DOCSLIB.ORG

(12) United States Patent (10) Patent No.: US 7,951,382 B2 Gelber Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) United States Patent (10) Patent No.: US 7,951,382 B2 Gelber Et Al US007951382B2 (12) United States Patent (10) Patent No.: US 7,951,382 B2 Gelber et al. (45) Date of Patent: May 31, 2011 (54) METHODS FORTREATMENT OF TYPE 2 WO O3,O14151 A2 2/2003 DABETES WO 2004/084797 A2 10, 2004 WO 2005/055956 6, 2005 (75) Inventors: Cohava Gelber, Nokesville, VA (US); W 38885 33.9 Liping Liu, Manassas, VA (US); Zhidong Xie, Manassas, VA (US); OTHER PUBLICATIONS Pranvera Ikonomi, Manassas, VA (US); Antibody Directory (2006), Antichymotrypsin, 3 pages. John R Simms, Haymarket, VA (US); Belagaje et al. (1979) The Journal of Biochemistry 254:5765-5780. Catherine R Auge, Haymarket, VA (US) Better et al. (1988), Science 240: 1041-1043. Boulianne et al. (1984), Nature 312:643-646. (73) Assignee: American Type Culture Collection, Budde et al. (2005), Combinatorial Chemistry & High Throughput Manassas, VA (US) Screening 8:775-781. Burke et al. (1999), Arch. Intern. Med. 159: 1450-1456. (*) Notice: Subject to any disclaimer, the term of this Cabilly et al. (1984) Proc. Natl. Acad. Sci. USA 81:3273-3277. patent is extended or adjusted under 35 Chater et al. (1986) In: Sixth International Symposium on U.S.C. 154(b) by 0 days. Actinomycetales Biology, Akademiai Kaido, Budapest, Hungary pp. 45-54. (21) Appl. No.: 12/759,072 DeLong et al. (1988) Biometrics 44:837-845. Eddy et al. (2003) Diabetes Care 26:3102-31 10. (22) Filed: Apr. 13, 2010 Eddy et al. (2003) Diabetes Care 26:3093-3101. Glover (1985) ed. DNA Cloning vol. II. pp. 143-238, IRL Press. (65) Prior Publication Data Glover (1985) ed. DNA Cloning vol. II. pp. 45-66, IRL Press. US 2010/O197596 A1 Aug. 5, 2010 Gorman et al. (1982) Proc. Natl. Acad. Sci. USA 79:6777-6781. Griffin et al., (2000) Diabetes Metabolism Research and Reviews, Related U.S. Application Data 16:164-171 Grosschedl et al. (1985) Cell 41:885-897. (60) Division of application No. 12/319,883, filed on Jan. Gryczan (1982), Academic Press, NY. pp. 307-329. 12, 2009, now abandoned, which is a Hanson et al. (2002) Diabetes 51:3120-3127. continuation-in-part of application No. 1 1/901,925, Horvath et al. (2004) Journal of Molecular Evolution 59:488-497. filed on Sep. 18, 2007, now abandoned, which is a Hu et al. (2004) Diabetes 53:693-700. continuation-in-part of application No. Izaki (1978), Jpn. J. Bacteriol. 33:729-742. PCT/US2007/007875, filed on Mar. 28, 2007. John et al. (1986) Reviews of Infectious Diseases 8:693-704. Johnston et al. (1988) Science 203:614-625. (60) Provisional application No. 60/841,717, filed on Sep. Kannel et al. (1976) The American Journal of Cardiology 38:46-51. 