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Secretion of N-ERC/Mesothelin and Expression of C-ERC/Mesothelin in Human Pancreatic Ductal Carcinoma
1375-1380 10/11/08 14:44 Page 1375 ONCOLOGY REPORTS 20: 1375-1380, 2008 Secretion of N-ERC/mesothelin and expression of C-ERC/mesothelin in human pancreatic ductal carcinoma KOICHI INAMI1,2, KAZUNORI KAJINO1, MASAAKI ABE1, YOSHIAKI HAGIWARA1,3, MASAHIRO MAEDA3, MASAFUMI SUYAMA2, SUMIO WATANABE2 and OKIO HINO1 Departments of 1Pathology and Oncology and 2Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421; 3Immuno-Biological Laboratories, 5-1 Aramachi, Takasaki-shi, Gunma 370-0831, Japan Received July 28, 2008; Accepted September 12, 2008 DOI: 10.3892/or_00000155 Abstract. ERC/mesothelin gene (MSLN) encodes a Introduction precursor protein, which is cleaved by proteases to generate N-ERC/mesothelin and C-ERC/mesothelin. N-ERC/ ERC/mesothelin gene (MSLN) encodes a 71 kDa precursor mesothelin is a soluble protein, also known as megakaryocyte- protein, which is cleaved by proteases to yield 31 kDa N- potentiating factor, which is released into extracellular terminal (N-ERC/mesothelin) and 40 kDa C-terminal (C-ERC/ space. N-ERC/mesothelin is known to be a serum marker of mesothelin) proteins (1,2). N-ERC/mesothelin, originally mesothelioma. We have previously developed an enzyme- identified as megakaryocyte-potentiating factor (MPF), is linked immunosorbent assay system for N-ERC/mesothelin, soluble and released into extracellular space (1-9). C-ERC/ which can detect mesothelioma. C-ERC/mesothelin is mesothelin is a glycoprotein tethered to the cell surface by expressed in normal mesothelial cell, pancreatic cancers, glycosyl-phosphatidyl-inositol (GPI) anchor. Some forms ovarian cancers, mesotheliomas and some other cancers. of C-ERC/mesothelin are released into extra-cellular space Pancreatic ductal carcinoma remains a fatal disease because by aberrant splicing or proteases (1,2,10-13). -
Value of Mesothelin Immunostaining in the Diagnosis of Mesothelioma Nelson G
Value of Mesothelin Immunostaining in the Diagnosis of Mesothelioma Nelson G. Ordóñez, M.D. University of Texas M.D. Anderson Cancer Center, Houston, Texas tained with the standard panel of immunohisto- Mesothelin is a cell surface antigen of unknown chemical markers used for the diagnosis of me- function that is strongly expressed in mesothelial sotheliomas are equivocal. Because mesothelin is a cells. Although it was reported in 1992 that immu- highly sensitive positive marker for epithelioid me- nostaining with the K1 anti-mesothelin antibody sotheliomas, a negative staining for this marker is could be very useful in distinguishing between epi- an indication against such a diagnosis; however, thelioid mesotheliomas and pulmonary adenocar- because of its limited utility, it is not recommended cinomas, no further studies have been published on for inclusion in the standard panel of immunohis- the value of this marker in the diagnosis of me- tochemical markers used in the distinction between sotheliomas. To determine whether mesothelin can mesotheliomas and adenocarcinomas. assist in discriminating epithelioid mesotheliomas from lung adenocarcinomas or from other carcino- KEY WORDS: Adenocarcinoma, Immunohisto- mas metastatic to the serosal membranes, 55 me- chemistry, Mesothelin, Mesothelioma. sotheliomas (44 epithelioid, 3 biphasic, and 8 sar- Mod Pathol 2003;16(3):192–197 comatoid), 48 carcinomas of the lung (31 adenocarcinomas, 17 squamous carcinomas), and A well-known problem in surgical pathology is the 86 nonpulmonary adenocarcinomas (14 ovary, 5 distinction of pleural mesothelioma from periph- peritoneum, 9 endometrium, 11 pancreas, 4 stom- eral pulmonary adenocarcinoma involving the ach, 16 colon, 12 breast, 9 kidney, 4 thyroid, and 2 pleura or from a metastatic adenocarcinoma origi- prostate) were investigated for mesothelin expres- nating from a distant organ and presenting as a sion using the recently available 5B2 anti- tumor of unknown origin. -
Mesothelin's Role As a Biomarker and Therapeutic Target for Malignant
