DOCSLIB.ORG

Kallikrein-Related Peptidases 6 and 10 Are Elevated in Cerebrospinal Fluid

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Kallikrein-Related Peptidases 6 and 10 Are Elevated in Cerebrospinal Fluid Goldhardt et al. Translational Neurodegeneration (2019) 8:25 https://doi.org/10.1186/s40035-019-0168-6 RESEARCH Open Access Kallikrein-related peptidases 6 and 10 are elevated in cerebrospinal fluid of patients with Alzheimer’s disease and associated with CSF-TAU and FDG-PET Oliver Goldhardt1* , Inanna Warnhoff1, Igor Yakushev2, Ilijana Begcevic5, Hans Förstl1, Viktor Magdolen3, Antoninus Soosaipillai4, Eleftherios Diamandis4,5, Panagiotis Alexopoulos1,6 and Timo Grimmer1 Abstract Background: Alterations in the expression of human kallikrein-related peptidases (KLKs) have been described in patients with Alzheimer’s disease (AD). We elucidated the suitability of KLK6, KLK8 and KLK10 to distinguish AD from NC and explored associations with established AD biomarkers. Methods: KLK levels in cerebrospinal fluid (CSF), as determined by ELISA, were compared between 32 AD patients stratified to A/T/(N) system with evidence for amyloid pathology and of 23 normal controls with normal AD biomarkers. Associations between KLK levels and clinical severity, CSF and positron emission tomography (PET) based AD biomarkers were tested for. Results: Levels of KLK6 and KLK10 were significantly increased in AD. KLK6 differed significantly between AD A+/T+/N+ and AD A+/T−/N+ or NC with an AUC of 0.922. CSF pTau and tTau levels were significantly associated with KLK6 in AD. Conclusions: KLK6 deserves further investigations as a potential biomarker of Tau pathology in AD. Keywords: Alzheimer’s disease (AD), Kallikrein-like peptidase (KLK),KLK6,KLK8,KLK10,Cerebralamyloidload, Cerebrospinal fluid (CSF), Amyloid 1–42; Aβ1–42; Aβ42,Tauprotein,Totaltau,tTau,Phosphotau,pTau,Positronemission tomography (PET) Background cerebrospinal fluid (CSF) [4]. Aβ accumulation can be In sporadic Alzheimer’s disease (AD) impaired cerebral measured by [11C]PiB (Pittsburgh Compound B)-PET amyloid clearance is considered to drive amyloid (Aβ)ac- ([C11]PiB-PET) [5] and impaired amyloid clearance by de- cumulation [1] which results in pathognomonic Aβ plaque creased concentration of Aβ42 in the CSF [4]. formation [2]. Aβ initiates a pathophysiological cascade Kallikrein-related peptidases (KLKs) constitute a fam- including neuronal injury. Accumulative neuronal injury ily of 15 highly conserved trypsin- or chymotrypsin-like can be indicated by AD imaging biomarkers such as hypo- serine proteases [6] displaying various functions. All metabolism by [18F]fluorodeoxyglucose-position emission KLK genes are located on chromosome 19q13.4, in a tomography ([18F]FDG-PET) [3]. Current rate of cell region that has been associated with familiar AD [7]. death can be determined by elevated levels of the KLK1, 4–8, 10, 11, 13 and 14 are expressed in the cortex intracellular, microtubule originated total tau (tTau) and as well as in the hippocampus [8, 9]. KLKs might also tau pathology by phosphorylated tau (pTau) in the play a role in the pathophysiology of sporadic AD [10]. * Correspondence: [email protected] KLK6 1 Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, KLK6 was detected outside the brain in the serum, Technical University of Munich, School of Medicine, Ismaninger Str. 22, 81675 Munich, Germany nipple aspirate fluid, breast cyst fluid, seminal plasma, Full list of author information is available at the end of the article amniotic fluid and breast cancer cytosols [11]. However, © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Goldhardt et al. Translational Neurodegeneration (2019) 8:25 Page 2 of 13 the highest expression of KLK6 in humans is observed BBB via increased concentrations of the Aβ efflux in the central nervous system [8]. KLK6 is strongly transporter lipoprotein-receptor related protein 1 (LRP1), expressed in the luminal cells lining the choroid plexus increased Aβ phagocytosis, and counteracts tau hyperpho- [12], in the grey matter of the brain and in peripheral sphorylation via downstream effects on GSK3β [30]. The nerves [13]. KLK6 is predominantly expressed in oligo- impact of KLK8 on the neurovascular