1, 2006. Kendall et al. (1987) Journal of Bacteriology 169:4177-4183. Khorana (1979) Science 203:614-625. (51) Int. Cl. Kohler et al. (1975) Nature 256:495-497. A6 IK38/17 (2006.01) Kozbor et al. (1983) Immunology Today 4:72-79. (52) U.S. Cl. ..................................... 424/198.1:530/300 Lathe et al. (1985) J. Molec. Biol. 183: 1-12. Lindström (2003) Diabetes Care 26:725-731. (58) Field of Classification Search ........................ None Liu et al. (1987) The Journal of Immunology 139:3521-3526. See application file for complete search history. Liu et al. (1987) Proc. Natl. Acad. Sci. USA 84:3439-3443. Marks et al. (1993) Bio/Technology 11:1145-1149. (56) References Cited Meigs et al. (2004) JAMA 291: 1978-1986. Miller et al. (1989) Bio/Technology 7:698-704. U.S. PATENT DOCUMENTS Mischak et al. (2004) Clinical Science 107:485-495. 4,230,767 A 10, 1980 Isaka et al. Morrison et al. (1984) Proc. Natl. Acad. Sci. USA 81:6851-6855. 4,233,402 A 11/1980 Maggio et al. Muller (1983) Methods in Enzymology 92:589-601. 4,275,149 A 6, 1981 Litman et al. Neuberger et al. (1985) Nature 314:268-270. 4,376, 110 A 3, 1983 David et al. Nyyssönen et al. (1993) Bio/Technology 11:591-595. 4,522,811 A 6/1985 Eppstein et al. 4,659,678 A 4, 1987 Forrest et al. (Continued) 4,699,880 A 10, 1987 Goldstein 4,727,022 A 2f1988 Skold et al. 5,744,305 A 4, 1998 Fodor et al. Primary Examiner — Ruixiang Li 7,255,988 B2 8, 2007 Halle et al. (74) Attorney, Agent, or Firm — Nixon Peabody LLP 7,648,825 B2 1/2010 Ellis et al. 2004/0224304 A1 11/2004 Berggren (57) ABSTRACT 2007/00597 22 A1 3/2007 Salonen et al. The present invention relates generally to the identification of FOREIGN PATENT DOCUMENTS biological markers associated with an increased risk of devel EP O125O23 11, 1984 oping Diabetes, as well as methods of using such biological EP O171496 2, 1986 markers in diagnosis and prognosis of Diabetes. The biologi EP O173494 3, 1986 EP O1841.87 6, 1986 cal markers of the invention may indicate new targets for EP 1615035 1, 2006 therapy or constitute new therapeutics for the treatment or JP 2003235573 8, 2003 prevention of Diabetes. WO 86/O1533 3, 1986 WO 87,02671 5, 1987 6 Claims, 23 Drawing Sheets US 7,951,382 B2 Page 2 OTHER PUBLICATIONS Sun et al. (1987) Proc. Natl. Acad. Sci. USA 84:214-218. UniProtKB/Swiss-Prot PO100 (1991) Serpina3, 8 pages. O’Marcaigh et al. (1993) Clinical Pediatrics 32:485-491. Okayama et al. (1983) Mol. Cell. Biol. 3:280. UniProtKB/Swiss-Prot Q63556 (1996) Serpina3M, 4 pages. Potter et al. (1984) Proc. Natl. Acad. Sci. USA 81:7161. Velculescu et al. (1995) Science 270:484-487. Sabinet al. (1989) BioTechnology 7:705-709. Wahl et al. (1983) The Journal of Nuclear Medicine 24:316-325. Sahagan et al. (1986) The Journal of Immunology 137: 1066-1074. Weidle et al. (1987) Gene 51:21-29. Shultz (1996) Clinical Interpretation of Laboratory Procedures, pp. Whittle et al. (1987) Protein Engineering 1:499-505. 