DOCSLIB.ORG

Biomarker Analysis of Morquio Syndrome

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Biomarker Analysis of Morquio Syndrome Martell et al. Orphanet Journal of Rare Diseases 2011, 6:84 http://www.ojrd.com/content/6/1/84 RESEARCH Open Access Biomarker analysis of Morquio syndrome: identification of disease state and drug responsive markers Lisa Martell1, Kelly Lau1, Miranda Mei1, Vicki Burnett2, Celeste Decker1 and Erik D Foehr1* Abstract Background: This study was conducted to identify potential biomarkers that could be used to evaluate disease progression and monitor responses to enzyme replacement therapy (ERT) in patients with mucopolysaccharidosis (MPS) IVA. Methods: Levels of 88 candidate biomarkers were compared in plasma samples from 50 healthy controls and 78 MPSIVA patients not receiving ERT to test for significant correlations to the presence of MPSIVA. MPSIVA samples were also tested for correlations between candidate biomarkers and age, endurance, or urinary keratin sulfate (KS) levels. Then, levels of the same 88 analytes were followed over 36 weeks in 20 MPSIVA patients receiving ERT to test for significant correlations related to ERT, age, or endurance. Results: Nineteen candidate biomarkers were significantly different between MPSIVA and unaffected individuals. Of these, five also changed significantly in response to ERT: alpha-1-antitrypsin, eotaxin, lipoprotein(a), matrix metalloprotein (MMP)-2, and serum amyloid P. Three of these were significantly lower in MPSIVA individuals versus unaffected controls and were increased during ERT: alpha-1-antitrypsin, lipoprotein(a), and serum amyloid P. Conclusions: Candidate biomarkers alpha-1-antitrypsin, lipoprotein(a), and serum amyloid P may be suitable markers, in addition to urinary KS, to follow the response to ERT in MPSIVA patients. Background GALNS activity [1,2]. The International Morquio Regis- Mucopolysaccharidosis (MPS) IVA (OMIM #253000), try and the Morquio Clinical Assessment Program (Mor- also known as Morquio A syndrome, is an autosomal CAP, also known as MOR-001) found considerable recessive lysosomal storage disorder caused by deficient morbitity and mortality in MPSIVA individuals, including activity of N-acetylgalactosamine-6-sulfatase (GALNS) frequent surgical procedures, limited mobility, poor [1]. GALNS catalyzes the degradation of the glycosami- endurance and pulmonary function, and death in the sec- noglycans (GAGs), KS and chondroitin-6-sulfate (CS). In ond or third decade of life for patients with a severe phe- individuals affected with MPSIVA, KS and CS accumu- notype (about 68% of MPSIVA patients) [1,3]. Urinary late in the tissues, causing skeletal dysplasia, coarse facial GAG testing is used to screen for MPSIVA, with enzyme features, restricted growth and short stature, joint hyper- activity measurement in blood or fibroblasts to confirm mobility, valvular heart disease, pulmonary disease, diagnosis [1,2]. The incidence of MPSIVA ranges from 1 obstructive sleep apnea, hepatomegaly, corneal clouding, in 40,000 to 1 in 450,000 live births [1,2]. hearing loss, and poorly formed teeth [1]. Because more Currently there is no treatment for MPSIVA, only sup- than 150 mutations in the gene encoding GALNS have portive measures such as surgeries for skeletal dysplasia, been identified, there is considerable clinical heterogene- oxygen for poor lung function, and antibiotics for lung ity ranging from mild to severe based on the residual infections [1,2]. However, ERT with recombinant human (rh) GALNS (BMN110) is under clinical development, ERT provides a supply of the deficient enzyme and is * Correspondence: [email protected] available for MPS I, MPS II, and MPS VI [4]. 1BioMarin Pharmaceutical Inc. Novato, CA USA Full list of author information is available at the end of the article © 2011 Martell et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Martell et al. Orphanet Journal of Rare Diseases 2011, 6:84 Page 2 of 10 http://www.ojrd.com/content/6/1/84 In a mouse model of MPSIVA [5]. rhGALNS mark- this particular disease study. Analysis of samples was per- edly decreased storage in visceral organs, heart valves, formed using the Luminex platform. ligaments, connective tissues, and brain [6]. ERT (rhGALNS, BMN110) for MPSIVA is evaluated in a MOR-001 Phase I/II human trial. The clinical trial is a multicenter, The MOR-001 study is a multicenter, multinational, open-label, dose-escalation study to evaluate safety, tol- longitudinal clinical assessment of patients with MPS erability, and efficacy of BMN 110 in patients with MPS IVA not receiving ERT. This longitudinal study aims to IVA (clinical trial #NCT00884949) between 5 and 18 catalogue the spectrum of symptoms and biochemical years of age [7]. A global double blind, randomized, pla- abnormalities of subjects with MPS IVA. There have cebo-controlled Phase III study of BMN 110 in MPSIVA been 129 subjects enrolled through 2009 [3]. Analytes was initiated in 