28 results on '"Celso A. Reis"'
Search Results
2. Polymeric nanoparticles targeting Sialyl-Tn in gastric cancer: A live tracking under flow conditions
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Francisca Diniz, Maria Azevedo, Flávia Sousa, Hugo Osório, Diana Campos, Paula Sampaio, Joana Gomes, Bruno Sarmento, and Celso A. Reis
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Biomaterials ,Biomedical Engineering ,Bioengineering ,Cell Biology ,Molecular Biology ,Biotechnology - Abstract
Drug delivery using nanoparticles (NPs) represents a potential approach for therapy in cancer, such gastric cancer (GC) due to their targeting ability and controlled release properties. The use of advanced nanosystems that deliver anti-cancer drugs specifically to tumor cells may strongly rely on the expression of cancer-associated targets. Glycans aberrantly expressed by cancer cells are attractive targets for such delivery strategy. Sialylated glycans, such as Sialyl-Tn (STn) are aberrantly expressed in several epithelial tumors, including GC, being a potential target for a delivery nanosystem. The aim of this study was the development of NPs surface-functionalized with a specific antibody targeting the STn glycan and further evaluate this nanosystem effectiveness regarding its specificity and recognition capacity. Our results showed that the NPs surface-functionalized with anti-STn antibody efficiently are recognized by cells displaying the cancer-associated STn antigen under static and live cell monitoring flow conditions. This uncovers the potential use of such NPs for drug delivery in cancer. However, flow exposure was disclosed as an important biomechanical parameter to be taken into consideration. Here we presented an innovative and successful methodology to live track the NPs targeting STn antigen under shear stress, simulating the physiological flow. We demonstrate that unspecific binding of NPs agglomerates did not occur under flow conditions, in contrast with static assays. This robust approach can be applied for
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- 2022
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3. Glycosyltransferases EXTL2 and EXTL3 cellular balance dictates heparan sulfate biosynthesis and shapes gastric cancer cell motility and invasion
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Catarina Marques, Juliana Poças, Catarina Gomes, Isabel Faria-Ramos, Celso A. Reis, Romain R. Vivès, Ana Magalhães, Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), and ANR-17-CE11-0040,SULFatAS,Structure et activités des sulfatases extracellulaires SULF(2017)
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Stomach Neoplasms ,Cell Movement ,Tumor Microenvironment ,Humans ,Glycosyltransferases ,Membrane Proteins ,Heparitin Sulfate ,Cell Biology ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,N-Acetylglucosaminyltransferases ,Molecular Biology ,Biochemistry ,Heparan Sulfate Proteoglycans - Abstract
Heparan sulfate (HS) proteoglycans (HSPGs) are abundant glycoconjugates in cells' glycocalyx and extracellular matrix. By acting as scaffolds for protein-protein interactions, HSPGs modulate extracellular ligand gradients, cell signaling networks, and cell-extracellular matrix crosstalk. Aberrant expression of HSPGs and enzymes involved in HSPG biosynthesis and processing has been reported in tumors, with impact in cancer cell behavior and tumor microenvironment properties. However, the roles of specific glycosyltransferases in the deregulated biosynthesis of HSPGs are not fully understood. In this study, we established glycoengineered gastric cancer cell models lacking either exostosin-like glycosyltransferase 2 (EXTL2) or EXTL3 and revealed their regulatory roles in both HS and chondroitin sulfate (CS) biosynthesis and structural features. We showed that EXTL3 is key for initiating the synthesis of HS chains in detriment of CS biosynthesis, intervening in the fine-tuned balance of the HS/CS ratio in cells, while EXTL2 functions as a negative regulator of HS biosynthesis, with impact over the glycoproteome of gastric cancer cells. We demonstrated that KO of EXTL2 enhanced HS levels along with concomitant upregulation of Syndecan-4, which is a major cell surface carrier of HS. This aberrant HS expression profile promoted a more aggressive phenotype, characterized by higher cellular motility and invasion, and impaired activation of Ephrin type-A 4 cell surface receptor tyrosine kinase. Our findings uncover the biosynthetic roles of EXTL2 and EXTL3 in the regulation of cancer cell GAGosylation and proteoglycans expression and unravel the functional consequences of aberrant HS/CS balance in cellular malignant features.