192-199. Wirth et al. (2002) Proteomics 2: 1445-1451. Stefan et al. (2006) Diabetes Care 29:853-857. Wu et al. (1978) Prog. Nucl. Acid Res. Molec. Biol. 21:101-141. Sternet al. (1984) American Journal of Epidemiology 120:834-851. Yoshikawa et al. (1986) Jpn. J. Cancer Res. 77:1122-1133. Sternet al. (1993) Diabetes 42:706-714. Zweig et al. (1992) Clinical Chemistry 38: 1425-1428. U.S. Patent May 31, 2011 Sheet 1 of 23 US 7,951,382 B2 #7TW10dSTELLVEID?ZI | I’50IJI 07 G| to n n n n U.S. Patent May 31, 2011 Sheet 7 of 23 US 7,951,382 B2 U.S. Patent May 31, 2011 Sheet 8 of 23 US 7,951,382 B2 U.S. Patent May 31, 2011 Sheet 9 of 23 US 7,951,382 B2 E - Name van U.S. Patent OSHO U.S. Patent May 31, 2011 Sheet 12 of 23 US 7,951,382 B2 $$$98 ECp) 0I(5)IAI 8p) ]]NWISISJ?DO NOISS}\!908d,! C790 Z9e cioS ZEp (7. 9W OeudiaS y) I Lyuds IdnN 958 SNWHOOTO U.S. Patent May 31, 2011 Sheet 13 of 23 US 7,951,382 B2 Q.) VII'9IJI |WIJTS U.S. Patent May 31, 2011 Sheet 14 of 23 US 7,951,382 B2 |-,··\, HIMNS), U.S. Patent ~$100·| U.S. Patent May 31, 2011 Sheet 16 of 23 US 7,951,382 B2 S d40 U.S. Patent May 31, 2011 Sheet 17 Of 23 US 7,951,382 B2 U.S. Patent May 31, 2011 Sheet 18 of 23 US 7,951,382 B2 (O3I’50IJI |WHISMSINHINETd|N|00 U.S. Patent May 31, 2011 Sheet 19 Of 23 US 7,951,382 B2 CIZI‘50IJI U.S. Patent May 31, 2011 Sheet 20 of 23 US 7,951,382 B2 £I’9IJI U.S. Patent May 31, 2011 Sheet 21 of 23 US 7,951,382 B2 n a ts O as ers S =2 to N a 25 1d a 9go w O r1. o ere S. S. n O C se s o o (or o s s essa (%). SI-8VIO U.S. Patent May 31, 2011 Sheet 22 of 23 US 7,951,382 B2 U.S. Patent May 31, 2011 Sheet 23 of 23 US 7,951,382 B2 ZIS–E– 9I’50IJI 009 (IP/ful) 3A SOON19 OOOTS US 7,951,382 B2 1. 2 METHODS FOR TREATMENT OF TYPE 2 resistance to insulin uptake. Diabetes can also comprise DABETES abnormalities of carbohydrate, fat, and protein metabolism attributed to the deficient action of insulin on target tissues CROSS-REFERENCE TO RELATED resulting from insulin insensitivity or lack of insulin. APPLICATIONS 5 Type 2 Diabetes is the most common form of Diabetes, which typically develops as a result of a relative, rather than This application is a divisional of U.S. application Ser. No. absolute, insulin deficiency, in combination with the body’s 12/319,883, filed on Jan. 12, 2009 now abandoned, which is failure to use insulin properly (also known in the art as “insu a continuation-in-part of U.S. application Ser. No. 1 1/901, lin resistance'). Type 2 Diabetes often manifests in persons, 925, filed on Sep. 18, 2007 now abandoned, which is a con including children, who are overweight; other risk factors tinuation-in-part of International Application No. PCT/ include high cholesterol, high blood pressure, ethnicity, and US2007/007875, filed on Mar. 28, 2007, which claims benefit genetic factors, such as a family history of Diabetes. The of U.S. Provisional Application Ser. No. 60/841,717, filed on majority of patients with Type 2 Diabetes are obese, and Sep.
