DOCSLIB.ORG

Molecular Imaging of Breast Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

MOLECULAR IMAGING OF BREAST CANCER USING PARACEST MRI by BYUNGHEE YOO Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Thesis Advisor: Prof. Mark D. Pagel, Ph.D. Department of Biomedical Engineering CASE WESTERN RESERVE UNIVERSITY August, 2007 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of ________________BYUNGHEE YOO_____________________ candidate for the Doctor of Philosophy degree *. (signed) Mark D. Pagel, Ph.D. (chair of the committee) Raymon F. Muzic, Ph.D. Suneel S. Apte, Ph.D. Xin Yu, Sc.D. (date) June 15, 2007 *We also certify that written approval has been obtained for any proprietary material contained therein. Copyright © 2006 by Byunghee Yoo All rights reserved iii DEDICATION To my family and my mentors iv Table of Contents Title page …..……………………………………………………………..…………. …. i Committee signature …………..…………………………………………..………... …. ii Copyright……………………………………………………………………………. … iii Dedication ………………………………………………………………………..…. ….iv Table of Contents..………………………………………………………….….……. …..1 List of Tables..……………………………………………………………….…...…. …..4 List of Schemes…………………………………………………………….….….…. …..5 List of Figures……………………………………………………………….….….... …..6 Preface……………………………………………………………………….….….... …..8 Acknowledgements……………………………………………………..….………... .…10 List of Abbreviations…………………………………………………………………….12 Abstract……………………………………………………………….……………... .....13 Chapter I. Introduction………………………………………………………………… ..15 1. Breast cancer and molecular MR imaging……………………………………. ..16 A. Breast cancer and biomarkers……………………………………………... ..16 B. Detection of biomarkers in breast cancer………………………...……….. ..18 2. MRI and MR contrast…………………………………………………………. ..21 A. General concept of MRI………………………………...………………… ..21 B. T1, T2 relaxation times and contrast……………………………...……….. ..24 C. Paramagnetic Chemical Saturation Transfer (PARACEST) ……...……… ..30 3. References…………………………………………………………………….. ..35 Chapter II. Responsive MR contrast agents…………………………………………… ..41 1. Introduction……………………………………………………………………...42 2. Exogenous MR contrast agents……………………………………………….....42 3. Responsive MR contrast agents……………………………………………….. ..47 A. Responsive MRI contrast agents for molecular imaging of proteins……... ..47 a. Contrast agents that bind to proteins…………………………………. ..47 b. Contrast agents that are catalyzed by enzymes……………….......... ….49 B. Responsive MRI contrast agents for molecular imaging of nucleic acids... ..51 C. Responsive MRI contrast agents for molecular imaging of metabolites…. ..53 D. Responsive MRI contrast agents for molecular imaging of oxygen……… ..54 E. Responsive MRI contrast agents for molecular imaging of metal ions…......55 1 F. Responsive MRI contrast agents for molecular imaging of pH…………... ..57 G. Responsive MRI contrast agents for molecular imaging of temperature…. ..61 4. Future directions………………………………………………………………. ..62 5. References…………………………………………………………………….....66 Chapter III. Solution phase synthesis of molecular imaging contrast agents………........75 1. Introduction……………………………………………………………………...76 2. Experimental methods………………………………………………………… ..78 A. General methods…………………..………………………………………...78 B. Synthesis and characterization…………..………………………………... ..79 3. Results and discussions……………………………………………………….....87 4. Conclusions……………………………………………………………………...91 5. References…………………………………………………………………….....92 Chapter IV. Solid phase synthesis of molecular imaging contrast agents………….......101 1. Introduction…………………………………………………………………… 102 2. Experimental methods………………………………………………………… 105 A. General methods………………………………………….……..………… 105 B. Synthesis and characterization……………………………...…………….. 107 3. Results and discussions……………………………………………………….. 117 4. Conclusions…………………………………………………………………… 132 5. References…………………………………………………………………….. 134 Chapter V. Detection of enzyme activity using the PARACEST effect………………. 154 1. Introduction…………………………………………………………………… 155 2. Experimental methods………………………………………………………… 159 3. Results and discussions……………………………………………………….. 166 4. Conclusions…………………………………………………………………… 183 5. References…………………………………………………………………….. 185 Chapter VI. Contrast agents for DCE-MRI…………………………………………… 189 1. Angiogenesis and microvasculature…………………………………………... 189 2. Dynamic contrast-enhnaced magnetic resonance imaging (DCE-MRI)……… 191 A. Arterial input function (AIF)………………………………………..….…. 192 B. Contrast agents…………………………………………………..………... 194 a. Small molecular contrast agent (SMCA)…………………………….. 196 2 b. Intermediate molecular contrast agent (IMCA)……………………… 196 c. Large molecular contrast agent (LMCA)…………………………….. 198 3. Summary ………………………………………………………………………. 204 4. References…………………………………………………………………….. 206 Chapter VII. PARACEST DCE-MRI………………………………………………….. 