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- 2022
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4. Glycosylation in the Era of Cancer-Targeted Therapy: Where Are We Heading?
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Diana Campos, Joana Gomes, Meritxell Balmaña, Celso A. Reis, and Stefan Mereiter
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0301 basic medicine ,Cancer Research ,Glycan ,Glycosylation ,medicine.medical_treatment ,Bioinformatics ,Metastasis ,Targeted therapy ,03 medical and health sciences ,chemistry.chemical_compound ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Polysaccharides ,Neoplasms ,Biomarkers, Tumor ,Humans ,Medicine ,Molecular Targeted Therapy ,Neoplasm Metastasis ,Neoplasm Staging ,Clinical Trials as Topic ,biology ,business.industry ,Immunity ,Cancer ,Cancer signaling ,Immunotherapy ,medicine.disease ,3. Good health ,carbohydrates (lipids) ,030104 developmental biology ,Oncology ,chemistry ,Tumor progression ,030220 oncology & carcinogenesis ,Disease Progression ,biology.protein ,business ,Signal Transduction - Abstract
This review provides insights on the impact of glycosylation in cancer biology and its influence in the current approaches of targeted cancer therapies in the clinical setting. The roles of glycosylation in cancer signaling, tumor progression, and metastasis are reviewed as well as glycans and glycan-binding proteins in tumor immunomodulation. Moreover, the latest reports on glycans influencing targeted therapeutic approaches in cancer are summarized. Finally, we discuss the future challenges of the field, outlining potential applications of glycan-based biomarkers for patient stratification and strategies for improving personalized cancer treatment.
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- 2019
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5. Helicobacter pylori lipopolysaccharide structural domains and their recognition by immune proteins revealed with carbohydrate microarrays
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José Alexandre Ferreira, Ten Feizi, Maria Rosário Domingues, Ricardo Marcos-Pinto, Rui M. Ferreira, Celso A. Reis, Ana Magalhães, Ana S. P. Moreira, Manuel A. Coimbra, Nuno F. Azevedo, Lisete M. Silva, Viviana G. Correia, Ceu Figueiredo, Angelina S. Palma, Fátima Carneiro, UCIBIO - Applied Molecular Biosciences Unit, and DQ - Departamento de Química
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Adult ,Male ,Lipopolysaccharides ,Polymers and Plastics ,Lipopolysaccharide ,Microarray ,Polymers ,Galectins ,Receptors, Cell Surface ,Human sera ,02 engineering and technology ,Biology ,010402 general chemistry ,01 natural sciences ,Carbohydrate microarrays ,0305 Organic Chemistry ,Helicobacter Infections ,Microbiology ,chemistry.chemical_compound ,Host immune receptors ,Immune system ,Materials Chemistry ,Humans ,Lectins, C-Type ,Antigens, Bacterial ,Host Microbial Interactions ,Strain (chemistry) ,Helicobacter pylori ,Mass spectrometry ,Organic Chemistry ,Blood Proteins ,0303 Macromolecular and Materials Chemistry ,Middle Aged ,Carbohydrate ,021001 nanoscience & nanotechnology ,biology.organism_classification ,0104 chemical sciences ,Carbohydrate Sequence ,chemistry ,Immunoglobulin G ,biology.protein ,Female ,lipids (amino acids, peptides, and proteins) ,Antibody ,DNA microarray ,0210 nano-technology ,Cell Adhesion Molecules ,0908 Food Sciences - Abstract
