione, Marcello Maggiolini, Antonino Belfiore

Department of Urology Faculty Papers

We have previously demonstrated that, in prostate cancer cells, androgens up-regulate IGF-I receptor (IGF-IR) by inducing cAMP-response element-binding protein (CREB) activation and CREB-dependent IGF-IR gene transcription through androgen receptor (AR)-dependent membrane-initiated effects. This IGF-IR up-regulation is not blocked by classical antiandrogens and sensitizes cells to IGF-I-induced biological effects. Metformin exerts complex antitumoral functions in various models and may inhibit CREB activation in hepatocytes. We, therefore, evaluated whether metformin may affect androgen-dependent IGF-IR up-regulation. In the AR(+) LNCaP prostate cancer cells, we found that metformin inhibits androgen-induced CRE activity and IGF-IR gene transcription. CRE activity requires the formation of a CREB-CREB …

Recruitment Of The Adaptor Protein Grb2 To Egfr Tetramers, Noga Kozer, Dipak Barua, Christine Henderson, Eduoard C. Nice, Antony W. Burgess, William S. Hlavacek, Andrew H. A. Clayton

Chemical and Biochemical Engineering Faculty Research & Creative Works

Adaptor protein Grb2 binds phosphotyrosines in the epidermal growth factor (EGF) receptor (EGFR) and thereby links receptor activation to intracellular signaling cascades. Here, we investigated how recruitment of Grb2 to EGFR is affected by the spatial organization and quaternary state of activated EGFR. We used the techniques of image correlation spectroscopy (ICS) and lifetime-detected Förster resonance energy transfer (also known as FLIM-based FRET or FLIM-FRET) to measure ligand-induced receptor clustering and Grb2 binding to activated EGFR in BaF/3 cells. BaF/3 cells were stably transfected with fluorescently labeled forms of Grb2 (Grb2-mRFP) and EGFR (EGFR-eGFP). Following stimulation of the cells with …

Architecture Of Viral Genome-Delivery Molecular Machines., Anshul Bhardwaj, Adam S. Olia, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

From the abyss of the ocean to the human gut, bacterial viruses (or bacteriophages) have colonized all ecosystems of the planet earth and evolved in sync with their bacterial hosts. Over 95% of bacteriophages have a tail that varies greatly in length and complexity. The tail complex interrupts the icosahedral capsid symmetry and provides both an entry for viral genome-packaging during replication and an exit for genome-ejection during infection. Here, we review recent progress in deciphering the structure, assembly and conformational dynamics of viral genome-delivery tail machines. We focus on the bacteriophages P22 and T7, two well-studied members of the …

Serum Levels Of Soluble Icam-1 In Children With Pulmonary Artery Hypertension, Melahat Melek Oguz, Ayse Deniz Oguz, Cihat Sanli, Ayhan Cevik

The Texas Heart Institute Journal

This prospective cross-sectional study attempted to determine both the usefulness of the serum intercellular adhesion molecule-1 (ICAM-1) as a biomarker for pulmonary artery hypertension secondary to congenital heart disease and the nature of this marker's association with catheter angiographic findings.

Our study included a total of 70 male and female children, comprising 30 patients with both pulmonary artery hypertension and congenital heart disease, 20 patients with congenital heart disease alone, and 20 healthy control subjects. Levels of ICAM-1 in plasma samples from all groups were measured by the enzyme-linked immunosorbent assay method. Cardiac catheterization was also performed in all patients. …

A Dedicated Binding Mechanism For The Visual Control Of Movement., Alexandra Reichenbach, David W Franklin, Peter Zatka-Haas, Jörn Diedrichsen

Brain and Mind Institute Researchers' Publications

The human motor system is remarkably proficient in the online control of visually guided movements, adjusting to changes in the visual scene within 100 ms [1-3]. This is achieved through a set of highly automatic processes [4] translating visual information into representations suitable for motor control [5, 6]. For this to be accomplished, visual information pertaining to target and hand need to be identified and linked to the appropriate internal representations during the movement. Meanwhile, other visual information must be filtered out, which is especially demanding in visually cluttered natural environments. If selection of relevant sensory information for online control …