function to trans- dendrocytes, pyramidal cells and astrocytes. It can be port Aβ over the BBB can be measured in the blood in found in certain neuroendocrine cells [14] and in the mice [30] and potentially in the CSF. endothelial cells of cerebral vessels. The latter suggests These associations have not been shown in humans its involvement in the blood-brain barrier (BBB) [15]. with AD, but KLK8 mRNA expression is increased in KLK6 can cleave components of the BBB and can induce the mural and human hippocampus in comparison to inflammation [16]. In non-injured CNS, KLK6 immuno- NC [9], and KLK8 levels are increased in hippocampal reactivity is mainly found in oligodendroglia and brain extracts patients with AD and in the brain of neurons [17], while KLK6 is induced in astrocytes with healthy woman compared to men [31]. neuronal injury [18]. In neurons, it is released from mitochondria into the cytoplasm due to various cellular KLK10 stress and processes alpha-synuclein in Lewy-body KLK10 is expressed by glandular epithelia, e. g. in the disease [19]. kidney and in the gastrointestinal tract, and by the KLK6 appears to exhibit an anti-amyloidogenic poten- choroid plexus epithelium, by peripheral nerves, and by tial [20] and has been linked to AD: in extracts of differ- certain neuroendocrine organs [32]. Whereas KLK10 ent brain regions of patients with AD, KLK6 levels are RNA expression in the hippocampus did not differ lower as compared to controls [21, 22], KLK6 mRNA significantly between AD patients and NC [9], in CSF in levels are decreased in the hippocampus as well [9]. In AD, the protein levels were found to be decreased in blood, current results are conflicting: one study did not frontotemporal dementia (FTD) [33]. detect any significant difference in KLK6 levels in the Inflammation appears to be a common factor for alter- serum of AD patients as compared to cognitively normal ations of KLKs levels in AD, cancer and other diseases control (NC) [23], whereas in another study a striking [34] as well as inflammation appears to be a pathogen- 10-fold increase in the blood was reported [12]. In the etic factor among several neurological diseases [35]. cerebrospinal fluid (CSF), KLK6 levels were increased in In AD, KLKs can be hypothesized to either be directly histopathologically confirmed AD patients (n = 10) of involved in amyloid accumulation or indirectly in im- undisclosed clinical severity compared to controls (n = munological processes caused by or leading to amyloid 10) [12]. In another study, CSF KLK6 levels did not pathology. In the current work, we aimed at testing differ neither between subjective cognitive impairment whether KLK6, KLK8 and KLK10 levels in CSF are able (n = 43) and AD (n = 43), nor between clinically diag- to differentiate between AD patients with positive AD nosed normal controls (n = 58) and clinically diagnosed biomarkers and NC, and whether KLKs are associated AD (n = 28) or clinically diagnosed progressive mild with the established AD biomarkers. cognitive impairment (MCI) (n = 28) [24]. KLK8 Methods KLK8 is a synaptic, plasticity-modulating extracellular Patient recruitment, inclusion and exclusion criteria serine protease [21]. KLK8 cleaves the epinephrine Patients were selected in the Centre for Cognitive receptor B2 (EPHB2) that is involved in mechanisms of Disorders, an out-patient clinic of the Department of neuronal plasticity [25]. Upregulation of EPHB2 leads to Psychiatry and Psychotherapy of the Technical improved cognition [26] and less hyperphosphorylated University of Munich. Study participants had been tau in vitro and in hippocampus in human tau trans- referred for the evaluation of cognitive impairment by genic mice [27]. In the hippocampus of AD patients general practitioners, neurologists, psychiatrists or and mice transgenic for human amyloid precursor pro- other institutions, and had undergone a standardized tein (hAPP), KLK8 is upregulated and EPHB2 decreased diagnostic procedure with a detailed somatic, neuro- [28, 29]. In transgenic AD mice, KLK8 is increased in logic and psychiatric examination, as well as extensive early disease stages (before measurable behavior abnor- neuropsychological testing, including the Mini-Mental malities