218 1. Introduction…………………………………………………………………… 219 2. Experimental methods………………………………………………………… 220 A. Synthesis of molecular imaging probes………………...………………… 220 B. Cell culture and flank tumor model……………………..………………... 224 C. PARACEST DCE-MRI………………………………..…………………. 224 D. Analysis of DCE-MRI data…………………………...…………………... 227 3. Results………………………………………………………………………… 235 A. Contrast agents………………………………………….……..………….. 235 B. Tumor model and catheterization………………………...……………….. 238 C. T1 DCE-MRI……………………………………………………………… 240 D. PARACEST DCE-MRI…………………………………...………………. 241 4. Discussion……………………………………………………………………... 247 5. References…………………………………………………………………….. 251 Chapter VIII. Future research…………………………………………………………. 254 1. Development of contrast agents………………………………………………. 256 A. Synthesis of DOTA derivatives…………………………..………………. 256 B. Polymeric / dendrimeric templates………………………..……………… 265 2. Applications for diagnostic/clinical research…………………………………. 266 3. Detection of endopeptidase activity…………………………………………... 269 Appendix……………………………………………………………………………….276 A1. Michaelis-Menten kinetics versus CEST concentration calibration…..……… 276 A2. MEROPS database……………………………………………………………. 282 3 List of Tables Table 2.1 Structures of responsive MR contrast agents………………….……………..72 Table 4.1 The amine contents on the resin measured by picric acid titration….……… 113 Table 5.1 Michaelis-Menten kinetics parameters……………………………….…….. 177 Table 5.2 Stratification of human proteases by catalytic mechanism………….……… 182 Table 6.1 Examples of blood pool agents (BPAs) in DCE-MRI……………….…....... 195 Table 7.1 The loading amounts of each contrast agents.……………………….……… 226 Table 7.2 Three standard kinetic parameters in DCE-MRI………………….………… 230 Table 7.3 Working quantities in DCE-MRI………………………………….………... 231 Table 7.4 Relaxivities of contrast agents for DCE-MRI experiments……….………... 235 Trans Table 7.5 Summary of K from T1 and PARACEST DCE-MRI……….…………... 242 Table 8.1 MMP’s substrate peptide sequences…………………..………….………… 275 Table A1.1 A comparison of graphical analysis methods to evaluate Michaelis-Menten kinetics parameters………………………………………………………... 278 Table A2.1 Human peptidases…………………………………………….…………… 284 4 List of Schemes Scheme 3.1 Synthesis of α-brominated glycine templates……….…...………………. .95 Scheme 3.2 Synthesis of α-amino-DOTA derivatives and coupling to a peptide backbone carboxylate group………………………………………………. .96 Scheme 4.1 Preparation of amino-DOTA pre-loaded polymeric support….…….….....141 Scheme 4.2 Synthesis of peptidyl contrast agents……………………….…………….142 Scheme 7.1 Synthesis of DOTAMGly…………………………………………………253 Scheme 8.1 Tentative synthetic pathway of Fmoc-Gly(DOTA-tBu)-OH…….……...... 259 Scheme 8.2 Proposed mechanism of enzyme responsive peptidyl phosphate DOTA.... 260 Scheme 8.3 Tentative synthetic scheme of peptidyl phosphate DOTA with doxorubicin.…………………………………………………………. 261 Scheme 8.4 Tentative enzyme responsive MR contrast agent based on trimethyl lock mechanism………………………………………………………………… 262 Scheme 8.5 Tentative synthetic pathway of Fmoc-Gly(DOTA-tBu) derivative for ligation…………………………………………………………………….. 263 Scheme 8.6 Tentative synthetic pathway of Fmoc-AA(DOTA-tBu)-OH…….……...... 264 5 List of Figures Figure 1.1 The tipping and relaxation of magnetization Mo relative to Bo…………… .23 Figure 1.2 Schematic of the interactions of water molecules with a lanthanide (III)-based contrast agent………………………………. .29 Figure 1.3 Chemical structures of DOTA, DOTAM and DOTAMGly………………... .32 Figure 1.4 Schematics for the mechanism of PARACEST effects……………………. .33 Figure 3.1 1H-NMR spectrum of Cbz-Gly(OH)-OH………………………………….. .97 Figure 3.2 1H-NMR spectrum of Cbz-Gly(OMe)-OMe……………………………..... .97 Figure 3.3 1H-NMR spectrum of Cbz-Gly(Br)-OMe………………………………...... .98 Figure 3.4 1H-NMR spectrum of Boc-Gly(Br)-tBu…………………………………… .98 Figure 3.5 1H-NMR spectrum of Boc-Gly-tBu-DO3A-tBu (Boc-amino-DOTA)…...... .99 Figure 3.6 1H-NMR spectrum of Cbz-Gly-OMe-DO3A-tBu (Cbz-amino-DOTA).…... .99 Figure 3.7 1H-NMR spectrum of amino-DOTA……………………………………..... 100 Figure 3.8 Maldi-Mass Spectral analysis of Ac-PLGMWSG-amino-DOTA…………. 100 Figure 4.1 Ninhydrin color test to qualitatively analyze the amine content on the resin………………………………………………………………... 113 Figure 4.2 The amine content following CBZ cleavage versus reaction time ....... 143 Figure 4.3 Two possible transition states of Et2AlCl and CBZ-aminoDOTA Wang resin………………………………………………………………… 144 Figure 4.4 The PARACEST spectra…………………………………………………… 145 Figure 4.5 The proximity of amide hydrogens to Tm3+……………………………….. 146 Figure 4.6 Dependencies of the PARACEST effects on environmental conditions…... 147 Figure 4.7 The calibration of the PARACEST effect relative to concentration……….. 148 Figure 4.8 1H-NMR Spectrum of Cbz-Gly(OH)-OH…………………………………. 149 Figure 4.9 1H-NMR
Recommended publications
  • Effects of Glycosylation on the Enzymatic Activity and Mechanisms of Proteases