Aging Aggravates Nitrate-Mediated Ros/Rns Changes., Qian Fan, Lifen Chen, Shujuan Cheng, Fang Li, Wayne Bond Lau, Le Feng Wang, Jing Hua Liu

Department of Emergency Medicine Faculty Papers

Nitrates are the most frequently prescribed and utilized drugs worldwide. The elderly are a major population receiving nitrate therapy. Both nitrates and aging can increase in vivo reactive oxygen species (ROS) and reactive nitrogen species (RNS). To date, the effects of aging upon nitrate-induced ROS/RNS alteration are unknown. The present study tested the effects of aging upon nitrate-induced ROS/RNS alteration in vivo. 32 adults and 43 elderly unstable angina (UA) patients were subjected to 48 hours of isosorbide dinitrate intravenous injection (50  μg/minutes) in this clinical study. Blood samples were obtained at baseline and conclusion. Outcome measures of oxidative stress …

How To Get The Most From Microarray Data: Advice From Reverse Genomics, Ivan P. Gorlov, Ji-Yeon Yang, Jinyoung Byun, Christopher Logothetis, Olga Y. Gorlova, Kim-Anh Do, Christopher Amos

Dartmouth Scholarship

Whole-genome profiling of gene expression is a powerful tool for identifying cancer-associated genes. Genes differentially expressed between normal and tumorous tissues are usually considered to be cancer associated. We recently demonstrated that the analysis of interindividual variation in gene expression can be useful for identifying cancer associated genes. The goal of this study was to identify the best microarray data–derived predictor of known cancer associated genes. We found that the traditional approach of identifying cancer genes—identifying differentially expressed genes—is not very efficient. The analysis of interindividual variation of gene expression in tumor samples identifies cancer-associated genes more effectively. The results …

Isoform- And Species-Specific Control Of Inositol 1,4,5-Trisphosphate (Ip3) Receptors By Reactive Oxygen Species., Száva Bánsághi, Tünde Golenár, Muniswamy Madesh, György Csordás, Satish P. Ramachandrarao, Kumar Sharma, David I Yule, Suresh K Joseph, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Reactive oxygen species (ROS) stimulate cytoplasmic [Ca(2+)] ([Ca(2+)]c) signaling, but the exact role of the IP3 receptors (IP3R) in this process remains unclear. IP3Rs serve as a potential target of ROS produced by both ER and mitochondrial enzymes, which might locally expose IP3Rs at the ER-mitochondrial associations. Also, IP3Rs contain multiple reactive thiols, common molecular targets of ROS. Therefore, we have examined the effect of superoxide anion (O2) on IP3R-mediated Ca(2+) signaling. In human HepG2, rat RBL-2H3, and chicken DT40 cells, we observed [Ca(2+)]c spikes and frequency-modulated oscillations evoked by a O2 donor, xanthine (X) + xanthine oxidase (XO), dose-dependently. …

Palatal Mucosa Derived Fibroblasts Present An Adaptive Behavior Regarding Cytokine Secretion When Grafted Onto The Gingival Margin, Fabíola Pontes Azevedo, Ana Carolina Morandini, Carla Renata Sipert, Thiago José Dionísio, Carlos Ferreira Santos, Carla Andreotti Damante, Maria Lúcia Rubo De Rezende, Adriana Campos Passanezi Sant'ana, Sebastião Luiz Aguiar Greghi

All Dugoni School of Dentistry Faculty Articles

BACKGROUND: Considering that grafted gingival tissue might have to be adapted to the receptor area and that fibroblasts have the ability to respond to bacterial stimuli through the release of various cytokines, this study investigated whether fibroblasts from the palatal mucosa behave differently when grafted onto the gingival margin regarding cytokine secretion.

