DOCSLIB.ORG

CD46 Expression Is Indicative of Shorter Revival-Free Survival for Ovarian Cancer Patients

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
CD46 Expression Is Indicative of Shorter Revival-Free Survival for Ovarian Cancer Patients ANTICANCER RESEARCH 26: 4943-4948 (2006) CD46 Expression is Indicative of Shorter Revival-free Survival for Ovarian Cancer Patients PAWEL SUROWIAK1,2,3, VERENA MATERNA1, ADAM MACIEJCZYK3, IRINA KAPLENKO4, MAREK SPACZYNSKI4, MANFRED DIETEL1, HERMANN LAGE1 and MACIEJ ZABEL2,5 1Institute of Pathology, Charité Campus Mitte, D-10117 Berlin, Germany; 2Chair and Department of Histology and Embryology, University School of Medicine, ul. Chalubinskiego 6a, 50-356 Wroclaw; 3Lower Silesian Centre of Oncology, pl. Hirszfelda 12, 53-413 Wroclaw; 4Chair and Department of Obstetrics and Gynaecology and 5Chair and Department of Histology and Embryology, University School of Medicine, ul. Swiecickiego 6, 60-781 Poznan, Poland Abstract. Background: The membrane cofactor protein CD46 cure very rarely. Despite the introduction of novel represents a complement inhibitor, which protects autologous chemotherapy regimens, the frequency of 5 - year survival cells from complement - mediated cytotoxicity. CD46 may of patients at all clinical stages has not exceeded 40%, in the exhibit the potential to protect tumor cells from the immune last 20 years (2). Therefore, intense efforts are being made responses of the host. The present study aimed to evaluate the in numerous centres to detect new prognostic factors, which prognostic significance of CD46 expression in ovarian cancers. might prove valuable towards studies on new therapeutic Materials and Methods: The analyses were performed on 73 approaches. ovarian cancer samples. Immunohistochemical reactions were The absence of the host’s immune response to the performed on paraffin sections of tumors using monoclonal presence of tumor cells represents one of the circumstances, antibodies directed against CD46. The immunohistochemical which promotes development of the tumor. The reactions and the clinical observations results were subjected to phenomenon may be explained by the expression of statistical analysis. Results: Expression of CD46 was complement regulatory proteins (CRPs) on tumor cells (3). demonstrated in 60% of primary laparotomy cases and in 70% Presence of CRPs on the cell membrane inhibits the secondary cytoreduction cases. Kaplan-Meier analysis showed formation of C3/C5 complexes. CD46 (MCP – membrane that a significantly shorter revival-free time was linked to cases cofactor protein) is a membrane protein (4) present on the with CD46 expression at PL (p=0.01). Conclusion: Ovarian surface of multiple types of epithelial cells, on endothelium, cancers manifest CD46 expression that is linked to a less and blood cells (3). However, it is absent from erythrocytes. favourable prognosis. The protein functions as a complement inhibitor. Expression of the protein has also been demonstrated in Ovarian cancers are frequent gynaecological tumors in various types of tumors and in cell lines derived from those women. About 190,000 new cases and 114,000 deaths from neoplasms (5-7). Expression of CD46 is more pronounced ovarian cancer are estimated to occur worldwide annually. on tumor cells than in the surrounding healthy tissues (8). The highest rates are reported in Scandinavia and Eastern The augmented expression of CD46 on tumor cells has been Europe, the USA and Canada (1). Due to their localisation suggested to represent the mechanism, which protects the and consequent late diagnosis, as well as the aggressive cells from the immune reaction (7, 8). To date, no studies course of the disease, therapy of ovarian cancers results in a have been performed on the potential prognostic significance of the estimation of CD46 expression in ovarian cancers. Thus, the