cancers Review Hitting the Bull’s-Eye: Mesothelin’s Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma Dannel Yeo 1,2,3 , Laura Castelletti 1,2,3 , Nico van Zandwijk 2,3,4 and John E. J. Rasko 1,2,3,5,* 1 Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW 2050, Australia; [email protected] (D.Y.); [email protected] (L.C.) 2 Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia; [email protected] 3 Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, NSW 2050, Australia 4 Concord Repatriation General Hospital, Sydney Local Health District (SLHD), Concord, NSW 2139, Australia 5 Gene and Stem Cell Therapy Program, Centenary Institute, The University of Sydney, Camperdown, NSW 2050, Australia * Correspondence: [email protected]; Tel.: +61-295656160 Simple Summary: Mesothelioma is a deadly disease with a dismal prognosis. Since its discovery, mesothelin, a cell surface protein, has been a promising biomarker and therapeutic target due to its overexpression in mesothelioma and limited expression in normal cells. This review summarizes the clinical studies that have examined mesothelin as a biomarker and therapeutic target in mesothelioma and explores future perspectives in its role to improve patient management. Abstract: Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin Citation: Yeo, D.; Castelletti, L.; van (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. -
Análise Integrativa De Perfis Transcricionais De Pacientes Com
UNIVERSIDADE DE SÃO PAULO FACULDADE DE MEDICINA DE RIBEIRÃO PRETO PROGRAMA DE PÓS-GRADUAÇÃO EM GENÉTICA ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Ribeirão Preto – 2012 ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Tese apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo para obtenção do título de Doutor em Ciências. Área de Concentração: Genética Orientador: Prof. Dr. Eduardo Antonio Donadi Co-orientador: Prof. Dr. Geraldo A. S. Passos Ribeirão Preto – 2012 AUTORIZO A REPRODUÇÃO E DIVULGAÇÃO TOTAL OU PARCIAL DESTE TRABALHO, POR QUALQUER MEIO CONVENCIONAL OU ELETRÔNICO, PARA FINS DE ESTUDO E PESQUISA, DESDE QUE CITADA A FONTE. FICHA CATALOGRÁFICA Evangelista, Adriane Feijó Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas. Ribeirão Preto, 2012 192p. Tese de Doutorado apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo. Área de Concentração: Genética. Orientador: Donadi, Eduardo Antonio Co-orientador: Passos, Geraldo A. 1. Expressão gênica – microarrays 2. Análise bioinformática por module maps 3. Diabetes mellitus tipo 1 4. Diabetes mellitus tipo 2 5. Diabetes mellitus gestacional FOLHA DE APROVAÇÃO ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas. -
Dynamic Repression by BCL6 Controls the Genome-Wide Liver Response To
RESEARCH ARTICLE Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis Meredith A Sommars1, Krithika Ramachandran1, Madhavi D Senagolage1, Christopher R Futtner1, Derrik M Germain1, Amanda L Allred1, Yasuhiro Omura1, Ilya R Bederman2, Grant D Barish1,3,4* 1Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States; 2Department of Pediatrics, Case Western Reserve University, Cleveland, United States; 3Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, United States; 4Jesse Brown VA Medical Center, Chicago, United States Abstract Transcription is tightly regulated to maintain energy homeostasis during periods of feeding or fasting, but the molecular factors that control these alternating gene programs are incompletely understood. Here, we find that the B cell lymphoma 6 (BCL6) repressor is enriched in the fed state and converges genome-wide with PPARa to potently suppress the induction of fasting transcription. Deletion of hepatocyte Bcl6 enhances lipid catabolism and ameliorates high- fat-diet-induced steatosis. In Ppara-null mice, hepatocyte Bcl6 ablation restores enhancer activity at PPARa-dependent genes and overcomes defective fasting-induced fatty acid oxidation and lipid accumulation. Together, these findings identify BCL6 as a negative regulator of oxidative metabolism and reveal that alternating recruitment of repressive and activating transcription factors to -