    Effects of Glycosylation on the Enzymatic Activity and Mechanisms of Proteases

    International Journal of Molecular Sciences Review Effects of Glycosylation on the Enzymatic Activity and Mechanisms of Proteases Peter Goettig Structural Biology Group, Faculty of Molecular Biology, University of Salzburg, Billrothstrasse 11, 5020 Salzburg, Austria; [email protected]; Tel.: +43-662-8044-7283; Fax: +43-662-8044-7209 Academic Editor: Cheorl-Ho Kim Received: 30 July 2016; Accepted: 10 November 2016; Published: 25 November 2016 Abstract: Posttranslational modifications are an important feature of most proteases in higher organisms, such as the conversion of inactive zymogens into active proteases. To date, little information is available on the role of glycosylation and functional implications for secreted proteases. Besides a stabilizing effect and protection against proteolysis, several proteases show a significant influence of glycosylation on the catalytic activity. Glycans can alter the substrate recognition, the specificity and binding affinity, as well as the turnover rates. However, there is currently no known general pattern, since glycosylation can have both stimulating and inhibiting effects on activity. Thus, a comparative analysis of individual cases with sufficient enzyme kinetic and structural data is a first approach to describe mechanistic principles that govern the effects of glycosylation on the function of proteases. The understanding of glycan functions becomes highly significant in proteomic and glycomic studies, which demonstrated that cancer-associated proteases, such as kallikrein-related peptidase 3, exhibit strongly altered glycosylation patterns in pathological cases. Such findings can contribute to a variety of future biomedical applications. Keywords: secreted protease; sequon; N-glycosylation; O-glycosylation; core glycan; enzyme kinetics; substrate recognition; flexible loops; Michaelis constant; turnover number 1.
  • Serine Proteases with Altered Sensitivity to Activity-Modulating