aim of the present study was to evaluate the prognostic value of the immunohistochemical estimation Correspondence to: PD Dr. Hermann Lage, Charité Campus Mitte, of CD46 expression, in a group of ovarian cancer samples. Institute of Pathology, Charitéplatz 1, D-10117 Berlin, Germany. Tel: +49-30-450 536 045, Fax: +49-30-450 536 900, e-mail: Materials and Methods [email protected] Patients and specimens. Immunohistochemical examination was Key Words: Ovarian carcinoma, CD46, prognosis, immuno- performed retrospectively on tissue samples taken for routine histochemistry. diagnostic purposes. Forty three patients operated in 1999-2002 0250-7005/2006 $2.00+.40 4943 ANTICANCER RESEARCH 26: 4943-4948 (2006) on account of ovarian carcinoma at the Department of Table I. Patient and tumor characteristics. Gynaecology and Obstetrics, University Medical School in Poznan, Poland, were qualified for the studies. The cases were Characteristics No. (%)3 selected based on the availability of tissue and were not stratified for known pre-operative or pathological prognostic factors. The All patients study was approved by an Institutional Review Board (IRB) and 43 (100) 1 the patients gave their informed consent, before their inclusion Age (mean 51.0) in the study. Following the primary laparotomy (PL), all the ≤50 20 (47) 50-60 16 (37) patients were subjected to chemotherapy, using platinum-based >60 7 (16) schemes (Table I). Thirty-six patients from the same group were Grade1 subjected also to the secondary cytoreduction (SCR). In 7 cases, 1 7 (16) no secondary cytoreduction was performed due to advancement 2 18 (42) of the disease. In 6 cases, no tumor cells were detected in the 3 18 (42) material originating from the SCR. The patients were monitored FIGO1 via periodic medical check-ups, serum CA-125 levels, I 1 (2) ultrasonographic and radiological examinations. During the II 1 (2) follow-up period, 22 patients (51%) had recurrent disease and III 41 (95) 13 patients (30%) died of the disease. The mean revival-free Histology1 survival time was 16.9 months (range 0 to 52 months), while the Serous 37 (86) mean overall-disease-free survival time was 24.6 months (range 6 Endometrioid 3 (7) to 52 months). Other 3 (7) Samples from studied tumors were fixed in 10% buffered Clinical response2 formalin and then embedded in paraffin. In each case, hematoxylin Complete response 16 (37) and eosin stained preparations were subjected to histopathological Stable disease 5 (12) evaluation by two pathologists. The stage of the tumors was Progressive disease 22 (51) assessed according to the International Federation of Gynaecology Chemotherapy (in total) and Obstetrics (9). Tumors were graded according to the Silverberg Cisplatin/Paclitaxel 31 (72) grading system (10). Cisplatin/Cyclophosphamide/Adriblastin 6 (14) Cisplatin/Cyclophosphamide/Paclitaxel 3 (7) Cisplatin/Cyclophosphamide/Paclitaxel/Adriblastin 2 (5) Immunohistochemistry. Formalin-fixed, paraffin-embedded tissue Carboplatin/Paclitaxel 1 (2) was freshly cut (4 Ìm). The sections were mounted on Superfrost slides (Menzel Gläser, Germany), dewaxed with xylene and 1Data are given for the first operation/diagnosis implemented. gradually rehydrated. Activity of endogenous peroxidase was 2According to RECIST (Response Evaluation Criteria in Solid blocked by 30 min incubation in 1% H2O2. The sections were Tumours) (13). boiled for 15 min in a microwave oven in Antigen Retrieval 3Differences in the sum in groups are due to rounding up. Solution (DakoCytomation, Denmark) at 250W. This was followed by immunohistochemical reactions using the monoclonal mouse antibodies (clone 169-1-E4.3) against CD46 (Ancell Corporation, MN, USA). The antibodies were diluted 1:400 in the Antibody Control reactions. The control reactions included: (A) six samples Diluent, Background Reducing (DakoCytomation, Denmark). The