occur) as compared to wildtype mice [30]. State Examination (MMSE) [36]. To estimate clinical Furthermore, in mice, inhibition of KLK8 with anti- severity, the Clinical Dementia Rating scale (CDR) KLK8-antibodies leads to enhanced structural neuroplasti- [37] was assessed, and the global score (global CDR) city, improved cognition, reduced Aβ concentrations in and the quantitative score of CDR subcategories the frontal cortex, improved amyloid clearance over the (CDR-sum of boxes, CDR-SOB) [38] were calculated. Goldhardt et al. Translational Neurodegeneration (2019) 8:25 Page 3 of 13 Patients had to score ≥ 0.5 on global CDR to be the primary sensomotor cortex on visual inspection at considered
Load more

Recommended publications
  • Downloaded from Genomic Data Common Website (GDC at Accessed on 2019)
    G C A T T A C G G C A T genes Article Molecular Pathways Associated with Kallikrein 6 Overexpression in Colorectal Cancer Ritu Pandey 1,2,*, Muhan Zhou 3, Yuliang Chen 3, Dalila Darmoul 4 , Conner C. Kisiel 2, Valentine N. Nfonsam 5 and Natalia A. Ignatenko 1,2 1 Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, USA; [email protected] 2 University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA; [email protected] 3 Bioinformatics Shared Resource, University of Arizona Cancer Center, Tucson, AZ 85724, USA; [email protected] (M.Z.); [email protected] (Y.C.) 4 Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Lariboisière Hospital, 75010 Paris, France; [email protected] 5 Department of Surgery, Section of Surgical Oncology, University of Arizona, Tucson, AZ 85724, USA; [email protected] * Correspondence: [email protected] Abstract: Colorectal cancer (CRC) remains one of the leading causes of cancer-related death world- wide. The high mortality of CRC is related to its ability to metastasize to distant organs. The kallikrein-related peptidase Kallikrein 6 (KLK6) is overexpressed in CRC and contributes to cancer cell invasion and metastasis. The goal of this study was to identify KLK6-associated markers for the CRC prognosis and treatment. Tumor Samples from the CRC patients with significantly elevated Citation: Pandey, R.; Zhou, M.; Chen, KLK6 transcript levels were identified in the RNA-Seq data from Cancer Genome Atlas (TCGA) Y.; Darmoul, D.; Kisiel, C.C.; and their expression profiles were evaluated using Gene Ontology (GO), Phenotype and Reactome Nfonsam, V.N.; Ignatenko, N.A.
    [Show full text]
  • Kallikrein 13: a New Player in Coronaviral Infections
    bioRxiv preprint doi: https://doi.org/10.1101/2020.03.01.971499; this version posted March 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Kallikrein 13: a new player in coronaviral infections. 2 3 Aleksandra Milewska1,2, Katherine Falkowski2, Magdalena Kalinska3, Ewa Bielecka3, 4 Antonina Naskalska1, Pawel Mak4, Adam Lesner5, Marek Ochman6, Maciej Urlik6, Jan 5 Potempa2,7, Tomasz Kantyka3,8, Krzysztof Pyrc1,* 6 7 1 Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian 8 University, Gronostajowa 7a, 30-387 Krakow, Poland. 9 2 Microbiology Department, Faculty of Biochemistry, Biophysics and Biotechnology, 10 Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland. 11 3 Laboratory of Proteolysis and Post-translational Modification of Proteins, Malopolska 12 Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, 13 Poland. 14 4 Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and 15 Biotechnology, Jagiellonian University, Gronostajowa 7 St., 30-387, Krakow, Poland. 16 5 University of Gdansk, Faculty of Chemistry, Wita Stwosza 63, 80-308 Gdansk, Poland. 17 6 Department of Cardiac, Vascular and Endovascular Surgery and Transplantology, Medical 18 University of Silesia in Katowice, Silesian Centre for Heart Diseases, Zabrze, Poland. 19 7 Centre for Oral Health and Systemic Diseases, University of Louisville School of Dentistry, 20 Louisville, KY 40202, USA. 21 8 Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, 22 5020 Bergen, Norway 23 24 25 26 27 28 29 30 31 * Correspondence should be addressed to Krzysztof Pyrc ([email protected]), Virogenetics 32 Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, 33 Gronostajowa 7, 30-387 Krakow, Poland; Phone number: +48 12 664 61 21; www: 34 http://virogenetics.info/.