    Serine Proteases with Altered Sensitivity to Activity-Modulating

    (19) & (11) EP 2 045 321 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 08.04.2009 Bulletin 2009/15 C12N 9/00 (2006.01) C12N 15/00 (2006.01) C12Q 1/37 (2006.01) (21) Application number: 09150549.5 (22) Date of filing: 26.05.2006 (84) Designated Contracting States: • Haupts, Ulrich AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 51519 Odenthal (DE) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • Coco, Wayne SK TR 50737 Köln (DE) •Tebbe, Jan (30) Priority: 27.05.2005 EP 05104543 50733 Köln (DE) • Votsmeier, Christian (62) Document number(s) of the earlier application(s) in 50259 Pulheim (DE) accordance with Art. 76 EPC: • Scheidig, Andreas 06763303.2 / 1 883 696 50823 Köln (DE) (71) Applicant: Direvo Biotech AG (74) Representative: von Kreisler Selting Werner 50829 Köln (DE) Patentanwälte P.O. Box 10 22 41 (72) Inventors: 50462 Köln (DE) • Koltermann, André 82057 Icking (DE) Remarks: • Kettling, Ulrich This application was filed on 14-01-2009 as a 81477 München (DE) divisional application to the application mentioned under INID code 62. (54) Serine proteases with altered sensitivity to activity-modulating substances (57) The present invention provides variants of ser- screening of the library in the presence of one or several ine proteases of the S1 class with altered sensitivity to activity-modulating substances, selection of variants with one or more activity-modulating substances. A method altered sensitivity to one or several activity-modulating for the generation of such proteases is disclosed, com- substances and isolation of those polynucleotide se- prising the provision of a protease library encoding poly- quences that encode for the selected variants.
  • Chrystelle Bonnart

    Chrystelle Bonnart

    UNIVERSITE TOULOUSE III – PAUL SABATIER U.F.R. Sciences T H E S E Pour obtenir le grade de DOCTEUR DE L’UNIVERSITE TOULOUSE III Discipline : Physiopathologie moléculaire, cellulaire et intégrée Présentée et soutenue par Chrystelle Bonnart Le 20 novembre 2007 Etude fonctionnelle de LEKTI et de sa nouvelle cible, l’élastase 2 pancréatique Directeur de thèse : Pr Alain Hovnanian JURY Pr Alain Hovnanian, Président Pr Pierre Dubus, rapporteur Pr Michèle Reboud-Ravaux, rapporteur Dr Heather Etchevers, examinateur 2 Heureux sont les fêlés, car ils laissent passer la lumière… Michel Audiard 3 REMERCIEMENTS Tout d’abord, mes remerciements s’adressent à mon directeur de thèse, Alain Hovnanian, pour m’avoir accueillie dans son équipe, pour m’avoir rapidement fait confiance en me laissant une grande autonomie et pour m’avoir encouragée à participer à des congrès internationaux. Je tiens à remercier Pr Pierre Dubus et Pr Michèle Reboud-Ravaux pour m’avoir fait l’honneur d’évaluer ce travail de thèse. Je remercie également Dr Heather Etchevers pour sa présence dans le jury de thèse. Je remercie vivement les enseignant-chercheurs et professeurs de l’UPS que j’ai eu l’occasion de croiser pendant mon monitorat. Tout d’abord, merci à Estelle Espinos, tu as assumé ton rôle de tutrice avec brio, tu as été à mes côtés dans mes débuts hésitants, merci pour ta disponibilité. Merci à Martine Briet et Pascale Bélenguer, qui m’ont fait bénéficier de leur grande expérience de l’enseignement. Un merci particulier à Nathalie Ortega, que j’ai eu la chance de rencontrer dans ma dernière année de monitorat.
  • A Potential Role in the D-Binding Protein (Gc-Globulin) to Elastase