METHODS: Biopsies from the palatal mucosa were collected at the time of free gingival graft surgery, and after four months re-collection was performed upon surgery for root coverage. Fibroblasts were isolated by the explant technique, cultured and stimulated with Porphyromonas gingivalis (Pg) and Escherichia coli (Ec) LPS for …

Interaction Between Allelic Variations In Vitamin D Receptor And Retinoid X Receptor Genes On Metabolic Traits, Karani S. Vimaleswaran, Alana Cavadino, Diane J. Berry, Massimo Mangino, Peter Andrews, Jason H. Moore

Dartmouth Scholarship

Low vitamin D status has been shown to be a risk factor for several metabolic traits such as obesity, diabetes and cardiovascular disease. The biological actions of 1, 25-dihydroxyvitamin D, are mediated through the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptor, gamma (RXRG). Hence, we examined the potential interactions between the tagging polymorphisms in the VDR (22 tag SNPs) and RXRG (23 tag SNPs) genes on metabolic outcomes such as body mass index, waist circumference, waist-hip ratio (WHR), high- and low-density lipoprotein (LDL) cholesterols, serum triglycerides, systolic and diastolic blood pressures and glycated haemoglobin in the 1958 …

Integrated Assessment Of Predicted Mhc Binding And Cross-Conservation With Self Reveals Patterns Of Viral Camouflage, Lu He, Anne S. De Groot, Andres H. Gutierrez, William D. Martin, Lenny Moise, Chris Bailey-Kellogg

Dartmouth Scholarship

Immune recognition of foreign proteins by T cells hinges on the formation of a ternary complex sandwiching a constituent peptide of the protein between a major histocompatibility complex (MHC) molecule and a T cell receptor (TCR). Viruses have evolved means of "camouflaging" themselves, avoiding immune recognition by reducing the MHC and/or TCR binding of their constituent peptides. Computer-driven T cell epitope mapping tools have been used to evaluate the degree to which articular viruses have used this means of avoiding immune response, but most such analyses focus on MHC-facing ‘agretopes'. Here we set out a new means of evaluating the …

Prevalence Of Small-For-Gestational Age And Its Mortality Risk Varies By Choice Of Birth-Weight-For-Gestation Reference Population, Joanne D. Katz, Lauren A. Wu, Luke C. Mullany, Christian L. Coles, Anne C.C. Lee, Naoko Kozuki, James M. Tielsch

Global Health Faculty Publications

Background

We use data from rural Nepal and South India to compare the prevalence of small-for-gestational-age (SGA) and neonatal mortality risk associated with SGA using different birth-weight-for-gestation reference populations.

Methods

We identified 46 reference populations in low-, middle-, and high-income countries, of which 26 met the inclusion criteria of being commonly cited and having numeric 10th percentile cut points published. Those reference populations were then applied to populations from two community-based studies to determine SGA prevalence and its relative risk of neonatal mortality.

Results

The prevalence of SGA ranged from 10.5% to 72.5% in Nepal, and 12.0% to 78.4% in …

Genes With A Large Intronic Burden Show Greater Evolutionary Conservation On The Protein Level, Olga Gorlova, Alexey Fedorov, Christopher Logothetis, Christopher Amos, Ivan Gorlov

Dartmouth Scholarship

Background: The existence of introns in eukaryotic genes is believed to provide an evolutionary advantage by increasing protein diversity through exon shuffling and alternative splicing. However, this eukaryotic feature is associated with the necessity of exclusion of intronic sequences, which requires considerable energy expenditure and can lead to splicing errors. The relationship between intronic burden and evolution is poorly understood. The goal of this study was to analyze the relationship between the intronic burden and the level of evolutionary conservation of the gene. Results: We found a positive correlation between the level of evolutionary conservation of a gene and its …

Mitochondrial-Targeted Curcuminoids: A Strategy To Enhance Bioavailability And Anticancer Efficacy Of Curcumin, Cheruku Apoorva Reddy, Venkateswarlu Somepalli, Trimurtulu Golakoti, Anantha Koteswararao Kanugula, Santosh Karnewar, Karthikraj Rajendiran, Nagarjuna Vasagiri, Sripadi Prabhakar, Periannan Kuppusamy, Srigiridhar Kotamraju, Vijay Kumar Kutala