    [Show full text]
  • Aberrant Human Tissue Kallikrein Levels in the Stratum Corneum and Serum of Patients with Psoriasis: Dependence on Phenotype, Severity and Therapy N
    CLINICAL AND LABORATORY INVESTIGATIONS DOI 10.1111/j.1365-2133.2006.07743.x Aberrant human tissue kallikrein levels in the stratum corneum and serum of patients with psoriasis: dependence on phenotype, severity and therapy N. Komatsu,* à K. Saijoh,§ C. Kuk,* F. Shirasaki,à K. Takeharaà and E.P. Diamandis* *Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada àDepartment of Dermatology and §Department of Hygiene, Graduate School of Medical Science, School of Medicine, Kanazawa University, Kanazawa, Japan Summary Correspondence Background Human tissue kallikreins (KLKs) are a family of 15 trypsin-like or Eleftherios P. Diamandis. chymotrypsin-like secreted serine proteases (KLK1–KLK15). Multiple KLKs have E-mail: [email protected] been quantitatively identified in normal stratum corneum (SC) and sweat as can- didate desquamation-related proteases. Accepted for publication 7 November 2006 Objectives To quantify KLK5, KLK6, KLK7, KLK8, KLK10, KLK11, KLK13 and KLK14 in the SC and serum of patients with psoriasis, and their variation Key words between lesional and nonlesional areas and with phenotype, therapy and severity. diagnostic marker, human kallikreins, psoriasis, The overall SC serine protease activities were also measured. serine proteases, stratum corneum, therapy Methods Enzyme-linked immunosorbent assays and enzymatic assays were used. Conflicts of interest Results The lesional SC of psoriasis generally contained significantly higher levels None declared. of all KLKs. KLK6, KLK10 and KLK13 levels were significantly elevated even in the nonlesional SC. The overall trypsin-like, plasmin-like and furin-like activities were significantly elevated in the lesional SC.
    [Show full text]
  • Human Tissue Kallikrein Expression in the Stratum Corneum and Serum of Atopic Dermatitis Patients
    DOI:10.1111/j.1600-0625.2007.00562.x www.blackwellpublishing.com/EXD Original Article Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients Nahoko Komatsu1,2,3,4, Kiyofumi Saijoh4, Cynthia Kuk1, Amber C. Liu1, Saba Khan1, Fumiaki Shirasaki3, Kazuhiko Takehara3 and Eleftherios P. Diamandis1,2 1Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada; 2Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; 3Department of Dermatology, Graduate School of Medical Science, School of Medicine, Kanazawa University, Kanazawa, Japan; 4Department of Hygiene, Graduate School of Medical Science, School of Medicine, Kanazawa University, Kanazawa, Japan Correspondence: Eleftherios P. Diamandis, MD, PhD, FRCPC, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada, Tel.: +1 416 586 8443, Fax: +1 416 586 8628, e-mail: [email protected] Accepted for publication 9 March 2007 Abstract: Human tissue kallikreins are a family of 15 trypsin- or differ significantly. In the serum of AD patients, KLK8 was chymotrypsin-like secreted serine proteases (KLK1–KLK15). Many significantly elevated and KLK5 and KLK11 were significantly KLKs have been identified in normal stratum corneum (SC) and decreased. However, their serum levels were not modified by sweat, and are candidate desquamation-related proteases. We corticosteroid topical agents. The alterations of KLK levels in the report quantification by enzyme-linked immunosorbent assay SC of AD were more pronounced than those in the serum. KLK7 (ELISA) of KLK5, KLK6, KLK7, KLK8, KLK10, KLK11, KLK13 and in the serum was significantly correlated with eosinophil counts in KLK14 in the SC and serum of atopic dermatitis (AD) patients by the blood of AD patients, while KLK5, KLK8 and KLK11 were ELISA, and examine their variation with clinical phenotype, significantly correlated with LDH in the serum.