2011 [8]. were profiled and quantified from plasma samples With ERT in development for MPS IVA, identification obtained from the initial visit of the first 78 of MPS of biomarkers to evaluate disease progression and IVA subjects and compared with the samples from 50 response to treatment becomes more important. To date, controls subjects (61% female, female age range 21-70, KS has been identified as an important biomarker for mean female age 45; 39% male, male age range 24-71, MPS IVA [9] as it accumulates in the tissues, particularly mean male age 47). Analyte profiles obtained in the the cartilage, cornea, and heart valves, in MPS IVA MPSIVA group were then sub-analyzed to determine if patients [10]. KS storage in the cartilage causes cartilage any significant correlations existed to subject age, per- disruption, which contributes to increased circulating formance in an endurance test (6 minute walk test; 6 levels of KS in MPS IVA patients relative to healthy indivi- MWT), or levels of urinary KS (uKS). duals. KS can be quantified in urine and plasma and may be helpful for screening and for following the clinical MOR-002 course and efficacy of treatment [9,11]. KS levels in urine The MOR-002 study is a multicenter, open-label, dose- and plasma have been shown to vary with age (with escalation study to evaluate the safety, tolerability, and plasma levels generally peaking between 5 to 10 years of efficacy of BMN 110 in patients with MPS IVA between age and urine levels peaking between 1 and 5 years of age) 5 and 18 years of age. Twenty subjects enrolled in the and increase with clinical severity of MPS IVA [12]. study, and 18 subjects completed 36 weeks of therapy While KS is an important and treatment-related biomar- with weekly 4 to 5 hours intravenous infusions of BMN ker to track MPSIVA disease progression and response to 110. The study used 3 consecutive 12-week dosing inter- ERT, it is not known whether there are additional biomar- vals (the dose escalation phase), using the following kers associated with MPS IVA and their relationship to KS regimen: levels, disease severity, disease progression and response to Weeks 1012: 0.1 mg/kg/week ERT. The goal of the current study is to identify additional Weeks 13-24: 1.0 mg/kg/week candidate biomarkers that support evaluations of disease Weeks 25-36: 2.0 mg/kg/week progression and monitoring response to ERT and examine Subjects completing the 36-week dose-escalation per- their relationships with levels of KS. iod had the option to continue drug treatment for an additional 36 weeks. Subjects continuing treatment after Methods the dose-escalation period received weekly 4 to 5 hour Analytes intravenous (IV) infusions of BMN 110 at a dose of 1.0 To identify and evaluate potential biomarkers for MPS mg/kg/week. Clinical outcomes included measures of IVA, this study examined 88 different analytes from endurance (6 MWT), 3 minute stair climb test (3 plasma samples obtained from 50 healthy adult control MSCT) and pulmonary function (forced vital capacity subjects, 78 MPS IVA subjects not receiving ERT from [FVC]), examined at baseline and weeks 6, 12, 18, 24, the MOR-001 study, and 20 subjects receiving ERT with 30, 36, 48, 60, and 72 [7]. BMN 110 from the MOR-002 study. The analytes for this The same 88 analytes studied in MOR-001 patients study were from the Human Multi-Analyte Profile were profiled longitudinally in 20 MOR-002 study sub- (MAP)v1.6fromRulesBasedMedicine(AustinTX). jects at baseline, 12, 24, and 36 weeks post-ERT during This is an 88-biomarker MAP providing quantitative the dose escalating phase. Analyte profiles were then multiplexed assays covering different biological pathways. sub-analyzed to determine if any significant correlations Biomarkers included in this MAP were selected to pro- existed to subject age or performance in the 6 MWT. vide a comprehensive understanding of complex drug Both MOR-001 and MOR-002 were approved by an and disease effects. The analytes on the Human MAP Institutional Review Board and informed consent was v1.6 are a pre-set panel and were not custom selected for obtained from all human subjects. Martell et al. Orphanet Journal of Rare Diseases 2011, 6:84 Page 3 of 10 http://www.ojrd.com/content/6/1/84 Statistical analysis significantly higher in MPS IVA subjects versus unaf- T-tests were performed to check for significant differ- fected controls, and the other 16 were significantly ences in analytes between MPS IVA patients and unaf- lower in MPS IVA subjects compared to controls. fected control subjects (for MOR-001), between older (over 9.5 years) and younger (9.5 years or less) MPS Analyte correlations in MPS IVA subjects not receiving IVA subjects, between MPS IVA subjects with high ERT (> 24.6 μg/mg creatinine) and low (≤ 24.6 μg/mg creati- Correlation with age nine) uKS, and between MPS IVA subjects with high Table 3 lists the 11 analytes that were significantly differ- (> 235 meters) and low (≤ 235 meters) 6 MWT scores.