Dartmouth Scholarship

Although the anti-cancer effects of curcumin has been shown in various cancer cell types, in vitro, pre-clinical and clinical studies showed only a limited efficacy, even at high doses. This is presumably due to low bioavailability in both plasma and tissues, particularly due to poor intracellular accumulation. A variety of methods have been developed to achieve the selective targeting of drugs to cells and mitochondrion. We used a novel approach by conjugation of curcumin to lipophilic triphenylphosphonium (TPP) cation to facilitate delivery of curcumin to mitochondria. TPP is selectively taken up by mitochondria driven by the membrane potential by several …

Headstrong Intervention For Pediatric Migraine Headache: A Randomized Clinical Trial., Michael A. Rapoff, Mark Connelly, Jennifer Bickel, Scott W. Powers, Andrew D. Hershey, Janelle R. Allen, Cynthia W. Karlson, Catrina C. Litzenburg, John M. Belmont

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: The purpose of this study was to evaluate the efficacy of a self-guided CD-ROM program ("Headstrong") containing cognitive-behavioral self-management strategies versus an educational CD-ROM program for treating headaches, headache-related disability, and quality of life.

METHODS: Participants were 35 children ages 7-12 years with migraine recruited from one university medical center and two children's hospital headache clinics. Participants were randomly assigned to complete the Headstrong or educational control CD-ROM program over a 4-week period. Data on headache frequency, duration, and severity, migraine-related disability, and quality of life (QOL) were obtained at baseline, post-intervention, and 3-months post-intervention.

RESULTS: At post-intervention, Headstrong …

Adiponectin Inhibits Tumor Necrosis Factor-Α-Induced Vascular Inflammatory Response Via Caveolin-Mediated Ceramidase Recruitment And Activation., Yajing Wang, Xiaoliang Wang, Wayne Bond Lau, Yuexing Yuan, David Booth, Jing-Jing Li, Rosario Scalia, Kyle Preston, Erhe Gao, Walter Koch, Xin-Liang Ma

Department of Medicine Faculty Papers

RATIONALE: Anti-inflammatory and vascular protective actions of adiponectin are well recognized. However, many fundamental questions remain unanswered.

OBJECTIVE: The current study attempted to identify the adiponectin receptor subtype responsible for adiponectin's vascular protective action and investigate the role of ceramidase activation in adiponectin anti-inflammatory signaling.

METHODS AND RESULTS: Adiponectin significantly reduced tumor necrosis factor (TNF)α-induced intercellular adhesion molecule-1 expression and attenuated TNFα-induced oxidative/nitrative stress in human umbilical vein endothelial cells. These anti-inflammatory actions were virtually abolished by adiponectin receptor 1 (AdipoR1-), but not AdipoR2-, knockdown (KD). Treatment with adiponectin significantly increased neutral ceramidase (nCDase) activity (3.7-fold; P87% of adiponectin-induced nCDase …

Serum And Glucocorticoid-Inducible Kinase1 Increases Plasma Membrane Wt-Cftr In Human Airway Epithelial Cells By Inhibiting Its Endocytic Retrieval, Jennifer M. Bomberger, Bonita A. Coutermarsh, Roxanna L. Barnaby, J. Denry Sato, M. Christine Chapline, Bruce A. Stanton

Dartmouth Scholarship

Background: Chloride (Cl) secretion by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) located in the apical membrane of respiratory epithelial cells plays a critical role in maintenance of the airway surface liquid and mucociliary clearance of pathogens. Previously, we and others have shown that the serum and glucocorticoid-inducible kinase-1 (SGK1) increases wild type CFTR (wt-CFTR) mediated Cl transport in Xenopus oocytes by increasing the amount of wt-CFTR protein in the plasma membrane. However, the effect of SGK1 on the membrane abundance of wt-CFTR in airway epithelial cells has not been examined, and the mechanism whereby SGK1 increases membrane wt-CFTR has …