HEG1 Is a Novel Mucin-Like Membrane Protein That Serves As a Diagnostic and Therapeutic Target for Malignant Mesothelioma
www.nature.com/scientificreports OPEN HEG1 is a novel mucin-like membrane protein that serves as a diagnostic and therapeutic target Received: 28 October 2016 Accepted: 02 March 2017 for malignant mesothelioma Published: 31 March 2017 Shoutaro Tsuji1,*,, Kota Washimi1,2,*, Taihei Kageyama1, Makiko Yamashita1, Mitsuyo Yoshihara1, Rieko Matsuura1, Tomoyuki Yokose2, Yoichi Kameda3, Hiroyuki Hayashi4, Takao Morohoshi5, Yukio Tsuura6, Toshikazu Yusa7, Takashi Sato8, Akira Togayachi8, Hisashi Narimatsu8, Toshinori Nagasaki1,9, Kotaro Nakamoto1,9, Yasuhiro Moriwaki9, Hidemi Misawa9, Kenzo Hiroshima10, Yohei Miyagi1 & Kohzoh Imai1,11 The absence of highly specific markers for malignant mesothelioma (MM) has served an obstacle for its diagnosis and development of molecular-targeting therapy against MM. Here, we show that a novel mucin-like membrane protein, sialylated protein HEG homolog 1 (HEG1), is a highly specific marker for MM. A monoclonal antibody against sialylated HEG1, SKM9-2, can detect even sarcomatoid and desmoplastic MM. The specificity and sensitivity of SKM9-2 to MM reached 99% and 92%, respectively; this antibody did not react with normal tissues. This accurate discrimination by SKM9-2 was due to the recognition of a sialylated O-linked glycan with HEG1 peptide. We also found that gene silencing of HEG1 significantly suppressed the survival and proliferation of mesothelioma cells; this result suggests that HEG1 may be a worthwhile target for function-inhibition drugs. Taken together, our results indicate that sialylated HEG1 may be useful as a diagnostic and therapeutic target for MM. Malignant mesothelioma (MM) is a fatal tumor caused by past exposure to asbestos1. MM victims number ~3,000, 5,000, and 1,300 per year in the United States, Western Europe, and Japan, respectively1,2. -
Mesothelin Domain-Specific Monoclonal Antibodies and Use Thereof
(19) TZZ¥¥ Z¥_T (11) EP 3 327 037 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 30.05.2018 Bulletin 2018/22 C07K 16/30 (2006.01) A61K 39/395 (2006.01) C12N 5/0783 (2010.01) (21) Application number: 17210140.4 (22) Date of filing: 16.08.2013 (84) Designated Contracting States: • HO, Mitchell AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Urbana, MD 21704 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • PASTAN, Ira, H. PL PT RO RS SE SI SK SM TR Potomac, MD 20854 (US) • PHUNG, Yen, T. (30) Priority: 21.08.2012 US 201261691719 P Annandale, VA 22003 (US) • ZHANG, Yifan (62) Document number(s) of the earlier application(s) in Haymarket, VA 20169 (US) accordance with Art. 76 EPC: 13753475.6 / 2 888 282 (74) Representative: Gowshall, Jonathan Vallance Forresters IP LLP (71) Applicant: The U.S.A. as represented by the Skygarden Secretary, Erika-Mann-Strasse 11 Department of Health and Human Services 80636 München (DE) Bethesda, MD 20892-7660 (US) Remarks: (72) Inventors: This application was filed on 22.12.2017 as a •GAO,Wei divisional application to the application mentioned Rockville, MD 20852 (US) under INID code 62. • HASSAN, Raffit Gaithersburg, MD 20878 (US) (54) MESOTHELIN DOMAIN-SPECIFIC MONOCLONAL ANTIBODIES AND USE THEREOF (57) Described herein is the use of rabbit hybridoma of mesothelin with subnanomolar affinity. These antibod- technology, along with a panel of truncated mesothelin ies do not compete for binding with the mesothelin-spe- domain fragments, to identify anti-mesothelin mAbs that cific immunotoxin SS1P or mesothelin-specific antibody bind specific regions of mesothelin. -
Significance of Mesothelin and CA125 Expression in Endometrial Carcinoma