Load more

Recommended publications
  • Pathophysiology of Mucopolysaccharidosis
    Pathophysiology of Mucopolysaccharidosis Dr. Christina Lampe, MD The Center for Rare Diseases, Clinics for Pediatric and Adolescent Medicine Helios Dr. Horst Schmidt Kliniken, Wiesbaden, Germany Inborn Errors of Metabolism today - more than 500 diseases (~10 % of the known genetic diseases) 5000 genetic diseases - all areas of metabolism involved - vast majority are recessive conditions 500 metabolic disorders - individually rare or very rare - overall frequency around 1:800 50 LSD (similar to Down syndrome) LSDs: 1: 5.000 live births MPS: 1: 25.000 live births 7 MPS understanding of pathophysiology and early diagnosis leading to successful therapy for several conditions The Lysosomal Diseases (LSD) TAY SACHS DIS. 4% WOLMAN DIS. ASPARTYLGLUCOSAMINURIA SIALIC ACID DIS. SIALIDOSIS CYSTINOSIS 4% SANDHOFF DIS. 2% FABRY DIS. 7% POMPE 5% NIEMANN PICK C 4% GAUCHER DIS. 14% Mucopolysaccharidosis NIEMANN PICK A-B 3% MULTIPLE SULPH. DEF. Mucolipidosis MUCOLIPIDOSIS I-II 2% Sphingolipidosis MPSVII Oligosaccharidosis GM1 GANGLIOSIDOSIS 2% MPSVI Neuronale Ceroid Lipofuszinois KRABBE DIS. 5% MPSIVA others MPSIII D A-MANNOSIDOSIS MPSIII C MPSIIIB METACHROMATIC LEUKOD. 8% MPS 34% MPSIIIA MPSI MPSII Initial Description of MPS Charles Hunter, 1917: “A Rare Disease in Two Brothers” brothers: 10 and 8 years hearing loss dwarfism macrocephaly cardiomegaly umbilical hernia joint contractures skeletal dysplasia death at the age of 11 and 16 years Description of the MPS Types... M. Hunter - MPS II (1917) M. Hurler - MPS I (1919) M. Morquio - MPS IV (1929) M. Sanfilippo - MPS III (1963) M. Maroteaux-Lamy - MPS IV (1963) M. Sly - MPS VII (1969) M. Scheie - MPS I (MPS V) (1968) M. Natowicz - MPS IX (1996) The Lysosome Lysosomes are..
    [Show full text]
  • Remote Ischemic Preconditioning (RIPC) Modifies Plasma Proteome in Humans
    Remote Ischemic Preconditioning (RIPC) Modifies Plasma Proteome in Humans Michele Hepponstall1,2,3,4, Vera Ignjatovic1,3, Steve Binos4, Paul Monagle1,3, Bryn Jones1,2, Michael H. H. Cheung1,2,3, Yves d’Udekem1,2, Igor E. Konstantinov1,2,3* 1 Haematology Research, Murdoch Childrens Research Institute; Melbourne, Victoria, Australia, 2 Cardiac Surgery Unit and Cardiology, Royal Children’s Hospital; Melbourne, Victoria, Australia, 3 Department of Paediatrics, The University of Melbourne; Melbourne, Victoria, Australia, 4 Bioscience Research Division, Department of Primary Industries, Melbourne, Victoria, Australia Abstract Remote Ischemic Preconditioning (RIPC) induced by brief episodes of ischemia of the limb protects against multi-organ damage by ischemia-reperfusion (IR). Although it has been demonstrated that RIPC affects gene expression, the proteomic response to RIPC has not been determined. This study aimed to examine RIPC induced changes in the plasma proteome. Five healthy adult volunteers had 4 cycles of 5 min ischemia alternating with 5 min reperfusion of the forearm. Blood samples were taken from the ipsilateral arm prior to first ischaemia, immediately after each episode of ischemia as well as, at 15 min and 24 h after the last episode of ischemia. Plasma samples from five individuals were analysed using two complementary techniques. Individual samples were analysed using 2Dimensional Difference in gel electrophoresis (2D DIGE) and mass spectrometry (MS). Pooled samples for each of the time-points underwent trypsin digestion and peptides generated were analysed in triplicate using Liquid Chromatography and MS (LC-MS). Six proteins changed in response to RIPC using 2D DIGE analysis, while 48 proteins were found to be differentially regulated using LC-MS.