of healthy human ovaries (from the archive of the Chair and sections were incubated with the antibody for one hour at room Department of Histology and Embryology, University School of temperature. Subsequently, they were incubated with biotinylated Medicine, Wroclaw, Poland) and (B) three smears of human blood, antibodies (15 min, room temperature) and with the streptavidin- fixed in a 1:1 mixture of acetone and methanol at –20ÆC (procedure biotinylated peroxidase complex (15 min, room temperature) such as that in the case of paraffin sections, but omitting xylene, (LSAB+, HRP, DakoCytomation, Denmark). NovaRed (Vector series of alcohols and boiling in the Target Retrieval Solution). Laboratories, UK) was used as a chromogen, employing 10 min incubation at room temperature. All the sections were Statistics. Statistical analysis of the results was performed in two stages. counterstained using Meyer’s hematoxylin. Each reaction was In the first stage, using the Statistica 98 PL (Statsoft, Poland) software, accompanied by the negative control, in which the specific relationships were examined between the expression of studied antibody was substituted by the Primary Mouse Negative Control antigen and clinical/pathological variables of studied cases (¯2 test), (DakoCytomation, Denmark). and, in the second stage, employing the Mann-Whitney U-test, CD46 was examined in the material originating from PL and SCR. Kaplan- Scoring of immunostaining results. Intensity of immunohistochemical Meier statistics and log-rank tests were performed using SPSS reactions was estimated independently, by two pathologists. In cases software (release 10.0; SPSS Inc., Chicago, IL, USA) to estimate the of controversy, a re-evaluation was performed with the use of a significance of differences in survival times. The length of revival-free double-headed microscope. The case was diagnosed as positive [1] survival was defined as the time from the primary surgical treatment, when the expression was observed in all tumor cells or in numerous until the
Load more

Recommended publications
  • (CD147) Is Induced by C/Ebpβ and Is Differentially Expressed in ALK+
    Laboratory Investigation (2017) 97, 1095–1102 © 2017 USCAP, Inc All rights reserved 0023-6837/17 EMMPRIN (CD147) is induced by C/EBPβ and is differentially expressed in ALK+ and ALK − anaplastic large-cell lymphoma Janine Schmidt1, Irina Bonzheim1, Julia Steinhilber1, Ivonne A Montes-Mojarro1, Carlos Ortiz-Hidalgo2, Wolfram Klapper3, Falko Fend1 and Leticia Quintanilla-Martínez1 Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is characterized by expression of oncogenic ALK fusion proteins due to the translocation t(2;5)(p23;q35) or variants. Although genotypically a T-cell lymphoma, ALK+ ALCL cells frequently show loss of T-cell-specific surface antigens and expression of monocytic markers. C/EBPβ, a transcription factor constitutively overexpressed in ALK+ ALCL cells, has been shown to play an important role in the activation and differentiation of macrophages and is furthermore capable of transdifferentiating B-cell and T-cell progenitors to macrophages in vitro. To analyze the role of C/EBPβ for the unusual phenotype of ALK+ ALCL cells, C/EBPβ was knocked down by RNA interference in two ALK+ ALCL cell lines, and surface antigen expression profiles of these cell lines were generated using a Human Cell Surface Marker Screening Panel (BD Biosciences). Interesting candidate antigens were further analyzed by immunohistochemistry in primary ALCL ALK+ and ALK − cases. Antigen expression profiling revealed marked changes in the expression of the activation markers CD25, CD30, CD98, CD147, and CD227 after C/EBPβ knockdown. Immunohistochemical analysis confirmed a strong, membranous CD147 (EMMPRIN) expression in ALK+ ALCL cases. In contrast, ALK − ALCL cases showed a weaker CD147 expression.