    [Show full text]
  • Download, Or Email Articles for Individual Use
    Florida State University Libraries Faculty Publications The Department of Biomedical Sciences 2010 Functional Intersection of the Kallikrein- Related Peptidases (KLKs) and Thrombostasis Axis Michael Blaber, Hyesook Yoon, Maria Juliano, Isobel Scarisbrick, and Sachiko Blaber Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected] Article in press - uncorrected proof Biol. Chem., Vol. 391, pp. 311–320, April 2010 • Copyright ᮊ by Walter de Gruyter • Berlin • New York. DOI 10.1515/BC.2010.024 Review Functional intersection of the kallikrein-related peptidases (KLKs) and thrombostasis axis Michael Blaber1,*, Hyesook Yoon1, Maria A. locus (Gan et al., 2000; Harvey et al., 2000; Yousef et al., Juliano2, Isobel A. Scarisbrick3 and Sachiko I. 2000), as well as the adoption of a commonly accepted Blaber1 nomenclature (Lundwall et al., 2006), resolved these two fundamental issues. The vast body of work has associated 1 Department of Biomedical Sciences, Florida State several cancer pathologies with differential regulation or University, Tallahassee, FL 32306-4300, USA expression of individual members of the KLK family, and 2 Department of Biophysics, Escola Paulista de Medicina, has served to elevate the importance of the KLKs in serious Universidade Federal de Sao Paulo, Rua Tres de Maio 100, human disease and their diagnosis (Diamandis et al., 2000; 04044-20 Sao Paulo, Brazil Diamandis and Yousef, 2001; Yousef and Diamandis, 2001, 3 Program for Molecular Neuroscience and Departments of 2003;
    [Show full text]
  • Table S1. List of All Proteins Included in the Proseek® Multiplex Oncology I V2 96X96 Cancer Panel
    Table S1. List of all proteins included in the Proseek® Multiplex Oncology I v2 96x96 Cancer Panel. Adrenomedullin (AM) Ezrin (EZR) Latency-associated peptide transforming growth factor beta-1 (LAP TGF-beta-1) Amphiregulin (AR) Fas antigen ligand (FasL) Angiopoietin-1 receptor (TIE2) FAS-associated death domain protein (FADD) Lipopolysaccharide-induced tumor necrosis factor- alpha factor (LITAF) B-cell activating factor (BAFF) Fms-related tyrosine kinase 3 ligand (Flt3L) Cadherin-3 (CDH3) Folate receptor alpha (FR-alpha) Macrophage colony-stimulating factor 1 (CSF-1) Carbonic anhydrase IX (CAIX) Follistatin (FS) Matrix metalloproteinase-1 (MMP-1) Carcinoembryonic antigen (CEA) Furin (FUR) Melanoma-derived growth regulatory protein (MIA) Caspase-3 (CASP-3) Growth hormone (GH) MHC class I polypeptide-related sequence A (MIC-A) C-C motif chemokine 19 (CCL19) Growth/differentiation factor 15 (GDF-15) Midkine (MK) CD40 ligand (CD40-L) Heparin-binding EGF-like growth factor (HB-EGF) Monocyte chemotactic protein 1 (MCP-1) C-X-C motif chemokine 5 (CXCL5) Hepatocyte growth factor (HGF) Myeloid differentiation primary response protein MyD88 (MYD88) C-X-C motif chemokine 9 (CXCL9) ICOS ligand (ICOSLG) C-X-C motif chemokine 10 (CXCL10) Immunoglobulin-like transcript 3 (ILT-3) NF-kappa-B essential modulator (NEMO) C-X-C motif chemokine 11 (CXCL11) Integrin alpha-1 (ITGA1) NT-3 growth factor receptor (NTRK3) C-X-C motif chemokine 13 (CXCL13) Interferon gamma (IFN-gamma) Ovarian cancer-related tumor marker CA 125 (CA-125) Cyclin-dependent kinase inhibitor
    [Show full text]
  • Activation Profiles and Regulatory Cascades of the Human Kallikrein-Related Peptidases Hyesook Yoon