    [Show full text]
  • MPS Research Highlights at Worldsymposium 2020
    CME/CE MPS Research Highlights at WORLDSymposium 2020 Barbara Burton, MD Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago, IL Mucopolysaccharidoses • A group of lysosomal storage disorders • Genetic disorders in which mutations in different genes leads to abnormal accumulation of complex carbohydrates • Mucopolysaccharies or glycosaminoglycans • Numerous MPSs and each MPS may also have numerous subtypes • Often have striking skeletal features. May or may not have behavioral/cognitive difficulties NIH Rare Disease Database: MPS. 2019. https://rarediseases.info.nih.gov/diseases/7065/mucopolysaccharidosis Mucopolysaccharidoses MPS Type Common Name Gene Mutation Treatment MPS I Hurler syndrome IDUA HSCT, ERT, symptomatic/supportive MPS II Hunter syndrome IDS ERT, symptomatic/supportive MPS III Sanfilippo syndrome GNS, HGSNAT, Symptomatic/supportive NAGLU, SGSH MPS IV Morquio syndrome GALNS, GLB1 ERT, symptomatic/supportive MPS VI Maroteaux-Lamy syndrome ARSB ERT, symptomatic/supportive MPS VII Sly syndrome GUSB ERT, symptomatic/supportive NIH Rare Disease Database: MPS. 2019. https://rarediseases.info.nih.gov/diseases/7065/mucopolysaccharidosis WORLDSymposium • Annual conference focused on lysosomal storage disorders • MPSs, Fabry disease, Gaucher disease, etc • 4 day event every February • Day 1 & 2 – Basic research • Day 2 & 3 – Translational research • Day 3 & 4 – Clinical research • 446 poster presentation • 84 oral presentations MPS and Reproduction • Peter, Cagle; Atlanta, GA • Can women with MPS have normal menstruation and pregnancy? • Case-control study with 33 MPS women [MPS I (10), MPS IV (17), MPS VI (5), and MPS VII (1)] • Menstrual questionnaire • MPS women scored abnormally higher but difference not statistically significant • Pregnancy • 6 women with MPS had successful pregnancy. • Complications included spotting, gestational diabetes, prolonged labor, and excessive blood loss Peter, Cagle.