    A Potential Role in the D-Binding Protein (Gc-Globulin) to Elastase

    Elastase Controls the Binding of the Vitamin D-Binding Protein (Gc-Globulin) to Neutrophils: A Potential Role in the Regulation of C5a Co-Chemotactic Activity This information is current as of September 26, 2021. Stephen J. DiMartino, Anisha B. Shah, Glenda Trujillo and Richard R. Kew J Immunol 2001; 166:2688-2694; ; doi: 10.4049/jimmunol.166.4.2688 http://www.jimmunol.org/content/166/4/2688 Downloaded from References This article cites 64 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/166/4/2688.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Elastase Controls the Binding of the Vitamin D-Binding Protein (Gc-Globulin) to Neutrophils: A Potential Role in the Regulation of C5a Co-Chemotactic Activity1 Stephen J. DiMartino, Anisha B.
  • Intracellular Peptides: from Discovery to Function

    Intracellular Peptides: from Discovery to Function

    e u p a o p e n p r o t e o m i c s 3 ( 2 0 1 4 ) 143–151 Available online at www.sciencedirect.com ScienceDirect journal homepage: http://www.elsevier.com/locate/euprot Intracellular peptides: From discovery to function a,∗ b a,c d,∗∗ Emer S. Ferro , Vanessa Rioli , Leandro M. Castro , Lloyd D. Fricker a Department of Pharmacology, Biomedical Sciences Institute, University of São Paulo, São Paulo, SP, Brazil b Special Laboratory of Applied Toxicology-CeTICS, Butantan Institute, São Paulo, SP, Brazil c Department of Biophysics, Federal University of São Paulo, São Paulo, SP, Brazil d Department of Molecular Pharmacology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA a r t i c l e i n f o a b s t r a c t Article history: Peptidomics techniques have identified hundreds of peptides that are derived from proteins Received 8 October 2013 present mainly in the cytosol, mitochondria, and/or nucleus; these are termed intracellular Received in revised form peptides to distinguish them from secretory pathway peptides that function primarily out- 29 November 2013 side of the cell. The proteasome and thimet oligopeptidase participate in the production and Accepted 14 February 2014 metabolism of intracellular peptides. Many of the intracellular peptides are common among mouse tissues and human cell lines analyzed and likely to perform a variety of functions Keywords: within cells. Demonstrated functions include the modulation of signal transduction, mito- Peptides chondrial stress, and development; additional functions will likely be found for intracellular Cell signaling peptides.
  • Contents Supplemental Table 1