    [Show full text]
  • Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse
    Welcome to More Choice CD Marker Handbook For more information, please visit: Human bdbiosciences.com/eu/go/humancdmarkers Mouse bdbiosciences.com/eu/go/mousecdmarkers Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse CD3 CD3 CD (cluster of differentiation) molecules are cell surface markers T Cell CD4 CD4 useful for the identification and characterization of leukocytes. The CD CD8 CD8 nomenclature was developed and is maintained through the HLDA (Human Leukocyte Differentiation Antigens) workshop started in 1982. CD45R/B220 CD19 CD19 The goal is to provide standardization of monoclonal antibodies to B Cell CD20 CD22 (B cell activation marker) human antigens across laboratories. To characterize or “workshop” the antibodies, multiple laboratories carry out blind analyses of antibodies. These results independently validate antibody specificity. CD11c CD11c Dendritic Cell CD123 CD123 While the CD nomenclature has been developed for use with human antigens, it is applied to corresponding mouse antigens as well as antigens from other species. However, the mouse and other species NK Cell CD56 CD335 (NKp46) antibodies are not tested by HLDA. Human CD markers were reviewed by the HLDA. New CD markers Stem Cell/ CD34 CD34 were established at the HLDA9 meeting held in Barcelona in 2010. For Precursor hematopoetic stem cell only hematopoetic stem cell only additional information and CD markers please visit www.hcdm.org. Macrophage/ CD14 CD11b/ Mac-1 Monocyte CD33 Ly-71 (F4/80) CD66b Granulocyte CD66b Gr-1/Ly6G Ly6C CD41 CD41 CD61 (Integrin b3) CD61 Platelet CD9 CD62 CD62P (activated platelets) CD235a CD235a Erythrocyte Ter-119 CD146 MECA-32 CD106 CD146 Endothelial Cell CD31 CD62E (activated endothelial cells) Epithelial Cell CD236 CD326 (EPCAM1) For Research Use Only.
    [Show full text]
  • B-Cell Receptor Pathway Inhibitors Affect CD20 Levels and Impair Antitumor Activity of Anti-CD20 Monoclonal Antibodies
    Letters to the Editor 1163 13 Kuruvilla J, Gutierrez M, Shah BD, Gabrail NY, de Nully Brown P, 14 Yu L, Mohamed AJ, Simonson OE, Vargas L, Blomberg KE, Bjorkstrand B et al. Stone RM et al. Preliminary evidence of anti tumor activity of selinexor Proteasome-dependent autoregulation of Bruton tyrosine kinase (Btk) promoter (KPT-330) in a phase I trial of a first-in-class oral selective inhibitor via NF-kappaB. Blood 2008; 111: 4617–4626. of nuclear export (SINE) in patients (pts) with relapsed/refractory non 15BurgerJA,BurgerM,KippsTJ.Chronic lymphocytic leukemia B cells Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Blood 2013; express functional CXCR4 chemokine receptors that mediate spontaneous 122: 90. migration beneath bone marrow stromal cells. Blood 1999; 94: 3658–3667. Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu) B-cell receptor pathway inhibitors affect CD20 levels and impair antitumor activity of anti-CD20 monoclonal antibodies Leukemia (2014) 28, 1163–1167; doi:10.1038/leu.2014.12 also tested a primary MCL sample and upon treatment with BCR inhibitors observed a significant downregulation of surface CD20 levels and a trend towards impaired R-CDC and O-CDC (Supplementary Figure 1b). Moreover, we determined the Signaling via the aberrantly activated B-cell receptor (BCR) has a influence of BCR inhibitors on CD20 surface levels in a critical role in the pathogenesis of B-cell tumors by promoting series of 15 tumor cell lines, including Burkitt’s lymphoma (Ramos, survival and clonal expansion of malignant B cells.1,2 Multiple Daudi and BJAB), ALL (NALM-6), diffuse large B-cell lymphoma preclinical studies indicate that blocking various components of (BCR-dependent Ly-1, Ly-7, Ly-10, DHL-6, HBL-1, U2932 and the BCR signaling pathway holds a great therapeutic potential in BCR-independent Ly-4, Ly-19, Pfeiffer) and CLL (EHEB and MEC-1).