Load more

Recommended publications
  • Serpinb1 Controls Encephalitogenic T Helper Cells in Neuroinflammation
    SerpinB1 controls encephalitogenic T helper cells in neuroinflammation Lifei Houa,b,1,2, Deepak A. Raoc,d, Koichi Yukie,f, Jessica Cooleya, Lauren A. Hendersonb,g, A. Helena Jonssonc,d, Dion Kaisermanh, Mark P. Gormanb,i, Peter A. Nigrovicc,d,g, Phillip I. Birdh, Burkhard Becherj, and Eileen Remold-O’Donnella,b,k,2 aThe Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115; bDepartment of Pediatrics, Harvard Medical School, Boston, MA 02115; cDivision of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Boston, MA 02115; dDepartment of Medicine, Harvard Medical School, Boston, MA 02115; eDepartment of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA 02115; fDepartment of Anesthesiology, Harvard Medical School, Boston, MA 02115; gDivision of Immunology, Boston Children’s Hospital, Boston, MA 02115; hDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia; iDepartment of Neurology, Boston Children’s Hospital, Boston, MA 02115; jInflammation Unit, Institute of Experimental Immunology, University of Zurich, CH-8057 Zurich, Switzerland; and kDepartment of Hematology/Oncology, Harvard Medical School, Boston, MA 02115 Edited by Jean Laurent-Casanova, Rockefeller University, New York, NY, and approved August 27, 2019 (received for review April 5, 2019) SerpinB1, a protease inhibitor and neutrophil survival factor, was flammatory tissue injury and neutrophil death, and in naïve mice, recently linked with IL-17–expressing T cells. Here, we show that preserves the bone marrow reserve of mature neutrophils by serpinB1 (Sb1) is dramatically inducedinasubsetofeffector restricting spontaneous cell death mediated by the granule serine CD4 cells in experimental autoimmune encephalomyelitis (EAE).
    [Show full text]
  • Acinar Cell Apoptosis in Serpini2-Deficient Mice Models Pancreatic Insufficiency
    Acinar Cell Apoptosis in Serpini2-Deficient Mice Models Pancreatic Insufficiency Stacie K. Loftus1*, Jennifer L. Cannons1, Arturo Incao1, Evgenia Pak1, Amy Chen1, Patricia M. Zerfas2, Mark A. Bryant2, Leslie G. Biesecker1, Pamela L. Schwartzberg1, William J. Pavan1 1 Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America, 2 Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, Maryland, United States of America Pancreatic insufficiency (PI) when left untreated results in a state of malnutrition due to an inability to absorb nutrients. Frequently, PI is diagnosed as part of a larger clinical presentation in cystic fibrosis or Shwachman–Diamond syndrome. In this study, a mouse model for isolated exocrine PI was identified in a mouse line generated by a transgene insertion. The trait is inherited in an autosomal recessive pattern, and homozygous animals are growth retarded, have abnormal immunity, and have reduced life span. Mice with the disease locus, named pequen˜o (pq), exhibit progressive apoptosis of pancreatic acinar cells with severe exocrine acinar cell loss by 8 wk of age, while the islets and ductal tissue persist. The mutation in pq/pq mice results from a random transgene insertion. Molecular characterization of the transgene insertion site by fluorescent in situ hybridization and genomic deletion mapping identified an approximately 210-kb deletion on Chromosome 3, deleting two genes. One of these genes, Serpini2, encodes a protein that is a member of the serpin family of protease inhibitors. Reintroduction of only the Serpini2 gene by bacterial artificial chromosome transgenic complementation corrected the acinar cell defect as well as body weight and immune phenotypes, showing that deletion of Serpini2 causes the pequen˜o phenotype.