    Contents Supplemental Table 1

    Supplementary material Open Heart SUPPLEMENTAL MATERIAL TO “EXPLORATION OF PATHOPHYSIOLOGICAL PATHWAYS FOR INCIDENT ATRIAL FIBRILLATION – THE MALMÖ PREVENTIVE PROJECT” John Molvin, Amra Jujic, Olle Melander, Manan Pareek, Lennart Råstam, Ulf Lindblad, Bledar Daka, Margrét Leósdóttir, Peter M. Nilsson, Michael H. Olsen & Martin Magnusson Contents Supplemental table 1. Unadjusted Cox regression analyses examining all 92 proteins relation to incident atrial fibrillation ................................................................................... 2-3 List of abbreviations……………………………………………………………………………………………………………4 Molvin J, et al. Open Heart 2020; 7:e001190. doi: 10.1136/openhrt-2019-001190 Supplementary material Open Heart Supplemental table 1. Unadjusted Cox regression analyses examining all 92 proteins relation to incident atrial fibrillation Protein Hazard ratio (95% confidence interval) p-value PON3 0.80 (0.72-0.89) 7.3x10-5 IGFBP2 4.47 (1.42-14-1) 0.011 PAI 1.44 (0.65-3.18) 0.371 CTSD 2.45 (1.13-5.30) 0.023 FABP4 1.27 (1.13-1.44) 8.6x10-5 CD163 5.25 (1.14-24.1) 0.033 GAL4 1.30 (1.15-1.47) 3.5x10-5 LDL-receptor 0.81 (0.39-1.69) 0.582 IL1RT2 0.75 (0.24-2.34) 0.614 t-PA 2.75 (1.21-6.27) 0.016 SELE 0.99 (0.51-1.90) 0.969 CTSZ 2.97 (1.00-8.78) 0.050 GDF15 1.41 (1.25-1.59) 9.7x10-9 CSTB 3.75 (1.58-8.92) 0.003 MPO 4.48 (1.73-11.7) 0.002 PCSK9 1.18 (0.73-1.93) 0.501 IGFBP1 2.48 (1.42-4.35) 0.001 RARRES2 64.3 (1.87-2220.8) 0.021 ITGB2 1.01 (0.31-3.29) 0.990 CCL15 3.58 (0.96-13.3) 0.057 SCGB3A2 0.97 (0.71-1.32) 0.839 CHI3L1 1.26 (1.12-1.43)
  • Proteome Profiler Human Protease Array Kit

    Proteome Profiler Human Protease Array Kit

    Proteome ProfilerTM Array Human Protease Array Kit Catalog Number ARY021 For the parallel determination of the relative levels of selected human proteases. This package insert must be read in its entirety before using this product. For research use only. Not for use in diagnostic procedures. TABLE OF CONTENTS SECTION PAGE INTRODUCTION .....................................................................................................................................................................1 PRINCIPLE OF THE ASSAY ...................................................................................................................................................1 TECHNICAL HINTS .................................................................................................................................................................1 MATERIALS PROVIDED & STORAGE CONDITIONS ...................................................................................................2 OTHER SUPPLIES REQUIRED .............................................................................................................................................3 SUPPLIES REQUIRED FOR CELL LYSATE SAMPLES ...................................................................................................3 SUPPLIES REQUIRED FOR TISSUE LYSATE SAMPLES ...............................................................................................3 SAMPLE COLLECTION & STORAGE .................................................................................................................................4
  • Design of Ultrasensitive Probes for Human Neutrophil Elastase Through Hybrid Combinatorial Substrate Library Profiling

    Design of Ultrasensitive Probes for Human Neutrophil Elastase Through Hybrid Combinatorial Substrate Library Profiling

    Design of ultrasensitive probes for human neutrophil elastase through hybrid combinatorial substrate library profiling Paulina Kasperkiewicza, Marcin Porebaa, Scott J. Snipasb, Heather Parkerc, Christine C. Winterbournc, Guy S. Salvesenb,c,1, and Marcin Draga,b,1 aDivision of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw 50-370, Poland; bProgram in Cell Death and Survival Networks, Sanford-Burnham Medical Research Institute, La Jolla, CA 92024; and cCentre for Free Radical Research, Department of Pathology, University of Otago Christchurch, Christchurch 8140, New Zealand Edited* by Vishva M. Dixit, Genentech, San Francisco, CA, and approved January 15, 2014 (received for review October 1, 2013) The exploration of protease substrate specificity is generally possibilities. Here we demonstrate a general approach for the syn- restricted to naturally occurring amino acids, limiting the degree of thesis of combinatorial libraries containing unnatural amino acids, conformational space that can be surveyed. We substantially with subsequent screening and analysis of large sublibraries. We enhanced this by incorporating 102 unnatural amino acids to term this approach the Hybrid Combinatorial Substrate Library explore the S1–S4 pockets of human neutrophil elastase. This ap- (HyCoSuL). We demonstrate the utility of this approach in the proach provides hybrid natural and unnatural amino acid sequen- design of a highly selective substrate and activity-based probe. ces, and thus we termed it the Hybrid Combinatorial Substrate As a target protease, we selected human neutrophil elastase Library. Library results were validated by the synthesis of individ- (EC 3.4.21.37) (NE), a serine protease restricted to neutrophil ual tetrapeptide substrates, with the optimal substrate demon- azurophil granules (14).
  • A Case of Prohormone Convertase Deficiency Diagnosed with Type 2 Diabetes