    Florida State University Libraries Electronic Theses, Treatises and Dissertations The Graduate School 2008 Activation Profiles and Regulatory Cascades of the Human Kallikrein-Related Peptidases Hyesook Yoon Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected] FLORIDA STATE UNIVERSITY COLLEGE OF ARTS AND SCIENCES ACTIVATION PROFILES AND REGULATORY CASCADES OF THE HUMAN KALLIKREIN-RELATED PEPTIDASES By HYESOOK YOON A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy Degree Awarded: Fall Semester, 2008 The members of the Committee approve the dissertation of Hyesook Yoon defended on July 10th, 2008. ________________________ Michael Blaber Professor Directing Dissertation ________________________ Hengli Tang Outside Committee Member ________________________ Brian Miller Committee Member ________________________ Oliver Steinbock Committee Member Approved: ____________________________________________________________ Joseph B. Schlenoff, Chair, Department of Chemistry and Biochemistry The Office of Graduate Studies has verified and approved the above named committee members. ii ACKNOWLEDGMENTS I would like to dedicate this dissertation to my parents for all your support, and my sister and brother. I would also like to give great thank my advisor, Dr. Blaber for his patience, guidance. Without him, I could never make this achievement. I would like to thank to all the members in Blaber lab. They are just like family to me and I deeply appreciate their kindness, consideration and supports. I specially like to thank to Mrs. Sachiko Blaber for her endless guidance and encouragement. I would like to thank Dr Jihun Lee, Margaret Seavy, Rani and Doris Terry for helpful discussions and supports.
    [Show full text]
  • A Predictive Model for Prostate Cancer Incorporating PSA Molecular Forms
    www.nature.com/scientificreports OPEN A predictive model for prostate cancer incorporating PSA molecular forms and age Julia Oto1,5, Álvaro Fernández-Pardo1,5, Montserrat Royo1, David Hervás 2, Laura Martos1, César D. Vera-Donoso3, Manuel Martínez3, Mary J. Heeb4, Francisco España1, Pilar Medina1* & Silvia Navarro1* The diagnostic specifcity of prostate specifc antigen (PSA) is limited. We aimed to characterize eight anti-PSA monoclonal antibodies (mAbs) to assess the prostate cancer (PCa) diagnostic utility of diferent PSA molecular forms, total (t) and free (f) PSA and PSA complexed to α1-antichymotrypsin (complexed PSA). MAbs were obtained by immunization with PSA and characterized by competition studies, ELISAs and immunoblotting. With them, we developed sensitive and specifc ELISAs for these PSA molecular forms and measured them in 301 PCa patients and 764 patients with benign prostate hyperplasia, and analyzed their efectiveness to discriminate both groups using ROC curves. The free- to-total (FPR) and the complexed-to-total PSA (CPR) ratios signifcantly increased the diagnostic yield of tPSA. Moreover, based on model selection, we constructed a multivariable logistic regression model to predictive PCa that includes tPSA, fPSA, and age as predictors, which reached an optimism-corrected area under the ROC curve (AUC) of 0.86. Our model outperforms the predictive ability of tPSA (AUC 0.71), used in clinical practice. In conclusion, The FPR and CPR showed better diagnostic yield than tPSA. In addition, the PCa predictive model including age, fPSA and complexed PSA, outperformed tPSA detection efcacy. Our model may avoid unnecessary biopsies, preventing harmful side efects and reducing health expenses.