    [Show full text]
  • A Truncating Mutation in SERPINB6 Is Associated with Autosomal-Recessive Nonsyndromic Sensorineural Hearing Loss
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REPORT A Truncating Mutation in SERPINB6 Is Associated with Autosomal-Recessive Nonsyndromic Sensorineural Hearing Loss Aslı Sırmacı,1,2 Seyra Erbek,3 Justin Price,1,2 Mingqian Huang,4 Duygu Duman,5 F. Basxak Cengiz,5 Gu¨ney Bademci,1,2 Suna Tokgo¨z-Yılmaz,5 Burcu Hisxmi,5 Hilal O¨ zdag˘,6 Banu O¨ ztu¨rk,7 Sevsen Kulaksızog˘lu,8 Erkan Yıldırım,9 Haris Kokotas,10 Maria Grigoriadou,10 Michael B. Petersen,10 Hashem Shahin,11 Moien Kanaan,11 Mary-Claire King,12 Zheng-Yi Chen,4 Susan H. Blanton,1,2 Xue Z. Liu,2,13 Stephan Zuchner,1,2 Nejat Akar,5 and Mustafa Tekin1,2,* More than 270 million people worldwide have hearing loss that affects normal communication. Although astonishing progress has been made in the identification of more than 50 genes for deafness during the past decade, the majority of deafness genes are yet to be identified. In this study, we mapped a previously unknown autosomal-recessive nonsyndromic sensorineural hearing loss locus (DFNB91) to chromo- some 6p25 in a consanguineous Turkish family. The degree of hearing loss was moderate to severe in affected individuals. We subsequently identified a nonsense mutation (p.E245X) in SERPINB6, which is located within the linkage interval for DFNB91 and encodes for an intra- cellular protease inhibitor. The p.E245X mutation cosegregated in the family as a completely penetrant autosomal-recessive trait and was absent in 300 Turkish controls. The mRNA expression of SERPINB6 was reduced and production of protein was absent in the peripheral leukocytes of homozygotes, suggesting that the hearing loss is due to loss of function of SERPINB6.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Differential Gene Expression of Serine Protease Inhibitors in Bovine
    Hayashi et al. Reproductive Biology and Endocrinology 2011, 9:72 http://www.rbej.com/content/9/1/72 RESEARCH Open Access Differential gene expression of serine protease inhibitors in bovine ovarian follicle: possible involvement in follicular growth and atresia Ken-Go Hayashi, Koichi Ushizawa, Misa Hosoe and Toru Takahashi* Abstract Background: SERPINs (serine protease inhibitors) regulate proteases involving fibrinolysis, coagulation, inflammation, cell mobility, cellular differentiation and apoptosis. This study aimed to investigate differentially expressed genes of members of the SERPIN superfamily between healthy and atretic follicles using a combination of microarray and quantitative real-time PCR (QPCR) analysis. In addition, we further determined mRNA and protein localization of identified SERPINs in estradiol (E2)-active and E2-inactive follicles by in situ hybridization and immunohistochemistry. Methods: We performed microarray analysis of healthy (10.7 +/- 0.7 mm) and atretic (7.8 +/- 0.2 mm) follicles using a custom-made bovine oligonucleotide microarray to screen differentially expressed genes encoding SERPIN superfamily members between groups. The expression profiles of six identified SERPIN genes were further confirmed by QPCR analysis. In addition, mRNA and protein localization of four SERPINs was investigated in E2- active and E2-inactive follicles using in situ hybridization and immunohistochemistry. Results: We have identified 11 SERPIN genes expressed in healthy and atretic follicles by microarray analysis. QPCR analysis confirmed that mRNA expression of four SERPINs (SERPINA5, SERPINB6, SERPINE2 and SERPINF2) was greater in healthy than in atretic follicles, while two SERPINs (SERPINE1 and SERPING1) had greater expression in atretic than in healthy follicles. In situ hybridization showed that SERPINA5, SERPINB6 and SERPINF2 mRNA were localized in GCs of E2-active follicles and weakly expressed in GCs of E2-inactive follicles.
    [Show full text]
  • Characterisation of Serpinb2 As a Stress Response Modulator
    University of Wollongong Research Online University of Wollongong Thesis Collection 1954-2016 University of Wollongong Thesis Collections 2015 Characterisation of SerpinB2 as a stress response modulator Jodi Anne Lee University of Wollongong Follow this and additional works at: https://ro.uow.edu.au/theses University of Wollongong Copyright Warning You may print or download ONE copy of this document for the purpose of your own research or study. The University does not authorise you to copy, communicate or otherwise make available electronically to any other person any copyright material contained on this site. You are reminded of the following: This work is copyright. Apart from any use permitted under the Copyright Act 1968, no part of this work may be reproduced by any process, nor may any other exclusive right be exercised, without the permission of the author. Copyright owners are entitled to take legal action against persons who infringe their copyright. A reproduction of material that is protected by copyright may be a copyright infringement. A court may impose penalties and award damages in relation to offences and infringements relating to copyright material. Higher penalties may apply, and higher damages may be awarded, for offences and infringements involving the conversion of material into digital or electronic form. Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong. Recommended Citation Lee, Jodi Anne, Characterisation of SerpinB2 as a stress response modulator, Doctor of Philosophy thesis, School of Biological Sciences, University of Wollongong, 2015. https://ro.uow.edu.au/theses/4538 Research Online is the open access institutional repository for the University of Wollongong.