    [Show full text]
  • Pancancer Progression Human Vjune2017
    Gene Symbol Accession Alias/Prev Symbol Official Full Name AAMP NM_001087.3 - angio-associated, migratory cell protein ABI3BP NM_015429.3 NESHBP|TARSH ABI family, member 3 (NESH) binding protein ACHE NM_000665.3 ACEE|ARACHE|N-ACHE|YT acetylcholinesterase ACTG2 NM_001615.3 ACT|ACTA3|ACTE|ACTL3|ACTSG actin, gamma 2, smooth muscle, enteric ACVR1 NM_001105.2 ACTRI|ACVR1A|ACVRLK2|ALK2|FOP|SKR1|TSRI activin A receptor, type I ACVR1C NM_145259.2 ACVRLK7|ALK7 activin A receptor, type IC ACVRL1 NM_000020.1 ACVRLK1|ALK-1|ALK1|HHT|HHT2|ORW2|SKR3|TSR-I activin A receptor type II-like 1 ADAM15 NM_207195.1 MDC15 ADAM metallopeptidase domain 15 ADAM17 NM_003183.4 ADAM18|CD156B|CSVP|NISBD|TACE ADAM metallopeptidase domain 17 ADAM28 NM_014265.4 ADAM 28|ADAM23|MDC-L|MDC-Lm|MDC-Ls|MDCL|eMDC II|eMDCII ADAM metallopeptidase domain 28 ADAM8 NM_001109.4 CD156|MS2 ADAM metallopeptidase domain 8 ADAM9 NM_001005845.1 CORD9|MCMP|MDC9|Mltng ADAM metallopeptidase domain 9 ADAMTS1 NM_006988.3 C3-C5|METH1 ADAM metallopeptidase with thrombospondin type 1 motif, 1 ADAMTS12 NM_030955.2 PRO4389 ADAM metallopeptidase with thrombospondin type 1 motif, 12 ADAMTS8 NM_007037.4 ADAM-TS8|METH2 ADAM metallopeptidase with thrombospondin type 1 motif, 8 ADAP1 NM_006869.2 CENTA1|GCS1L|p42IP4 ArfGAP with dual PH domains 1 ADD1 NM_001119.4 ADDA adducin 1 (alpha) ADM2 NM_001253845.1 AM2|dJ579N16.4 adrenomedullin 2 ADRA2B NM_000682.4 ADRA2L1|ADRA2RL1|ADRARL1|ALPHA2BAR|alpha-2BAR adrenoceptor alpha 2B AEBP1 NM_001129.3 ACLP AE binding protein 1 AGGF1 NM_018046.3 GPATC7|GPATCH7|HSU84971|HUS84971|VG5Q
    [Show full text]
  • Supporting Information for Proteomics DOI 10.1002/Prca.200780101
    Supporting Information for Proteomics DOI 10.1002/prca.200780101 Paul Cutler, Emma L. Akuffo, Wanda M. Bodnar, Deborah M. Briggs, John B. Davis, Christine M. Debouck, Steven M. Fox, Rachel A. Gibson, Darren A. Gormley, Joanna D. Holbrook, A. Jacqueline Hunter, Emma E. Kinsey, Rabinder Prinjha, Jill C. Richardson, Allen D. Roses, Marjorie A. Smith, Nikos Tsokanas, David R. Will, Wen Wu, John W. Yates and Israel S. Gloger Proteomic identification and early validation of complement 1 inhibitor and pigment epithelium-derived factor: Two novel biomarkers of Alzheimer’s disease in human plasma ª 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.clinical.proteomics-journal.com Supplementary Table 1: Complete list of proteins identified from spots derived from 2D gel analysis of human plasma. Each protein was observed to be in a spot showing altered expression between Alzheimer’s disease and matched control by statistical methods as described in the Methods section. Each protein is identified by the gene description and the HUGO gene symbol. The number of “changing” spots in which this protein was observed is also given. HUGO Human Gene Number of Gene Description Symbol Spots alpha-1-B glycoprotein; A1BG 5 alpha-2-macroglobulin A2M 7 afamin; AFM 1 angiotensinogen (serpin peptidase inhibitor, clade A, member 8) AGT 4 alpha-2-HS-glycoprotein AHSG 3 albumin ALB 90 alpha-1-microglobulin/bikunin precursor; AMBP 1 annexin A1 ANXA1 1 amyloid P component, serum APCS 3 apolipoprotein A-I APOA1 14 apolipoprotein A-IV APOA4 2 apolipoprotein E APOE 2 apolipoprotein
    [Show full text]
  • Apolipoprotein H, an Acute Phase Protein, a Performing Tool for Ultra-Sensitive Detection and Isolation of Microorganisms from Different Origins
    2 Apolipoprotein H, an Acute Phase Protein, a Performing Tool for Ultra-Sensitive Detection and Isolation of Microorganisms from Different Origins Ilias Stefas1, Gregor Dubois2, Sylvia Tigrett1, Estelle Lucarz1 and Francisco Veas2 1ApoH-Technologies Faculty of Pharmacy, University Montpellier 1, Av Charles Flahault, Montpellier 2Comparative Molecular Immuno-Physiopathology Lab. UMR-MD3 Faculty of Pharmacy, University Montpellier 1, Av Charles Flahault, Montpellier France 1. Introduction Apolipoprotein H (ApoH), also known as beta2-glycoprotein I (ß2-GPI), is a plasma glycoprotein of 50 kDa. ApoH is present in human plasma at a concentration of between 150 and 300 mg/ml (Bouma et al., 1999). In blood, ApoH circulate in free conformations or bound to lipoproteins: chylomicrons, very low-density lipoprotein (VLDL), low density lipoprotein (LDL) and high-density lipoprotein (HDL). In addition, ApoH has a high affinity for triglyceride-rich lipoproteins. The amount of ApoH associated with plasma lipoproteins in healthy individuals varies according to the authors from 4 to 13% (Gambino et al., 1999a) up to about 40% (Polz & Kostner, 1979). ApoH is able to activate lipoprotein lipases (Lee et al., 1983). ApoH was isolated from the fraction of plasma lipoproteins, and described for the first time in 1961 by H. Schultze E (Schultze, 1961). In a lesser extent, ApoH is also associated to ß2-globulin fraction. ApoH is expressed in human liver, in intestinal cells and tissues (Averna et al., 1997). In rats, other sites of synthesis in low concentrations were identified as the kidney, small intestine, brain, cardiomyocytes of the heart, and at even lower in the spleen, stomach and prostate (Ragusa et al., 2006).