    [Show full text]
  • The Physiology and Pathobiology of Human Kallikrein-Related Peptidase 6 (KLK6 )
    Clin Chem Lab Med 2012;50(2):211–233 © 2012 by Walter de Gruyter • Berlin • Boston. DOI 10.1515/CCLM.2011.750 Review The physiology and pathobiology of human kallikrein-related peptidase 6 ( KLK6 ) Jane Bayani 1,2 and Eleftherios P. Diamandis 1 – 3, * surveys of normal and diseased genomes, transcriptomes, 1 Department of Laboratory Medicine and Pathobiology , proteomes and metabolomes. However, few, if any, biomark- University of Toronto, Toronto, ON, Canada ers have made their way to the clinic. Meanwhile, some FDA- 2 Samuel Lunenfeld Research Institute , Joseph and Wolf approved biomarkers are not used in standard clinical practice Lebovic Health Centre and Mt. Sinai Hospital, Toronto, and labelled as “ analyte-specifi c reagents (ASRs) ” , recom- ON, Canada mended for research purposes only (1) . Multiple biomarkers 3 Department of Clinical Biochemistry , Toronto General for disease diagnosis and personalised therapy are the way of Hospital, University Health Network, Toronto, ON , the future, but many still hope to fi nd simple biomarkers that Canada rival the likes of prostate specifi c antigen ( PSA ) for prostate cancer (2) . PSA , also known as kallikrein 3 ( KLK3 ), belongs to a unique family of 15 tissue kallikrein and kallikrein-related Abstract peptidase genes ( KLK s) (3 – 5) . Following the identifi cation The human kallikrein-related peptidase 6 ( KLK6 ) gene belongs of all human KLK family members in the late 1990s (6, 7) , to the 15-member kallikrein ( KLK ) gene family mapping to many investigators, including our group, have actively pur- chromosome 19q13.3 – 13.4. Encoding for an enzyme with sued the potential for other KLK family members as putative trypsin-like properties, KLK6 can degrade components of the biomarkers (3, 4) .
    [Show full text]
  • Prognostic Significance of Multiple Kallikreins in High-Grade Astrocytoma Kristen L
    Drucker et al. BMC Cancer (2015) 15:565 DOI 10.1186/s12885-015-1566-5 RESEARCH ARTICLE Open Access Prognostic significance of multiple kallikreins in high-grade astrocytoma Kristen L. Drucker1, Caterina Gianinni2, Paul A. Decker3, Eleftherios P. Diamandis4 and Isobel A. Scarisbrick1,5* Abstract Background: Kallikreins have clinical value as prognostic markers in a subset of malignancies examined to date, including kallikrein 3 (prostate specific antigen) in prostate cancer. We previously demonstrated that kallikrein 6 is expressed at higher levels in grade IV compared to grade III astrocytoma and is associated with reduced survival of GBM patients. Methods: In this study we determined KLK1, KLK6, KLK7, KLK8, KLK9 and KLK10 protein expression in two independent tissue microarrays containing 60 grade IV and 8 grade III astrocytoma samples. Scores for staining intensity, percent of tumor stained and immunoreactivity scores (IR, product of intensity and percent) were determined and analyzed for correlation with patient survival. Results: Grade IV glioma was associated with higher levels of kallikrein-immunostaining compared to grade III specimens. Univariable Cox proportional hazards regression analysis demonstrated that elevated KLK6- or KLK7-IR was associated with poor patient prognosis. In addition, an increased percent of tumor immunoreactive for KLK6 or KLK9 was associated with decreased survival in grade IV patients. Kaplan-Meier survival analysis indicated that patients with KLK6-IR < 10, KLK6 percent tumor core stained < 3, or KLK7-IR < 9 had a significantly improved survival. Multivariable analysis indicated that the significance of these parameters was maintained even after adjusting for gender and performance score. Conclusions: These data suggest that elevations in glioblastoma KLK6, KLK7 and KLK9 protein have utility as prognostic markers of patient survival.