    [Show full text]
  • What Is the Extent of the Role Played by Genetic Factors in Periodontitis?
    Perio Insight 4 Summer 2017 www.efp.org/perioinsight DEBATE EXPERT VIEW FOCUS RESEARCH Editor: Joanna Kamma What is the extent of the role played by genetic factors in periodontitis? Discover latest JCP research hile genetic factors are known to play a role in In a comprehensive overview of current knowledge, The Journal of Clinical Periodontology Wperiodontitis, a lot of research still needs to be they outline what is known today and discuss the (JCP) is the official scientific publication done to understand the mechanisms that are involved. most promising lines for future inquiry. of the European Federation of Indeed, the limited extent to which the genetic They note that the phenotypes of aggressive Periodontology (EFP). It publishes factors associated with periodontitis have been periodontitis (AgP) and chronic periodontitis (CP) may research relating to periodontal and peri- identified is “somewhat disappointing”, say Bruno not be as distinct as previously assumed because they implant diseases and their treatment. G. Loos and Deon P.M. Chin, from the Academic share genetic and other risk factors. The six JCP articles summarised in this Centre for Dentistry in Amsterdam. More on pages 2-5 edition of Perio Insight cover: (1) how periodontitis changes renal structures by oxidative stress and lipid peroxidation; (2) gingivitis and lifestyle influences on high-sensitivity C-reactive protein and interleukin 6 in adolescents; (3) the long-term efficacy of periodontal Researchers call regenerative therapies; (4) tooth loss in generalised aggressive periodontitis; (5) the association between diabetes for global action mellitus/hyperglycaemia and peri- implant diseases; (6) the efficacy of on periodontal collagen matrix seal and collagen sponge on ridge preservation in disease combination with bone allograft.
    [Show full text]
  • Molecular and Epigenetic Features of Melanomas and Tumor Immune
    Seremet et al. J Transl Med (2016) 14:232 DOI 10.1186/s12967-016-0990-x Journal of Translational Medicine RESEARCH Open Access Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab‑based immunotherapy in metastatic patients Teofila Seremet1,3*† , Alexander Koch2†, Yanina Jansen1, Max Schreuer1, Sofie Wilgenhof1, Véronique Del Marmol3, Danielle Liènard3, Kris Thielemans4, Kelly Schats5, Mark Kockx5, Wim Van Criekinge2, Pierre G. Coulie6, Tim De Meyer2, Nicolas van Baren6,7 and Bart Neyns1 Abstract Background: Ipilimumab (Ipi) improves the survival of advanced melanoma patients with an incremental long-term benefit in 10–15 % of patients. A tumor signature that correlates with this survival benefit could help optimizing indi- vidualized treatment strategies. Methods: Freshly frozen melanoma metastases were collected from patients treated with either Ipi alone (n: 7) or Ipi combined with a dendritic cell vaccine (TriMixDC-MEL) (n: 11). Samples were profiled by immunohistochemistry (IHC), whole transcriptome (RNA-seq) and methyl-DNA sequencing (MBD-seq). Results: Patients were divided in two groups according to clinical evolution: durable benefit (DB; 5 patients) and no clinical benefit (NB; 13 patients). 20 metastases were profiled by IHC and 12 were profiled by RNA- and MBD-seq. 325 genes were identified as differentially expressed between DB and NB. Many of these genes reflected a humoral and cellular immune response. MBD-seq revealed differences between DB and NB patients in the methylation of genes linked to nervous system development and neuron differentiation. DB tumors were more infiltrated by CD8+ and PD-L1+ cells than NB tumors.