    [Show full text]
  • Pathophysiological Mechanisms in Antiphospholipid Syndrome
    Review Pathophysiological mechanisms in antiphospholipid syndrome Antiphospholipid syndrome is a systemic autoimmune disease associated with thrombosis and recurrent fetal loss in the setting of detectable antiphospholipid (aPL) antibodies. The major antigenic target has been identified as b2-glycoprotein I (b2GPI), which mediates binding of aPL antibodies to target cells including endothelial cells, monocytes, platelets and trophoblasts, leading to prothrombotic and proinflammatory changes that ultimately result in thrombosis and fetal loss. This article summarizes recent insights into the role of b2GPI in normal hemostasis, interactions between aPL antibodies, b2GPI and cell- surface molecules, molecular prothrombotic and proinflammatory changes induced by aPL antibodies and pathogenic changes leading to fetal loss in antiphospholipid syndrome. New directions in therapy using these insights are examined. 1 n n Brock E Harper , KEYWORDS: annexin anti-b2-glycoprotein I antibody antiphospholipid antibodies n antiphospholipid syndrome n endothelial cell activation n pathogenesis n platelet Rohan Willis1 activation n pregnancy loss n thrombosis n treatment & Silvia S Pierangeli†1 1Department of Internal Medicine, Division of Rheumatology, University Antiphospholipid syndrome (APS) is a systemic and use of hormone-replacement therapy or oral of Texas Medical Branch, Galveston, autoimmune disease characterized by recurrent contraceptives [9]. By contrast, venous thrombo- TX, USA †Author for correspondence: thrombosis and fetal loss in the presence of per- sis was associated with presence of hypertriglyc- [email protected] sistently positive antiphospholipid (aPL) antibod- eridemia, presence of a hereditary thrombophilia ies (Abs) including lupus anticoagulant (LAC), or aCL IgG more than 40 IU [9]. IgG/IgM anticardiolipin (aCL) Abs and anti-b2- Antiphospholipid syndrome causes significant glycoprotein I (b2GPI) Abs [1–3].
    [Show full text]
  • Review Article Mouse Homologues of Human Hereditary Disease
    I Med Genet 1994;31:1-19 I Review article J Med Genet: first published as 10.1136/jmg.31.1.1 on 1 January 1994. Downloaded from Mouse homologues of human hereditary disease A G Searle, J H Edwards, J G Hall Abstract involve homologous loci. In this respect our Details are given of 214 loci known to be genetic knowledge of the laboratory mouse associated with human hereditary dis- outstrips that for all other non-human mam- ease, which have been mapped on both mals. The 829 loci recently assigned to both human and mouse chromosomes. Forty human and mouse chromosomes3 has now two of these have pathological variants in risen to 900, well above comparable figures for both species; in general the mouse vari- other laboratory or farm animals. In a previous ants are similar in their effects to the publication,4 102 loci were listed which were corresponding human ones, but excep- associated with specific human disease, had tions include the Dmd/DMD and Hprt/ mouse homologues, and had been located in HPRT mutations which cause little, if both species. The number has now more than any, harm in mice. Possible reasons for doubled (table 1A). Of particular interest are phenotypic differences are discussed. In those which have pathological variants in both most pathological variants the gene pro- the mouse and humans: these are listed in table duct seems to be absent or greatly 2. Many other pathological mutations have reduced in both species. The extensive been detected and located in the mouse; about data on conserved segments between half these appear to lie in conserved chromo- human and mouse chromosomes are somal segments.