    A Case of Prohormone Convertase Deficiency Diagnosed with Type 2 Diabetes

    Turkish CASE REPORT Archives of DOI: 10.14744/TurkPediatriArs.2020.36459 Pediatrics A case of prohormone convertase deficiency diagnosed with type 2 diabetes Gülin Karacan Küçükali1 , Şenay Savaş Erdeve1 , Semra Çetinkaya1 , Melikşah Keskin1 , Ayşe Derya Buluş2 , Zehra Aycan1 1Department of Pediatric Endocrinology, University of Health Science, Dr. Sami Ulus Obstetrics and Gynecology, Children’s Health and Disease Training and Research Hospital, Ankara, Turkey 2Department of Pediatric Endocrinology, University of Health Science, Keçiören Training and Research Hospital, Ankara, Turkey What is already known ABSTRACT on this topic? Prohormone convertase 1/3, encoded by the proprotein convertase subtilisin/kexin type 1 gene, • Prohormone convertase defi- is essential for processing prohormones; therefore, its deficiency is characterized by a defi- ciency is characterized by a de- ciency of variable levels in all hormone systems. Although a case of postprandial hypoglycemia ficiency of variable levels in all has been previously reported in the literature, prohormone convertase insufficiency with type hormone systems. 2 diabetes mellitus has not yet been reported. Our case, a 14-year-old girl, was referred due to • Postprandial hypoglycemia is a excess weight gain. She was diagnosed as having type 2 diabetes mellitus based on laboratory disorder of glucose metabolism test results. Prohormone convertase deficiency was considered due to the history of resistant reported in this disease. diarrhea during the infancy period and her rapid weight gain. Proinsulin level was measured as >700 pmol/L(3.60-22) during diagnosis. In genetic analysis, a c.685G> T(p.V229F) homozygous mutation in the PCSK1 gene was detected and this has not been reported in relation to this dis- order.
  • 1 No. Affymetrix ID Gene Symbol Genedescription Gotermsbp Q Value 1. 209351 at KRT14 Keratin 14 Structural Constituent of Cyto

    1 No. Affymetrix ID Gene Symbol Genedescription Gotermsbp Q Value 1. 209351 at KRT14 Keratin 14 Structural Constituent of Cyto

    1 Affymetrix Gene Q No. GeneDescription GOTermsBP ID Symbol value structural constituent of cytoskeleton, intermediate 1. 209351_at KRT14 keratin 14 filament, epidermis development <0.01 biological process unknown, S100 calcium binding calcium ion binding, cellular 2. 204268_at S100A2 protein A2 component unknown <0.01 regulation of progression through cell cycle, extracellular space, cytoplasm, cell proliferation, protein kinase C inhibitor activity, protein domain specific 3. 33323_r_at SFN stratifin/14-3-3σ binding <0.01 regulation of progression through cell cycle, extracellular space, cytoplasm, cell proliferation, protein kinase C inhibitor activity, protein domain specific 4. 33322_i_at SFN stratifin/14-3-3σ binding <0.01 structural constituent of cytoskeleton, intermediate 5. 201820_at KRT5 keratin 5 filament, epidermis development <0.01 structural constituent of cytoskeleton, intermediate 6. 209125_at KRT6A keratin 6A filament, ectoderm development <0.01 regulation of progression through cell cycle, extracellular space, cytoplasm, cell proliferation, protein kinase C inhibitor activity, protein domain specific 7. 209260_at SFN stratifin/14-3-3σ binding <0.01 structural constituent of cytoskeleton, intermediate 8. 213680_at KRT6B keratin 6B filament, ectoderm development <0.01 receptor activity, cytosol, integral to plasma membrane, cell surface receptor linked signal transduction, sensory perception, tumor-associated calcium visual perception, cell 9. 202286_s_at TACSTD2 signal transducer 2 proliferation, membrane <0.01 structural constituent of cytoskeleton, cytoskeleton, intermediate filament, cell-cell adherens junction, epidermis 10. 200606_at DSP desmoplakin development <0.01 lectin, galactoside- sugar binding, extracellular binding, soluble, 7 space, nucleus, apoptosis, 11. 206400_at LGALS7 (galectin 7) heterophilic cell adhesion <0.01 2 S100 calcium binding calcium ion binding, epidermis 12. 205916_at S100A7 protein A7 (psoriasin 1) development <0.01 S100 calcium binding protein A8 (calgranulin calcium ion binding, extracellular 13.
  • Durham E-Theses