Thanks are due to the University of Aveiro and FCT - Fundacao para a Ciencia e a Tecnologia/MCT (Portugal) for the financial support for the QOPNA Research Unit (UID/QUI/00062/2019), LAQV-REQUIMTE (UIDB/50006/2020), CICECO - Aveiro Institute of Materials (UIDB/50011/2020+UIDP/50011/2020), CESAM (UIDB/50017/2020+UIDP/50017/2020) and RNEM (LISBOA-01-0145-FEDER-402-022125), and LEPABE (UIDB/00511/2020) through national founds and, where applicable, co-financed by the FEDER - Fundo Europeu de Desenvolvimento Regional, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network; and the Applied Molecular Biosciences UnitUCIBIO which is financed by national funds from FCT (UIDB/04378/2020). This work was also supported by project grants from FCT (EXPL/BBB-BQB/0750/2012 and PTDC/BIA-MIB/31730/2017), a Biomedical Resource grant from Wellcome Trust (WT099197MA); and FCT individual grants to LMS (SFRH/BD/71455/2010), VGC (PD/BD/105727/2014), ASPM (SFRH/BD/80553/2011), AM (FRH/BPD/75871/2011), FCT researcher positions under the Individual Call to Scientific Employment Stimulus 2007 call to JAF (CEECIND/03186/2017) and to RMF (CEECIND/01854/2017), and FCT Investigator (GN12IF/00033/2012 GN212) to ASP. Made available in DSpace on 2021-10-09T04:54:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-02-01 publishersversion published
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- 2020
6. Detection of post-translational modifications using solid-phase proximity ligation assay
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Felipe Marques Souza de Oliveira, Benjamin Siart, Celso A. Reis, Karol Polom, Johan Heldin, Masood Kamali-Moghaddam, Stefan Mereiter, Niclas G. Karlsson, Doroteya Raykova, Franco Roviello, Qiujin Shen, and Peter Lönn
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p53 ,Male ,0301 basic medicine ,Glycosylation ,Solid-phase proximity ligation assay (SP-PLA) ,EGFR ,Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ,Bioengineering ,Computational biology ,Proximity ligation assay ,Biology ,Protein detection ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Stomach Neoplasms ,Humans ,CD44 ,Phosphorylation ,Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ,Molecular Biology ,Aged ,Immunoassay ,Detection limit ,E-cadherin ,Gastric cancer ,Post-translational modifications ,Biotechnology ,General Medicine ,Molecular biology ,3. Good health ,ErbB Receptors ,Hyaluronan Receptors ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Posttranslational modification ,Biomarker (medicine) ,Female ,Target protein ,Tumor Suppressor Protein p53 ,Protein Processing, Post-Translational - Abstract
Post-translational modifications (PTMs) regulate protein activities to help orchestrate and fine-tune cellular processes. Dysregulation of PTMs is often related with disorders and malignancies, and may serve as a precise biomarker of disease. Developing sensitive tools to measure and monitor low-abundant PTMs in tissue lysates or serum will be instrumental for opening up new PTM-based diagnostic avenues. Here, we investigate the use of solid-phase proximity ligation assay (SP-PLA) for detection of different PTMs. The assay depends on the recognition of the target protein molecule and its modification by three affinity binders. Using antibodies and lectins, we applied the method for detection of glycosylated CD44 and E-Cadherin, and phosphorylated p53 and EGFR. The assay was found to have superior dynamic range and limit of detection compared to standard ELISAs. In summary, we have established the use of SP-PLA as an appropriate method for sensitive detection of PTMs in lysates and sera, which may provide a basis for future PTM-based diagnostic and prognostic biomarkers.