Gene And Protein Sequence Optimization For High-Level Production Of Fully Active And Aglycosylated Lysostaphin In Pichia Pastoris, Hongliang Zhao, Kristina Blazanovic, Yoonjoo Choi, Chris Bailey-Kellogg, Karl E. Griswold

Dartmouth Scholarship

Lysostaphin represents a promising therapeutic agent for the treatment of staphylococcal infections, in particular those of methicillin-resistant Staphylococcus aureus (MRSA). However, conventional expression systems for the enzyme suffer from various limitations, and there remains a need for an efficient and cost-effective production process to facilitate clinical translation and the development of nonmedical applications. While Pichia pastoris is widely used for high-level production of recombinant proteins, there are two major barriers to the production of lysostaphin in this industrially relevant host: lack of expression from the wild-type lysostaphin gene and aberrant glycosylation of the wild-type protein sequence. The first barrier can …

Global Analysis Of Lysine Acetylation Suggests The Involvement Of Protein Acetylation In Diverse Biological Processes In Rice (Oryza Sativa)., Babi Ramesh Reddy Nallamilli, Mariola J. Edelmann, Xiaoxian Zhong, Feng Tan, Hana Mujahid, Jian Zhang, Bindu Nanduri, Zhaohua Peng

CALS Publications

Lysine acetylation is a reversible, dynamic protein modification regulated by lysine acetyltransferases and deacetylases. Recent advances in high-throughput proteomics have greatly contributed to the success of global analysis of lysine acetylation. A large number of proteins of diverse biological functions have been shown to be acetylated in several reports in human cells, E.coli, and dicot plants. However, the extent of lysine acetylation in non-histone proteins remains largely unknown in monocots, particularly in the cereal crops. Here we report the mass spectrometric examination of lysine acetylation in rice (Oryza sativa). We identified 60 lysine acetylated sites on 44 proteins of diverse …

A Randomized Trial Of Bevacizumab For Newly Diagnosed Glioblastoma., Mark R Gilbert, James J Dignam, Terri S Armstrong, Jeffrey S Wefel, Deborah T Blumenthal, Michael A Vogelbaum, Howard Colman, Arnab Chakravarti, Stephanie Pugh, Minhee Won, Robert Jeraj, Paul D Brown, Kurt A Jaeckle, David Schiff, Volker W Stieber, David G Brachman, Maria Werner-Wasik, Ivo W Tremont-Lukats, Erik P Sulman, Kenneth D Aldape, Walter J Curran, Minesh P Mehta

Department of Radiation Oncology Faculty Papers

BACKGROUND: Concurrent treatment with temozolomide and radiotherapy followed by maintenance temozolomide is the standard of care for patients with newly diagnosed glioblastoma. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor A, is currently approved for recurrent glioblastoma. Whether the addition of bevacizumab would improve survival among patients with newly diagnosed glioblastoma is not known.

METHODS: In this randomized, double-blind, placebo-controlled trial, we treated adults who had centrally confirmed glioblastoma with radiotherapy (60 Gy) and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy. …

Anthropomorphic Breast Phantoms With Physiological Water, Lipid, And Hemoglobin Content For Near-Infrared Spectral Tomography, Kelly E. Michaelsen, Venkataramanan Krishnaswamy, Adele Shenoy, Emily Jordan, Brian W. Pogue, Keith D. Paulsen

Dartmouth Scholarship

Breast mimicking tissue optical phantoms with sufficient structural integrity to be deployed as stand-alone imaging targets are developed and successfully constructed with biologically relevant concentrations of water, lipid, and blood. The results show excellent material homogeneity and reproducibility with inter- and intraphantom variability of 3.5 and 3.8%, respectively, for water and lipid concentrations ranging from 15 to 85%. The phantoms were long-lasting and exhibited water and lipid fractions that were consistent to within 5% of their original content when measured 2 weeks after creation. A breast-shaped three-compartment model of adipose, fibroglandular, and malignant tissues was created with water content ranging …