    [Show full text]
  • Analysis of Dynamic Molecular Networks for Pancreatic Ductal
    Pan et al. Cancer Cell Int (2018) 18:214 https://doi.org/10.1186/s12935-018-0718-5 Cancer Cell International PRIMARY RESEARCH Open Access Analysis of dynamic molecular networks for pancreatic ductal adenocarcinoma progression Zongfu Pan1†, Lu Li2†, Qilu Fang1, Yiwen Zhang1, Xiaoping Hu1, Yangyang Qian3 and Ping Huang1* Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors. The rapid progression of PDAC results in an advanced stage of patients when diagnosed. However, the dynamic molecular mechanism underlying PDAC progression remains far from clear. Methods: The microarray GSE62165 containing PDAC staging samples was obtained from Gene Expression Omnibus and the diferentially expressed genes (DEGs) between normal tissue and PDAC of diferent stages were profled using R software, respectively. The software program Short Time-series Expression Miner was applied to cluster, compare, and visualize gene expression diferences between PDAC stages. Then, function annotation and pathway enrichment of DEGs were conducted by Database for Annotation Visualization and Integrated Discovery. Further, the Cytoscape plugin DyNetViewer was applied to construct the dynamic protein–protein interaction networks and to analyze dif- ferent topological variation of nodes and clusters over time. The phosphosite markers of stage-specifc protein kinases were predicted by PhosphoSitePlus database. Moreover, survival analysis of candidate genes and pathways was per- formed by Kaplan–Meier plotter. Finally, candidate genes were validated by immunohistochemistry in PDAC tissues. Results: Compared with normal tissues, the total DEGs number for each PDAC stage were 994 (stage I), 967 (stage IIa), 965 (stage IIb), 1027 (stage III), 925 (stage IV), respectively. The stage-course gene expression analysis showed that 30 distinct expressional models were clustered.
    [Show full text]
  • Serpins—From Trap to Treatment
    MINI REVIEW published: 12 February 2019 doi: 10.3389/fmed.2019.00025 SERPINs—From Trap to Treatment Wariya Sanrattana, Coen Maas and Steven de Maat* Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands Excessive enzyme activity often has pathological consequences. This for example is the case in thrombosis and hereditary angioedema, where serine proteases of the coagulation system and kallikrein-kinin system are excessively active. Serine proteases are controlled by SERPINs (serine protease inhibitors). We here describe the basic biochemical mechanisms behind SERPIN activity and identify key determinants that influence their function. We explore the clinical phenotypes of several SERPIN deficiencies and review studies where SERPINs are being used beyond replacement therapy. Excitingly, rare human SERPIN mutations have led us and others to believe that it is possible to refine SERPINs toward desired behavior for the treatment of enzyme-driven pathology. Keywords: SERPIN (serine proteinase inhibitor), protein engineering, bradykinin (BK), hemostasis, therapy Edited by: Marvin T. Nieman, Case Western Reserve University, United States INTRODUCTION Reviewed by: Serine proteases are the “workhorses” of the human body. This enzyme family is conserved Daniel A. Lawrence, throughout evolution. There are 1,121 putative proteases in the human body, and about 180 of University of Michigan, United States Thomas Renne, these are serine proteases (1, 2). They are involved in diverse physiological processes, ranging from University Medical Center blood coagulation, fibrinolysis, and inflammation to immunity (Figure 1A). The activity of serine Hamburg-Eppendorf, Germany proteases is amongst others regulated by a dedicated class of inhibitory proteins called SERPINs Paulo Antonio De Souza Mourão, (serine protease inhibitors).
