Cdx1 and c-Myc Foster the Initiation of Transdifferentiation of the Normal Esophageal Squamous Epithelium toward Barrett's Esophagus

Barrett's esophagus is a premalignant condition whereby the normal stratified squamous esophageal epithelium undergoes a transdifferentiation program resulting in a simple columnar epithelium reminiscent of the small intestine. These changes are typically associated with the stratified squamous epithelium chronically exposed to acid and bile salts as a result of gastroesophageal reflux disease (GERD). Despite this well-defined epidemiologic association between acid reflux and Barrett's esophagus, the genetic changes that induce this transdifferentiation process in esophageal keratinocytes have remained undefined.To begin to identify the genetic changes responsible for transdifferentiaiton in Barrett's esophagus, we performed a microarray analysis of normal esophageal, Barrett's esophagus and small intestinal biopsy specimens to identify candidate signaling pathways and transcription factors that may be involved. Through this screen we identified the Cdx1 homeodomain transcription factor and the c-myc pathway as possible candidates. Cdx1 and c-myc were then tested for their ability to induce transdifferentiation in immortalized human esophageal keratinocytes using organotypic culturing methods. Analyses of these cultures reveal that c-myc and cdx1 cooperate to induce mucin production and changes in keratin expression that are observed in the epithelium of Barrett's esophagus.These data demonstrate the ability of Cdx1 and c-myc to initiate the earliest stages of transdifferentiation of esophageal keratinocytes toward a cell fate characteristic of Barrett's esophagus

Development of the pediatric daily ulcerative colitis signs and symptoms scale (DUCS): qualitative research findings

Abstract Background The purpose of this study is to develop patient-reported (PRO) and observer-reported (ObsRO) outcome measures of ulcerative colitis (UC) signs/symptoms in children aged 5–17 with mild/moderate UC. The daily ulcerative colitis signs and symptoms scale (DUCS) was developed in two phases. Phase I involved concept elicitation interviews with patients and healthcare providers, review of website posts and item generation. Phase II involved cognitive debriefing and assessment of usability and feasibility of the eDiaries. Participants were recruited from five US clinical sites, a research recruitment agency, and internet advertising. Thematic and content analysis was performed to identify concepts from Phase I. The Phase II cognitive debriefing interviews were analyzed iteratively to identify problems with clarity and relevance of eDiary content. The US Food and Drug Administration (FDA) also reviewed and provided feedback on the eDiaries. Results Phase I included 32 participants (22 remission; 10 active disease). Phase II included 38 participants (22 remission; 16 active disease). A core set of seven signs and symptoms emerged that were reported by at least 30% of the patients interviewed: abdominal pain, blood in stool, frequent stools, diarrhea, stool urgency, nighttime stools, and tiredness. Participant input influenced changes such as refinement of item wording, revision of graphics, and selection of response scales. Revisions suggested by FDA included simplifying the response scale and adding questions to capture symptoms during sleeping hours. Conclusions The findings of instrument development suggest that the DUCS PRO and ObsRO eDiaries are content-valid instruments for capturing the daily signs and symptoms of pediatric patients with mild to moderate UC in a clinical trial setting

Synthesis And Applications Of Ring Opening Metathesis Polymerization Based Functional Block Copolymers