Irf8 Suppresses Pathological Cardiac Remodelling By Inhibiting Calcineurin Signalling., Ding-Sheng Jiang, Xiang Wei, Xiao-Fei Zhang, Yu Liu, Yan Zhang, Ke Chen, Lu Gao, Heng Zhou, Xue-Hai Zhu, Peter P. Liu, Wayne Bond Lau, Xin-Liang Ma, Yunzeng Zou, Xiao-Dong Zhang, Guo-Chang Fan, Hongliang Li

Department of Emergency Medicine Faculty Papers

Interferon regulatory factor 8 (IRF8) is known to affect the innate immune response, for example, by regulating the differentiation and function of immune cells. However, whether IRF8 can influence cardiac hypertrophy is unknown. Here we show that IRF8 levels are decreased in human dilated/hypertrophic cardiomyopathic hearts and in murine hypertrophic hearts. Mice overexpressing Irf8 specifically in the heart are resistant to aortic banding (AB)-induced cardiac hypertrophy, whereas mice lacking IRF8 either globally or specifically in cardiomyocytes develop an aggravated phenotype induced by pressure overload. Mechanistically, we show that IRF8 directly interacts with NFATc1 to prevent NFATc1 translocation and thus inhibits …

Influence Networks Based On Coexpression Improve Drug Target Discovery For The Development Of Novel Cancer Therapeutics, Nadia M. Penrod, Jason H. Moore

Dartmouth Scholarship

Background: Thedemandfornovelmolecularlytargeteddrugswillcontinuetoriseaswemoveforwardtowardthe goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets. …

Safety With Ocrelizumab In Rheumatoid Arthritis: Results From The Ocrelizumab Phase Iii Program, Paul Emery, William Rigby, Paul P. Tak, Thomas Dörner, Ewa Olech, Carmen Martin, Laurie Millar, Helen Travers, Elena Fisheleva

Dartmouth Scholarship

Objective: The objective was to determine the safety of ocrelizumab (OCR) in patients with rheumatoid arthritis (RA).

Methods: This was an analysis of the double-blind, placebo-controlled periods and long-term follow-up of 4 OCR phase III trials in RA (SCRIPT, STAGE, FILM and FEATURE). Safety data per study and the results of a meta-analysis of serious infectious events (SIEs) are presented.

Results: Overall, 868 patients received placebo, 1064 patients OCR 200 mg×2 (or 400 mg×1) (OCR200), and 827 patients OCR 500 mg×2 (OCR500) plus background methotrexate (MTX) at baseline and 24 weeks. During the double-blind, placebo-controlled periods, the incidence of adverse …

A Novel In Vivo Model For Evaluating Functional Restoration Of A Tissue-Engineered Salivary Gland., Swati Pradhan-Bhatt, Daniel A Harrington, Randall L Duncan, Mary C Farach-Carson, Xinqiao Jia, Robert L Witt

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

OBJECTIVES/HYPOTHESIS: To create a novel model for development of a tissue-engineered salivary gland from human salivary gland cells that retains progenitor cell markers useful for treatment of radiation-induced xerostomia.

STUDY DESIGN: A three-dimensional (3D) hyaluronic acid (HA)-based hydrogel scaffold was used to encapsulate primary human salivary gland cells and to obtain organized acini-like spheroids. Hydrogels were implanted into rat models, and cell viability and receptor expression were evaluated.

METHODS: A parotid gland surgical resection model for xenografting was developed. Salivary cells loaded in HA hydrogels formed spheroids and in vitro were implanted in the three-fourths resected parotid bed of athymic …

Managing The Innovation Supply Chain To Maximize Personalized Medicine., Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Personalized medicine epitomizes an evolving model of care tailored to the individual patient. This emerging paradigm harnesses radical technological advances to define each patient's molecular characteristics and decipher his or her unique pathophysiological processes. Translated into individualized algorithms, personalized medicine aims to predict, prevent, and cure disease without producing therapeutic adverse events. Although the transformative power of personalized medicine is generally recognized by physicians, patients, and payers, the complexity of translating discoveries into new modalities that transform health care is less appreciated. We often consider the flow of innovation and technology along a continuum of discovery, development, regulation, and application …