Kakimoto et al. Diagnostic Pathology (2021) 16:28 https://doi.org/10.1186/s13000-021-01093-4 RESEARCH Open Access Significance of mesothelin and CA125 expression in endometrial carcinoma: a retrospective analysis Soichiro Kakimoto1, Morikazu Miyamoto1* , Takahiro Einama2, Yasuhiro Takihata2, Hiroko Matsuura1, Hideki Iwahashi1, Hiroki Ishibashi1, Takahiro Sakamoto1, Taira Hada1, Jin Suminokura1, Tsubasa Ito1, Rie Suzuki1, Ayako Suzuki1,3 and Masashi Takano1 Abstract Background: This study aimed to investigate the association between clinicopathologic factors, mesothelin, and cancer antigen (CA) 125 in endometrial carcinoma. Methods: Between 1989 and 2017, patients with endometrial carcinoma who underwent total hysterectomy and bilateral salpingo-oophorectomy at our hospital were identified. The association between either or both immunochemical expression of mesothelin and CA125 and clinicopathological features were retrospectively examined. Results: Among 485 patients, 171 were positive for mesothelin, 368 were positive for CA125, and 167 were positive for mesothelin and CA125. The expression of mesothelin and CA125 was positively correlated (p < 0.01). More patients with mesothelin expression showed myometrial invasion of more than 50% (p = 0.028) and positive lymphovascular invasion (p = 0.027). Similarly, more patients with co-expression of mesothelin and CA125 had myometrial invasion of more than 50% (p = 0.016) and positive lymphovascular invasion (p = 0.02). Patients with mesothelin expression and co-expression of mesothelin and CA125 demonstrated worse progression-free survival (PFS) and overall survival (OS). In the multivariate analysis, mesothelin expression and co-expression were poor prognostic factors for PFS (mesothelin expression: hazard ratio [HR] = 2.14, p < 0.01; co-expression: HR = 2.19, p < 0.01) and OS (mesothelin expression: HR = 2.18, p < 0.01; co-expression: HR = 2.22, p < 0.01). -
Structure and Expression Analyses of SVA Elements in Relation to Functional Genes
pISSN 1598-866X eISSN 2234-0742 Genomics Inform 2013;11(3):142-148 G&I Genomics & Informatics http://dx.doi.org/10.5808/GI.2013.11.3.142 ORIGINAL ARTICLE Structure and Expression Analyses of SVA Elements in Relation to Functional Genes Yun-Jeong Kwon, Yuri Choi, Jungwoo Eo, Yu-Na Noh, Jeong-An Gim, Yi-Deun Jung, Ja-Rang Lee, Heui-Soo Kim* Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 609-735, Korea SINE-VNTR-Alu (SVA) elements are present in hominoid primates and are divided into 6 subfamilies (SVA-A to SVA-F) and active in the human population. Using a bioinformatic tool, 22 SVA element-associated genes are identified in the human genome. In an analysis of genomic structure, SVA elements are detected in the 5′ untranslated region (UTR) of HGSNAT (SVA-B), MRGPRX3 (SVA-D), HYAL1 (SVA-F), TCHH (SVA-F), and ATXN2L (SVA-F) genes, while some elements are observed in the 3′UTR of SPICE1 (SVA-B), TDRKH (SVA-C), GOSR1 (SVA-D), BBS5 (SVA-D), NEK5 (SVA-D), ABHD2 (SVA-F), C1QTNF7 (SVA-F), ORC6L (SVA-F), TMEM69 (SVA-F), and CCDC137 (SVA-F) genes. They could contribute to exon extension or supplying poly A signals. LEPR (SVA-C), ALOX5 (SVA-D), PDS5B (SVA-D), and ABCA10 (SVA-F) genes also showed alternative transcripts by SVA exonization events. Dominant expression of HYAL1_SVA appeared in lung tissues, while HYAL1_noSVA showed ubiquitous expression in various human tissues. Expression of both transcripts (TDRKH_SVA and TDRKH_noSVA) of the TDRKH gene appeared to be ubiquitous. -
Generation of a Novel Mesothelin-Targeted Oncolytic Herpes Virus and Implemented Strategies for Manufacturing
International Journal of Molecular Sciences Article Generation of a Novel Mesothelin-Targeted Oncolytic Herpes Virus and Implemented Strategies for Manufacturing Guendalina Froechlich 1, Chiara Gentile 1,2, Luigia Infante 3, Carmen Caiazza 2, Pasqualina Pagano 1,2, Sarah Scatigna 1,2, Gabriella Cotugno 3, Anna Morena D’Alise 3, Armin Lahm 3, Elisa Scarselli 3, Alfredo Nicosia 1,2,3, Massimo Mallardo 2, Emanuele Sasso 1,2,3,* and Nicola Zambrano 1,2,* 1 CEINGE Biotecnologie Avanzate S.C.aR.L., Via G. Salvatore 486, 80145 Naples, Italy; [email protected] (G.F.); [email protected] (C.G.); [email protected] (P.P.); [email protected] (S.S.); [email protected] (A.N.) 2 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via Pansini 5, 80131 Naples, Italy; [email protected] (C.C.); [email