    [Show full text]
  • Assessing Changes in Biomarkers of Effect in Smokers Who Switch to a Closed System Electronic Cigarette
    Assessing Changes In Biomarkers Of Effect In Smokers Who Switch To A Closed System Electronic Cigarette Liz Mason | Kunming, China | 26th October 2018 CONTENT 1. Background Biomarkers of exposure and effect Study Aim 2. 5-day Study Study design Results 3. Two-year study Study design Results 4. Summary Study Conclusions Background 5-day Study Two year study Conclusions 2 | VAPOUR PRODUCTS HAVE BEEN SHOWN TO REDUCE BIOMARKERS OF EXPOSURE Previous studies have demonstrated that when a smoker switches to a vapour product, they are exposed to significantly lower levels of carcinogens and toxicants in the aerosol... Reduced formation of toxicants in blu™ e-cigarette …and significant reductions in biomarkers of exposure… aerosol vs. conventional cigarette smoke “Chemical Composition of myblu™ Pod-System E-Cigarette Aerosols: A Quantitative Comparison with Conventional Cigarette Smoke”, Poster presentation, 1st Scientific Summit Tobacco Harm Reduction (http://www.fontemscience.com/wp-content/uploads/2018/06/2018-04-18-aerosol-chemistry-thr-summit-2018-poster_final.pdf); Tayyarah R and Long GA. “Comparison of select analytes in aerosol from e-cigarettes with smoke from conventional cigarettes and with ambient air.” Regulatory toxicology and pharmacology 70 3 (2014). O’Connell et al (2016): Reductions in biomarkers of exposure (BoE) to harmful or potentially harmful constituents (HPHCs) following partial or complete substitution of cigarettes with electronic cigarettes in adult smokers, Toxicology Mechanisms and Methods, DOI: 10.1080/15376516.2016.1196282. http://www.fontemscience.com/wp-content/uploads/2017/05/fontem2research-1.pdf Background 5-day Study Two year study Conclusions 3 | VAPOUR PRODUCTS HAVE BEEN SHOWN TO REDUCE BIOMARKERS OF EXPOSURE What is the biological impact when a smoker switches to a vapour product? Clinical markers: • can be defined as a measurable biochemical, physiologic, behavioural, or other alteration in an organism.
    [Show full text]
  • Essential Genetics 5
    Essential genetics 5 Disease map on chromosomes 例 Gaucher disease 単一遺伝子病 天使病院 Prader-Willi syndrome 隣接遺伝子症候群，欠失が主因となる疾患 臨床遺伝診療室 外木秀文 Trisomy 13 複数の遺伝子の重複によって起こる疾患 挿画 Koromo 遺伝子の座位あるいは欠失等の範囲を示す Copyright (c) 2010 Social Medical Corporation BOKOI All Rights Reserved. Disease map on chromosome 1 Gaucher disease Chromosome 1q21.1 1p36 deletion syndrome deletion syndrome Adrenoleukodystrophy, neonatal Cardiomyopathy, dilated, 1A Zellweger syndrome Charcot-Marie-Tooth disease Emery-Dreifuss muscular Hypercholesterolemia, familial dystrophy Hutchinson-Gilford progeria Ehlers-Danlos syndrome, type VI Muscular dystrophy, limb-girdle type Congenital disorder of Insensitivity to pain, congenital, glycosylation, type Ic with anhidrosis Diamond-Blackfan anemia 6 Charcot-Marie-Tooth disease Dejerine-Sottas syndrome Marshall syndrome Stickler syndrome, type II Chronic granulomatous disease due to deficiency of NCF-2 Alagille syndrome 2 Copyright (c) 2010 Social Medical Corporation BOKOI All Rights Reserved. Disease map on chromosome 2 Epiphyseal dysplasia, multiple Spondyloepimetaphyseal dysplasia Brachydactyly, type D-E, Noonan syndrome Brachydactyly-syndactyly syndrome Peters anomaly Synpolydactyly, type II and V Parkinson disease, familial Leigh syndrome Seizures, benign familial Multiple pterygium syndrome neonatal-infantile Escobar syndrome Ehlers-Danlos syndrome, Brachydactyly, type A1 type I, III, IV Waardenburg syndrome Rhizomelic chondrodysplasia punctata, type 3 Alport syndrome, autosomal recessive Split-hand/foot malformation Crigler-Najjar
    [Show full text]
  • A Novel Mechanism of Thrombosis in Antiphospholipid Antibody Syndrome