    [Show full text]
  • NFKBIL1 Antibody (Center) Blocking Peptide Synthetic Peptide Catalog # Bp10682c
    10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 NFKBIL1 Antibody (Center) Blocking peptide Synthetic peptide Catalog # BP10682c Specification NFKBIL1 Antibody (Center) Blocking NFKBIL1 Antibody (Center) Blocking peptide - peptide - Background Product Information This gene encodes a divergent member of the Primary Accession Q9UBC1 I-kappa-Bfamily of proteins. Its function has not been determined. The genelies within the major histocompatibility complex (MHC) class NFKBIL1 Antibody (Center) Blocking peptide - Additional Information Iregion on chromosome 6. Multiple transcript variants encodingdifferent isoforms have been found for this gene. [provided byRefSeq]. Gene ID 4795 NFKBIL1 Antibody (Center) Blocking Other Names peptide - References NF-kappa-B inhibitor-like protein 1, Inhibitor of kappa B-like protein, I-kappa-B-like Clancy, R.M., et al. Arthritis Rheum. protein, IkappaBL, Nuclear factor of kappa 62(11):3415-3424(2010)Bailey, S.D., et al. light polypeptide gene enhancer in B-cells Diabetes Care inhibitor-like 1, NFKBIL1, IKBL 33(10):2250-2253(2010)Ucisik-Akkaya, E., et Format al. Mol. Hum. Reprod. Peptides are lyophilized in a solid powder 16(10):770-777(2010)Rose, J.E., et al. Mol. format. Peptides can be reconstituted in Med. 16 (7-8), 247-253 (2010) :Owecki, M.K., solution using the appropriate buffer as et al. Pol. Merkur. Lekarski needed. 28(167):366-370(2010) Storage Maintain refrigerated at 2-8°C for up to 6 months. For long term storage store at -20°C. Precautions This product is for research use only. Not for use in diagnostic or therapeutic procedures.
    [Show full text]
  • NFKBIL1 Antibody Cat
    NFKBIL1 Antibody Cat. No.: 56-654 NFKBIL1 Antibody Confocal immunofluorescent analysis of NFKBIL1 NFKBIL1 Antibody immunohistochemistry analysis in Antibody with MDA-MB435 cell followed by Alexa Fluor formalin fixed and paraffin embedded human brain tissue 488-conjugated goat anti-rabbit lgG (green).Actin filaments followed by peroxidase conjugation of the secondary have been labeled with Alexa Fluor 555 phalloidin antibody and DAB staining. (red).DAPI was used to stain the cell nuclear (blue). Specifications HOST SPECIES: Rabbit SPECIES REACTIVITY: Human HOMOLOGY: Predicted species reactivity based on immunogen sequence: Mouse, Pig This NFKBIL1 antibody is generated from rabbits immunized with a KLH conjugated IMMUNOGEN: synthetic peptide between 327-356 amino acids from the C-terminal region of human NFKBIL1. TESTED APPLICATIONS: IF, IHC-P, WB September 24, 2021 1 https://www.prosci-inc.com/nfkbil1-antibody-56-654.html For WB starting dilution is: 1:1000 APPLICATIONS: For IHC-P starting dilution is: 1:10~50 For IF starting dilution is: 1:10~50 PREDICTED MOLECULAR 43 kDa WEIGHT: Properties This antibody is purified through a protein A column, followed by peptide affinity PURIFICATION: purification. CLONALITY: Polyclonal ISOTYPE: Rabbit Ig CONJUGATE: Unconjugated PHYSICAL STATE: Liquid BUFFER: Supplied in PBS with 0.09% (W/V) sodium azide. CONCENTRATION: batch dependent Store at 4˚C for three months and -20˚C, stable for up to one year. As with all antibodies STORAGE CONDITIONS: care should be taken to avoid repeated freeze thaw cycles. Antibodies should not be exposed to prolonged high temperatures. Additional Info OFFICIAL SYMBOL: NFKBIL1 NF-kappa-B inhibitor-like protein 1, Inhibitor of kappa B-like protein, I-kappa-B-like ALTERNATE NAMES: protein, IkappaBL, Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-like 1, NFKBIL1, IKBL ACCESSION NO.: Q9UBC1 PROTEIN GI NO.: 44888077 GENE ID: 4795 USER NOTE: Optimal dilutions for each application to be determined by the researcher.
    [Show full text]