protected] (M.M.) 3 Nouscom S.R.L., Via di Castel Romano 100, 00128 Rome, Italy; [email protected] (L.I.); [email protected] (G.C.); [email protected] (A.M.D.); [email protected] (A.L.); [email protected] (E.S.) * Correspondence: [email protected] (E.S.); [email protected] (N.Z.) Abstract: Background: HER2-based retargeted viruses are in advanced phases of preclinical devel- opment of breast cancer models. Mesothelin (MSLN) is a cell-surface tumor antigen expressed in different subtypes of breast and non-breast cancer. Its recent identification as a marker of some triple-negative breast tumors renders it an attractive target, presently investigated in clinical trials employing antibody drug conjugates and CAR-T cells. -
Discovery and Systematic Characterization of Risk Variants and Genes For
medRxiv preprint doi: https://doi.org/10.1101/2021.05.24.21257377; this version posted June 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . 1 Discovery and systematic characterization of risk variants and genes for 2 coronary artery disease in over a million participants 3 4 Krishna G Aragam1,2,3,4*, Tao Jiang5*, Anuj Goel6,7*, Stavroula Kanoni8*, Brooke N Wolford9*, 5 Elle M Weeks4, Minxian Wang3,4, George Hindy10, Wei Zhou4,11,12,9, Christopher Grace6,7, 6 Carolina Roselli3, Nicholas A Marston13, Frederick K Kamanu13, Ida Surakka14, Loreto Muñoz 7 Venegas15,16, Paul Sherliker17, Satoshi Koyama18, Kazuyoshi Ishigaki19, Bjørn O Åsvold20,21,22, 8 Michael R Brown23, Ben Brumpton20,21, Paul S de Vries23, Olga Giannakopoulou8, Panagiota 9 Giardoglou24, Daniel F Gudbjartsson25,26, Ulrich Güldener27, Syed M. Ijlal Haider15, Anna 10 Helgadottir25, Maysson Ibrahim28, Adnan Kastrati27,29, Thorsten Kessler27,29, Ling Li27, Lijiang 11 Ma30,31, Thomas Meitinger32,33,29, Sören Mucha15, Matthias Munz15, Federico Murgia28, Jonas B 12 Nielsen34,20, Markus M Nöthen35, Shichao Pang27, Tobias Reinberger15, Gudmar Thorleifsson25, 13 Moritz von Scheidt27,29, Jacob K Ulirsch4,11,36, EPIC-CVD Consortium, Biobank Japan, David O 14 Arnar25,37,38, Deepak S Atri39,3, Noël P Burtt4, Maria C Costanzo4, Jason Flannick40, Rajat M 15 Gupta39,3,4, Kaoru Ito18, Dong-Keun Jang4, -
Novel Targets of Apparently Idiopathic Male Infertility
International Journal of Molecular Sciences Review Molecular Biology of Spermatogenesis: Novel Targets of Apparently Idiopathic Male Infertility Rossella Cannarella * , Rosita A. Condorelli , Laura M. Mongioì, Sandro La Vignera * and Aldo E. Calogero Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy; [email protected] (R.A.C.); [email protected] (L.M.M.); [email protected] (A.E.C.) * Correspondence: [email protected] (R.C.); [email protected] (S.L.V.) Received: 8 February 2020; Accepted: 2 March 2020; Published: 3 March 2020 Abstract: Male infertility affects half of infertile couples and, currently, a relevant percentage of cases of male infertility is considered as idiopathic. Although the male contribution to human fertilization has traditionally been restricted to sperm DNA, current evidence suggest that a relevant number of sperm transcripts and proteins are involved in acrosome reactions, sperm-oocyte fusion and, once released into the oocyte, embryo growth and development. The aim of this review is to provide updated and comprehensive insight into the molecular biology of spermatogenesis, including evidence on spermatogenetic failure and underlining the role of the sperm-carried molecular factors involved in oocyte fertilization and embryo growth. This represents the first step in the identification of new possible diagnostic and, possibly, therapeutic markers in the field of apparently idiopathic male infertility. Keywords: spermatogenetic failure; embryo growth; male infertility; spermatogenesis; recurrent pregnancy loss; sperm proteome; DNA fragmentation; sperm transcriptome 1. Introduction Infertility is a widespread condition in industrialized countries, affecting up to 15% of couples of childbearing age [1]. It is defined as the inability to achieve conception after 1–2 years of unprotected sexual intercourse [2].