    [Show full text]
  • Single-Cell RNA Sequencing Demonstrates the Molecular and Cellular Reprogramming of Metastatic Lung Adenocarcinoma
    ARTICLE https://doi.org/10.1038/s41467-020-16164-1 OPEN Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma Nayoung Kim 1,2,3,13, Hong Kwan Kim4,13, Kyungjong Lee 5,13, Yourae Hong 1,6, Jong Ho Cho4, Jung Won Choi7, Jung-Il Lee7, Yeon-Lim Suh8,BoMiKu9, Hye Hyeon Eum 1,2,3, Soyean Choi 1, Yoon-La Choi6,10,11, Je-Gun Joung1, Woong-Yang Park 1,2,6, Hyun Ae Jung12, Jong-Mu Sun12, Se-Hoon Lee12, ✉ ✉ Jin Seok Ahn12, Keunchil Park12, Myung-Ju Ahn 12 & Hae-Ock Lee 1,2,3,6 1234567890():,; Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell tran- scriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions. 1 Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea.
    [Show full text]
  • Flow Reagents Single Color Antibodies CD Chart
    CD CHART CD N° Alternative Name CD N° Alternative Name CD N° Alternative Name Beckman Coulter Clone Beckman Coulter Clone Beckman Coulter Clone T Cells B Cells Granulocytes NK Cells Macrophages/Monocytes Platelets Erythrocytes Stem Cells Dendritic Cells Endothelial Cells Epithelial Cells T Cells B Cells Granulocytes NK Cells Macrophages/Monocytes Platelets Erythrocytes Stem Cells Dendritic Cells Endothelial Cells Epithelial Cells T Cells B Cells Granulocytes NK Cells Macrophages/Monocytes Platelets Erythrocytes Stem Cells Dendritic Cells Endothelial Cells Epithelial Cells CD1a T6, R4, HTA1 Act p n n p n n S l CD99 MIC2 gene product, E2 p p p CD223 LAG-3 (Lymphocyte activation gene 3) Act n Act p n CD1b R1 Act p n n p n n S CD99R restricted CD99 p p CD224 GGT (γ-glutamyl transferase) p p p p p p CD1c R7, M241 Act S n n p n n S l CD100 SEMA4D (semaphorin 4D) p Low p p p n n CD225 Leu13, interferon induced transmembrane protein 1 (IFITM1). p p p p p CD1d R3 Act S n n Low n n S Intest CD101 V7, P126 Act n p n p n n p CD226 DNAM-1, PTA-1 Act n Act Act Act n p n CD1e R2 n n n n S CD102 ICAM-2 (intercellular adhesion molecule-2) p p n p Folli p CD227 MUC1, mucin 1, episialin, PUM, PEM, EMA, DF3, H23 Act p CD2 T11; Tp50; sheep red blood cell (SRBC) receptor; LFA-2 p S n p n n l CD103 HML-1 (human mucosal lymphocytes antigen 1), integrin aE chain S n n n n n n n l CD228 Melanotransferrin (MT), p97 p p CD3 T3, CD3 complex p n n n n n n n n n l CD104 integrin b4 chain; TSP-1180 n n n n n n n p p CD229 Ly9, T-lymphocyte surface antigen p p n p n
    [Show full text]
  • CD Markers Are Routinely Used for the Immunophenotyping of Cells
    ptglab.com 1 CD MARKER ANTIBODIES www.ptglab.com Introduction The cluster of differentiation (abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules. So-called CD markers are routinely used for the immunophenotyping of cells. Despite this use, they are not limited to roles in the immune system and perform a variety of roles in cell differentiation, adhesion, migration, blood clotting, gamete fertilization, amino acid transport and apoptosis, among many others. As such, Proteintech’s mini catalog featuring its antibodies targeting CD markers is applicable to a wide range of research disciplines. PRODUCT FOCUS PECAM1 Platelet endothelial cell adhesion of blood vessels – making up a large portion molecule-1 (PECAM1), also