    [Show full text]
  • Kallikrein-Related Peptidase Signalling Via Proteinase-Activated Receptors
    KALLIKREIN-RELATED PEPTIDASE SIGNALLING VIA PROTEINASE-ACTIVATED RECEPTORS by Aikaterini Oikonomopoulou A thesis submitted in conformity with the requirements for the Degree of Doctor of Philosophy Graduate Department of Laboratory Medicine and Pathobiology University of Toronto © Copyright by Aikaterini Oikonomopoulou 2008 Kallikrein-related peptidase signalling via proteinase-activated receptors Aikaterini Oikonomopoulou Doctor of Philosophy, 2008 Department of Laboratory Medicine and Pathobiology University of Toronto ABSTRACT The family of human kallikrein-related peptidases (KLKs) numbers 15 serine proteinases implicated in tumour progression. Despite the wide tissue distribution of KLKs and the numerous reports of their differential expression in pathological settings, the signalling mechanism(s) whereby these enzymes regulate tissue function are not yet known. Further, knowledge of the levels of their activity, as well as of their potential endogenous targets, has only been extracted from in vitro studies and cell culture systems. We hypothesized that KLKs can trigger tumour signalling via proteinase-activated receptors (PARs), a family of G-protein-coupled receptors. To test our hypothesis, we evaluated the ability of KLKs 5, 6, and 14: to activate or prevent signalling via PARs 1, 2, and 4 in cells and tissues expressing these receptors. Further, we used a novel activity-based probe approach, coupled with conventional immunoassay (ELISA), to determine the abundance of active KLK6 relative to total immunoreactive KLK6 in cancer-related biological fluids. We concluded that KLKs can regulate multiple signalling pathways triggered by PARs 1, 2, and 4, resulting in calcium release, platelet aggregation and vascular relaxation, and they can cause murine inflammation. Further, our activity-based ELISA demonstrated the presence of active KLK6 in ovarian cancer ascites fluids and cancer cell supernatants.
    [Show full text]
  • Is Generation of C3(H2O) Necessary for Activation of the Alternative Pathway T in Real Life? ⁎ Kristina N
    Molecular Immunology 114 (2019) 353–361 Contents lists available at ScienceDirect Molecular Immunology journal homepage: www.elsevier.com/locate/molimm Is generation of C3(H2O) necessary for activation of the alternative pathway T in real life? ⁎ Kristina N. Ekdahla,b, , Camilla Mohlinb, Anna Adlera, Amanda Åmana, Vivek Anand Manivela, Kerstin Sandholmb, Markus Huber-Langc, Karin Fromella, Bo Nilssona a Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden b Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden c Institute for Clinical and Experimental Trauma Immunology, University Hospital of Ulm, Ulm, Germany ARTICLE INFO ABSTRACT Keywords: In the alternative pathway (AP) an amplification loop is formed, which is strictly controlled by various fluid- Complement system phase and cell-bound regulators resulting in a state of homeostasis. Generation of the “C3b-like” C3(H2O) has C3(H2O) been described as essential for AP activation, since it conveniently explains how the initial fluid-phase AP Conformation convertase of the amplification loop is generated. Also, the AP has a status of being an unspecific pathway Analysis despite thorough regulation at different surfaces. Proteases During complement attack in pathological conditions and inflammation, large amounts of C3b are formed by Alternative pathway the classical/lectin pathway (CP/LP) convertases. After the discovery of LP´s recognition molecules and its tight interaction with the AP, it is increasingly likely that the AP acts in vivo mainly as a powerful amplification mechanism of complement activation that is triggered by previously generated C3b molecules initiated by the binding of specific recognition molecules. Also in many pathological conditions caused by a dysregulated AP amplification loop such as paroxysmal nocturnal hemoglobulinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), C3b is available due to minute LP and CP activation and/or generated by non-complement proteases.
    [Show full text]