Ring opening metathesis polymerization (ROMP) is established as one of the efficient controlled living polymerization methods which have various applications in polymer science and technology fields. The research presented in this dissertation addresses several applications of multifunctional well-defined norbornene-based block copolymers synthesized by ROMP using ruthenium-based Grubbs catalysts. These novel block copolymers were applied to stabilize maghemite nanoparticles, creating the superparamagnetic polymeric nanocomposites. The Jaggregation properties of the porphyrin dyes were improved via self-assembly with a customized norbornene polymer. Novel multimodal copolymer probes were synthesized for two-photon fluorescence integrin-targeted bioimaging. In Chapter 1 a brief overview of ROMP along with ruthenium metal catalysts and selected applications of the polymers related to this research is presented. Superparamagnetic maghemite nanoparticles are important in biotechnology fields, such as enhanced magnetic resonance imaging (MRI), magnetically controlled drug delivery, and biomimetics. However, cluster formation and eventual loss of nano-dimensions is a major obstacle for these materials. Chapter 2 presents a solution to this problem through nanoparticles stabiulized in a polymer matrix. The synthesis and chracterization of novel diblock copolymers, consisting of epoxy pendant anchoring groups to chelate maghemite nanoparticles and steric stabilizing groups, as well as generation of nanocomposites and their characterization, including surface morphologies and iv magnetic properties, is discussed in Chapter 2. In Chapter 3, further improvement of the nanocomposites by ligand modification and the synthesis of pyrazole-templated diblock copolymers and their impact to stabilize the maghemite nanocomposite are presented. Additionally, the organic soluble magnetic nanocomposites with high magnetizations were encapsulated in an amphiphilic copolymer and dispersed in water to assess their water stability by TEM. To gain a preliminary measure of biocopatibility of the micelle-encapsulated polymeric magnetic nanocomposites, cell-viability was determined. In Chapter 4, aggregation behaviors of two porphyrin-based dyes were investigated. A new amphiphilic homopolymer containing secondary amine moieties was synthesized and characterized. In low pH, the polymer became water soluble and initiated the stable Jaggregation of the porphyrin. Spectroscopic data supported the aggregation behavior. Two photon fluorescence microscopy (2PFM) has become a powerful technique in bioimaging for non-invasive imaging and potential diagnosis and treatment of a number of diseases via excitation in the near-infrared (NIR) region. The fluorescence emission upon two-photon absorption (2PA) is quadratically dependent with the intensity of excitation light (compared to the linear dependence in the case of one-photon absoprtion), offering several advantages for biological applications over the conventional one-photon absorption (1PA) due to the high 3D spatial resolution that is confined near the focal point along with less photodamage and interference from the biological tissues at longer wavelength (~700-900 nm). Hence, efficient 2PA absorbing fluorophores conjugated with specific targeting moieties provides an even better bioimaging probe to diagnose desired cellular processes or areas of interest The αVβ3 integrin v adhesive protein plays a significant role in regulating angiogenesis and is over-expressed in uncontrolled neovascularization during tumor growth, invasion, and metastasis. Cyclic-RGD peptides are well-known antagonists of αVβ3 integrin which suppress the angiogenesis process, thus preventing tumor growth. In Chapter 5 the synthesis, photophysical studies and bioimaging is reported for a versatile norbornene-based block copolymer multifunctional scaffold containing biocompatible (PEG), two-photon fluorescent (fluorenyl), and targeting (cyclic RGD peptide) moieties. This water-soluble polymeric multi scaffold probe with negligible cytotoxicity exhibited much stronger fluorescence and high localization in U87MG cells (that overexpress integrin) compared to control MCF7 cells. The norbornene-based polymers and copolymers have quite remarkable versatility for the creation of advanced functional magnetic, photonic, and biophotonic materials

UvA-DARE (Digital Academic Repository) Link to publication Citation for published version (APA): A novel reflux inhibitor lesogaberan (AZD3355) as add-on treatment in patients with GORD with persistent reflux symptoms despite proton pump inhibitor therapy

A novel reflux inhibitor lesogaberan (AZD3355) as add-on treatment in patients with GORD with persistent reflux symptoms despite proton pump inhibitor therapy: a randomised placebocontrolled trial Boeckxstaens, G.E.; Beaumont, H.; Hatlebakk, J.G.; Silberg, D.G.; Björck, K.; Karlsson, M.; Denison, H. : 10.1136/gut.2010.235630 Link to publication Citation for published version (APA): Boeckxstaens, G. E., Beaumont, H., Hatlebakk, J. G., Silberg, D. G., Björck, K., Karlsson, M., & Denison, H. (2011). A novel reflux inhibitor lesogaberan (AZD3355) as add-on treatment in patients with GORD with persistent reflux symptoms despite proton pump inhibitor therapy: a randomised placebo-controlled trial. Gut, 60(9), 1182-1188. https://doi.org/10.1136/gut.2010.235630 Published in: Gut DOI General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 29 Jun 2019 A novel reflux inhibitor lesogaberan (AZD3355) as add-on treatment in patients with GORD with persistent reflux symptoms despite proton pump inhibitor therapy: a randomised placebo-controlled trial ABSTRACT Objective To evaluate the efficacy and tolerability of add-on treatment with lesogaberan (AZD3355), a novel reflux inhibitor, in patients with persistent gastrooesophageal reflux disease (GORD) symptoms despite proton pump inhibitor (PPI) therapy. Methods A double-blind, placebo-controlled, randomised, parallel-group, multicentre phase IIA study was carried out in outpatient clinics. The study group comprised 244 adult patients with persistent GORD symptoms (heartburn and/or regurgitation) of at least mild intensity and for 3 days of 7 days before enrolment, despite $6 weeks of continuous PPI therapy. Patients received either lesogaberan (65 mg twice daily) or placebo in addition to PPI therapy for a period of 4 weeks. Symptom intensity, based on the Reflux Disease Questionnaire, was recorded twice daily. Treatment response (defined as at most one 24 h period with heartburn or regurgitation of not more than mild intensity during the last 7 days of treatment). Time to response, proportion of symptom-free days and measures of tolerability were also analysed. Results A total of 232 (114 lesogaberan-and 118 placebo-treated patients) of the 244 randomised patients were analysed for efficacy. Treatment with lesogaberan, compared with placebo, resulted in a significantly larger proportion of responders to treatment (16% vs 8% of patients; p¼0.026) and cumulative proportion of responders over time (log-rank p¼0.0195). Lesogaberan was well tolerated: adverse events of mostly mild to moderate intensity were reported in 45% of patients on lesogaberan and in 37% on placebo. Conclusions Lesogaberan add-on therapy to PPIs significantly improved heartburn and regurgitation symptoms; however, the proportion of responders was small. Clinical trial number NCT00394472