known as cluster of its intracellular junctions. PECAM-1 is also CD Number of differentiation 31 (CD31), is a member of present on the surface of hematopoietic the immunoglobulin gene superfamily of cell cells and immune cells including platelets, CD31 adhesion molecules. It is highly expressed monocytes, neutrophils, natural killer cells, on the surface of the endothelium – the thin megakaryocytes and some types of T-cell. Catalog Number layer of endothelial cells lining the interior 11256-1-AP Type Rabbit Polyclonal Applications ELISA, FC, IF, IHC, IP, WB 16 Publications Immunohistochemical of paraffin-embedded Figure 1: Immunofluorescence staining human hepatocirrhosis using PECAM1, CD31 of PECAM1 (11256-1-AP), Alexa 488 goat antibody (11265-1-AP) at a dilution of 1:50 anti-rabbit (green), and smooth muscle KD/KO Validated (40x objective). alpha-actin (red), courtesy of Nicola Smart. PECAM1: Customer Testimonial Nicola Smart, a cardiovascular researcher “As you can see [the immunostaining] is and a group leader at the University of extremely clean and specific [and] displays Oxford, has said of the PECAM1 antibody strong intercellular junction expression, (11265-1-AP) that it “worked beautifully as expected for a cell adhesion molecule.” on every occasion I’ve tried it.” Proteintech thanks Dr.
    [Show full text]
  • Multiomics of Azacitidine-Treated AML Cells Reveals Variable And
    Multiomics of azacitidine-treated AML cells reveals variable and convergent targets that remodel the cell-surface proteome Kevin K. Leunga, Aaron Nguyenb, Tao Shic, Lin Tangc, Xiaochun Nid, Laure Escoubetc, Kyle J. MacBethb, Jorge DiMartinob, and James A. Wellsa,1 aDepartment of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143; bEpigenetics Thematic Center of Excellence, Celgene Corporation, San Francisco, CA 94158; cDepartment of Informatics and Predictive Sciences, Celgene Corporation, San Diego, CA 92121; and dDepartment of Informatics and Predictive Sciences, Celgene Corporation, Cambridge, MA 02140 Contributed by James A. Wells, November 19, 2018 (sent for review August 23, 2018; reviewed by Rebekah Gundry, Neil L. Kelleher, and Bernd Wollscheid) Myelodysplastic syndromes (MDS) and acute myeloid leukemia of DNA methyltransferases, leading to loss of methylation in (AML) are diseases of abnormal hematopoietic differentiation newly synthesized DNA (10, 11). It was recently shown that AZA with aberrant epigenetic alterations. Azacitidine (AZA) is a DNA treatment of cervical (12, 13) and colorectal (14) cancer cells methyltransferase inhibitor widely used to treat MDS and AML, can induce interferon responses through reactivation of endoge- yet the impact of AZA on the cell-surface proteome has not been nous retroviruses. This phenomenon, termed viral mimicry, is defined. To identify potential therapeutic targets for use in com- thought to induce antitumor effects by activating and engaging bination with AZA in AML patients, we investigated the effects the immune system. of AZA treatment on four AML cell lines representing different Although AZA treatment has demonstrated clinical benefit in stages of differentiation. The effect of AZA treatment on these AML patients, additional therapeutic options are needed (8, 9).