    Vlachoyiannopoulos PG, Routsias JG. Ένας νέος μηχανισμός για την θρόμβωση στο σύνδρομο αντιφωσφολιπιδίων. J Autoimmun. 2010, 35(3):248-55. Antiphospholipid antibody syndrome (APS) is an autoimmune thrombophilia mediated by autoantibodies directed against phospholipid‐binding plasma proteins, mainly β2 Glycoprotein I (β2GPI)‐ a plasma apolipoprotein and prothrombin (PT). A subgroup of these antibodies termed "Lupus Anticoagulant" (LA) elongate in vitro the clotting times, this elongation not corrected by adding normal plasma in the detection system. The exact mechanism by which these autoantibodies induce thrombosis is not well understood. Resistance to natural anticoagulants such as protein C, impaired fibrinolysis, activation of endothelial cells to a pro‐coagulant phenotype and activation of platelets, are among the mechanisms partially supported by experimental evidence. Artificially dimerized β2GPI binds tightly to platelet membrane activating them. We search for mechanisms of natural dimerization of β2GPI by proteins of the platelet membranes and found that platelet factor 4 (PF4) assembled in homotetramers binds two molecules of β2GPI and this complex is recognized by anti‐β2GPI antibodies, the whole complexes being thrombogenic in terms of activating platelets as confirmed by p38MAP kinase phosphorylation and thromboxane B2 production. Of note PF4/heparin complexes are also immunogenic triggering the production of anti‐PF4/heparin antibodies which activate also platelets (the so‐called "heparin‐induced thrombocytopenia and thrombosis syndrome", HITT). The anti‐β2GPI antibodies activate platelets by their F(ab)2, while the anti‐PF4/heparin by their Fc fragments. Thus PF4 is a common denominator in the pathogenesis of APS and HITT which share also clinical characteristics such as thrombocytopenia and thrombosis.
    [Show full text]
  • Strand Breaks for P53 Exon 6 and 8 Among Different Time Course of Folate Depletion Or Repletion in the Rectosigmoid Mucosa
    SUPPLEMENTAL FIGURE COLON p53 EXONIC STRAND BREAKS DURING FOLATE DEPLETION-REPLETION INTERVENTION Supplemental Figure Legend Strand breaks for p53 exon 6 and 8 among different time course of folate depletion or repletion in the rectosigmoid mucosa. The input of DNA was controlled by GAPDH. The data is shown as ΔCt after normalized to GAPDH. The higher ΔCt the more strand breaks. The P value is shown in the figure. SUPPLEMENT S1 Genes that were significantly UPREGULATED after folate intervention (by unadjusted paired t-test), list is sorted by P value Gene Symbol Nucleotide P VALUE Description OLFM4 NM_006418 0.0000 Homo sapiens differentially expressed in hematopoietic lineages (GW112) mRNA. FMR1NB NM_152578 0.0000 Homo sapiens hypothetical protein FLJ25736 (FLJ25736) mRNA. IFI6 NM_002038 0.0001 Homo sapiens interferon alpha-inducible protein (clone IFI-6-16) (G1P3) transcript variant 1 mRNA. Homo sapiens UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 15 GALNTL5 NM_145292 0.0001 (GALNT15) mRNA. STIM2 NM_020860 0.0001 Homo sapiens stromal interaction molecule 2 (STIM2) mRNA. ZNF645 NM_152577 0.0002 Homo sapiens hypothetical protein FLJ25735 (FLJ25735) mRNA. ATP12A NM_001676 0.0002 Homo sapiens ATPase H+/K+ transporting nongastric alpha polypeptide (ATP12A) mRNA. U1SNRNPBP NM_007020 0.0003 Homo sapiens U1-snRNP binding protein homolog (U1SNRNPBP) transcript variant 1 mRNA. RNF125 NM_017831 0.0004 Homo sapiens ring finger protein 125 (RNF125) mRNA. FMNL1 NM_005892 0.0004 Homo sapiens formin-like (FMNL) mRNA. ISG15 NM_005101 0.0005 Homo sapiens interferon alpha-inducible protein (clone IFI-15K) (G1P2) mRNA. SLC6A14 NM_007231 0.0005 Homo sapiens solute carrier family 6 (neurotransmitter transporter) member 14 (SLC6A14) mRNA.
    [Show full text]