    Durham E-Theses

    Durham E-Theses Midgut proteases from larval spodoptera littoralis (lepidoptera: noctutoae) Lee, Michael James How to cite: Lee, Michael James (1992) Midgut proteases from larval spodoptera littoralis (lepidoptera: noctutoae), Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/5739/ Use policy The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that: • a full bibliographic reference is made to the original source • a link is made to the metadata record in Durham E-Theses • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult the full Durham E-Theses policy for further details. Academic Support Oce, Durham University, University Oce, Old Elvet, Durham DH1 3HP e-mail: [email protected] Tel: +44 0191 334 6107 http://etheses.dur.ac.uk MIDGUT PROTEASES FROM LARVAL SPODOPTERA LITTORALIS (LEPIDOPTERA: NOCTUTOAE) By Michael James Lee B.Sc. (Dunelm) The copyright of this thesis rests with the author. No quotation from it should be pubhshed without his prior written consent and information derived from it should be acknowledged. Being a thesis submitted for the degree of Doctor of Philosophy of the University of Durham. November, 1992 Hatfield College University of Durham 6 APR 1993 DECLARATION I hereby declare that the work presented in this document is based on research carried out by me, and that no part has been previously submitted for a degree in this or any other university.
  • Papel De Los Receptores De Estrógenos Alfa En El Crecimiento De Carcinomas Mamarios Murinos Con Respuesta Diferencial a Progestágenos

    Papel De Los Receptores De Estrógenos Alfa En El Crecimiento De Carcinomas Mamarios Murinos Con Respuesta Diferencial a Progestágenos

    Tesis Doctoral Papel de los receptores de estrógenos alfa en el crecimiento de carcinomas mamarios murinos con respuesta diferencial a progestágenos Giulianelli, Sebastián Jesús 2009 Este documento forma parte de la colección de tesis doctorales y de maestría de la Biblioteca Central Dr. Luis Federico Leloir, disponible en digital.bl.fcen.uba.ar. Su utilización debe ser acompañada por la cita bibliográfica con reconocimiento de la fuente. This document is part of the doctoral theses collection of the Central Library Dr. Luis Federico Leloir, available in digital.bl.fcen.uba.ar. It should be used accompanied by the corresponding citation acknowledging the source. Cita tipo APA: Giulianelli, Sebastián Jesús. (2009). Papel de los receptores de estrógenos alfa en el crecimiento de carcinomas mamarios murinos con respuesta diferencial a progestágenos. Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Cita tipo Chicago: Giulianelli, Sebastián Jesús. "Papel de los receptores de estrógenos alfa en el crecimiento de carcinomas mamarios murinos con respuesta diferencial a progestágenos". Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. 2009. Dirección: Biblioteca Central Dr. Luis F. Leloir, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires. Contacto: [email protected] Intendente Güiraldes 2160 - C1428EGA - Tel. (++54 +11) 4789-9293 UNIVERSIDAD DE BUENOS AIRES FACULTAD DE CIENCIAS EXACTAS Y NATURALES Departamento de Fisiología, Biología Molecular y Celular PAPEL DE LOS RECEPTORES DE ESTRÓGENOS ALFA EN EL CRECIMIENTO DE CARCINOMAS MAMARIOS MURINOS CON RESPUESTA DIFERENCIAL A PROGESTÁGENOS Tesis presentada para optar por el título de Doctor de la Universidad de Buenos Aires en el área Ciencias Biológicas Sebastián Jesús Giulianelli Director de Tesis: Claudia L.