    [Show full text]
  • Adenovirus Species B Interactions with CD46
    Adenovirus Species B interactions with CD46 Dan Gustafsson Institution of Clinical Microbiology, Department of Virology Umeå 2012 Responsible publisher under swedish law: the Dean of the Medical Faculty This work is protected by the Swedish Copyright Legislation (Act 1960:729) ISBN: 978-91-7459-368-6 ISSN: 0346-6612 Elektronisk version tillgänglig på http://umu.diva-portal.org/ Tryck/Printed by: Print&Media Umeå, Sweden 2012 To my family! Table of Contents Table of contents ……………………………………………………...……… i Abstract ……………………………………………………………………...…. iii Abbreviations …………………………………………………………………. iv Summary in Swedish, Populärvetenskaplig sammanfattning på svenska ……………………………………………………………………… vi List of papers …………………………………………………………………………… 1 Aim of thesis ………………………………………........................................... 2 Introduction ……………………………………………………........................ 3 History…………………………………………………………………………….. 3 Taxonomy…………………………………………………………………………. 3 Epidemiology and clinical features……………………………………………….. 5 Adenoviruses Structure ……………………………………………………. 6 General structure………………………………………………………………….. 6 The capsid………………………………………………………………………… 8 Major Proteins…………………………………………………………………….. 9 Hexon………………………………………………………………………………9 The Penton Base………………………………………………………………….. 10 The Fiber………………………………………………………………………….. 11 Minor Proteins…………………………………………………………………….. 14 Capsid proteins……………………………………………………………………. 14 Protein IIIa………………………………………………………………………… 14 Protein VI…………………………………………………………………………. 14 Protein VIII……………………………………………………………………….. 15 Protein IX………………………………………………………………………….
    [Show full text]
  • Complement Receptor CD46 Co-Stimulates Optimal Human CD8 T
    ARTICLE DOI: 10.1038/s41467-018-06706-z OPEN Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism Giuseppina Arbore1,2, Erin E. West3, Jubayer Rahman3, Gaelle Le Friec2, Nathalie Niyonzima3,4, Mehdi Pirooznia 3, Ilker Tunc3, Polychronis Pavlidis2, Nicholas Powell2, Yuesheng Li3, Poching Liu3, Aude Servais5, Lionel Couzi6, Veronique Fremeaux-Bacchi7, Leo Placais3, Alastair Ferraro8, Patrick R. Walsh9, David Kavanagh9, Behdad Afzali 3,10, Paul Lavender2, Helen J. Lachmann11 & Claudia Kemper2,3,12 1234567890():,; The induction of human CD4+ Th1 cells requires autocrine stimulation of the complement receptor CD46 in direct crosstalk with a CD4+ T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether human cytotoxic CD8+ T cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients with CD46 deficiency or with constitutively-active NLRP3, that CD46 delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis. Sur- prisingly, although CTLs express NLRP3, a canonical NLRP3 inflammasome is not required for normal human CTL activity, as CTLs from patients with hyperactive NLRP3 activity function normally. These findings establish autocrine complement and CD46 activity as integral components of normal human CTL biology, and, since CD46 is only present in humans, emphasize the divergent roles of innate immune sensors between mice and men. 1 Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy. 2 School of Immunology and Microbial Sciences, King’s College London, London, UK. 3 Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA.
    [Show full text]
  • Targeting Oncogenic Ras by the Clostridium Perfringens Toxin Tpel
    www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 23), pp: 16489-16500 Research Paper Targeting oncogenic Ras by the Clostridium perfringens toxin TpeL Björn Schorch1, Hannah Heni1, Nour-Imene Zahaf1, Tilman Brummer2,3,4, Marina Mione5,6, Gudula Schmidt1, Panagiotis Papatheodorou1,7,8 and Klaus Aktories1,4 1Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany 2Institut für Molekulare Medizin und Zellforschung, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany 3German Cancer Consortium (DKTK), Partner Site Freiburg, Germany, and German Cancer Research Center (DKFZ), Heidelberg, Germany 4Centre for Biological Signalling Studies (BIOSS), Albert-Ludwigs-Universität Freiburg, Freiburg, Germany 5Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggestein-Leopoldshafen, Germany 6Present Address: Center for Integrative Biology, University of Trento, Trento, Italy 7Present Address: Institute of Pharmaceutical Biotechnology, University of Ulm, Ulm, Germany 8Present Address: Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Ulm, Germany Correspondence to: Klaus Aktories, email: [email protected] Keywords: Clostridium perfringens toxin; glycosylation; immunotoxins; paradoxical activation; Ras Received: April 04, 2017 Accepted: March 02, 2018 Published: March 27, 2018 Copyright: Schorch et al. This is an open-access article distributed under the terms of
    [Show full text]
  • Early Complement Activation and Decreased Levels Of
    Early Complement Activation and Decreased Levels of Glycosylphosphatidylinositol-Anchored Complement Inhibitors in Human and Experimental Diabetic Retinopathy Jing Zhang, Chiara Gerhardinger, and Mara Lorenzi Diabetic retinal microangiopathy is characterized by operative in causing retinal vascular damage in diabetes increased permeability, leukostasis, microthrombosis, and how they are triggered are the objects of ongoing and apoptosis of capillary cells, all of which could be investigation. caused or compounded by activation of complement. In Activation of the complement cascade can both com- this study, we observed deposition of C5b-9, the termi- pound and initiate thrombosis, leukostasis, and apoptosis. nal product of complement activation, in the wall of On the one hand, microthrombi and leukostasis can cause ؎ retinal vessels of human eye donors with 9 3 years of ischemia-reperfusion, which activates complement via the type 2 diabetes, but not in the vessels of age-matched nondiabetic donors. C5b-9 often colocalized with von classical pathway (4), and apoptotic endothelial cells can Willebrand factor in luminal endothelium. C1q and C4, trigger the alternative pathway (5). On the other hand, the complement components unique to the classical complement activation is procoagulant, proinflammatory, pathway, were not detected in the diabetic retinas, and proapoptotic (6), and primary activation of comple- suggesting that C5b-9 was generated via the alternative ment on autologous cells can occur because of insufficient pathway, the spontaneous activation of which is regu- activity of plasma and/or cell surface inhibitors. Sponta- lated by complement inhibitors. The diabetic donors neous cleavage of plasma C3 generates C3b, which at- showed a prominent reduction in the retinal levels of taches covalently to the endothelial cell surface through CD55 and CD59, the two complement inhibitors linked to the plasma membrane by glycosylphosphatidylinosi- its reactive thioester group (5).
    [Show full text]
  • Identification of Cell-Surface Proteins Endocytosed by Human Brain
    pharmaceutics Article Identification of Cell-Surface Proteins Endocytosed by Human Brain Microvascular Endothelial Cells In Vitro Shingo Ito 1,2,3, Mariko Oishi 2, Seiryo Ogata 3, Tatsuki Uemura 3, Pierre-Olivier Couraud 4, Takeshi Masuda 1,2,3 and Sumio Ohtsuki 1,2,3,* 1 Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; [email protected] (S.I.); [email protected] (T.M.) 2 Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; [email protected] 3 Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; [email protected] (S.O.); [email protected] (T.U.) 4 Institut Cochin, Universite de Paris, Inserm U1016, CNRS UMR8104, 22 rue Méchain, 75014 Paris, France; [email protected] * Correspondence: [email protected]; Tel.: +81-96-371-4323 Received: 30 April 2020; Accepted: 18 June 2020; Published: 23 June 2020 Abstract: Cell-surface proteins that can endocytose into brain microvascular endothelial cells serve as promising candidates for receptor-mediated transcytosis across the blood–brain barrier (BBB). Here, we comprehensively screened endocytic cell-surface proteins in hCMEC/D3 cells, a model of human brain microvascular endothelial cells, using surface biotinylation methodology and sequential window acquisition of all theoretical fragment-ion spectra-mass spectrometry (SWATH-MS)-based quantitative proteomics. Using this method, we identified 125 endocytic cell-surface proteins from hCMEC/D3 cells.
    [Show full text]