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- 2018
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7. Lipid nanoparticles to counteract gastric infection without affecting gut microbiota
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Salette Reis, Maria Gomez-Lazaro, Celso A. Reis, Inês C. Gonçalves, Catarina L. Seabra, M. Cristina L. Martins, Cláudia Nunes, and M. Manuela Brás
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0301 basic medicine ,Drug ,medicine.drug_class ,media_common.quotation_subject ,Antibiotics ,Pharmaceutical Science ,02 engineering and technology ,Gut flora ,Helicobacter Infections ,Microbiology ,Surface-Active Agents ,03 medical and health sciences ,Lactobacillus ,medicine ,Humans ,Particle Size ,Mode of action ,media_common ,Drug Carriers ,Gastric Infection ,Bacteria ,Helicobacter pylori ,biology ,Chemistry ,Microbiota ,General Medicine ,021001 nanoscience & nanotechnology ,biology.organism_classification ,Lipids ,Anti-Bacterial Agents ,Gastrointestinal Microbiome ,Nanostructures ,030104 developmental biology ,Nanoparticles ,Cancer development ,0210 nano-technology ,Biotechnology - Abstract
Helicobacter pylori infection is one of the major risk factors for gastric cancer development. Available antibiotic-based treatments not only fail in around 20% of patients but also have a severe negative impact on the gut microbiota. Recently, we demonstrated that nanostructured lipid carriers (NLC), even without any drug loaded, are bactericidal against H. pylori at low concentrations. This work aims to clarify NLC mode of action and to evaluate if their bactericidal effect is specific to H. pylori without affecting bacteria from microbiota. NLC were produced by hot homogenization followed by ultrasonication method, using Precirol®ATO5 and Miglyol®812 as lipids and Tween®60 as a surfactant. NLC were able to eradicate H. pylori without affecting the other tested bacteria (Lactobacillus, E. coli, S. epidermidis and S. aureus). Bioimaging assays demonstrated that NLC rapidly bind to and cross the H. pylori bacterial membrane, destabilizing and disrupting it, which leads to leakage of the cytoplasmic contents and consequent bacterial death. In an era where efficient alternatives to antibiotics are urgent, NLC are an interesting route to be explored in the quest for new antibiotic-free therapies to fight H. pylori infection.
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- 2018
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8. Eucalyptus spp. outer bark extracts inhibit Helicobacter pylori growth: in vitro studies
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Armando J. D. Silvestre, Maria F. Duarte, M. Cristina L. Martins, Paula Parreira, Carmen S. R. Freire, Belinda Soares, and Celso A. Reis
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0301 basic medicine ,biology ,medicine.drug_class ,Antibiotics ,Helicobacter pylori ,biology.organism_classification ,law.invention ,Microbiology ,03 medical and health sciences ,030104 developmental biology ,law ,visual_art ,Eucalyptus globulus ,visual_art.visual_art_medium ,medicine ,CagA ,Eucalyptus nitens ,Bark ,Phytotherapy ,Antibacterial activity ,Agronomy and Crop Science - Abstract
Helicobacter pylori is the etiologic agent of several gastric disorders. The growing rates of unsuccessfulness of available antibiotics-based therapy led to the need for non-antibiotic compounds for H. pylori treatment. The antibacterial activity of Eucalyptus nitens and Eucalyptus globulus outer bark lipophilic extracts were evaluated against a panel of H. pylori strains, as well as the role of pure triterpenic acids and synthetic mixtures mimicking the natural extracts. Best results were obtained with E. nitens outer bark extract (MIC = 64 μg/mL) and it was demonstrated that after 6 h of exposure to the MIC, there was a significant decrease (>50%) in H. pylori growth. Moreover, it was determined that the antibacterial effect of Eucalyptus spp. outer bark extracts was due to the synergetic effect of four triterpenic acids, namely betulinic, betulonic, ursolic and oleanolic acids. Our findings open new perspectives for development of anti-H. pylori therapies based on the use of these plant extracts.
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- 2017
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9. The role of O-glycosylation in human disease
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Celso A. Reis, Henrique O Duarte, and Ana Magalhães
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0301 basic medicine ,Cell signaling ,Glycosylation ,Clinical Biochemistry ,macromolecular substances ,Disease ,Computational biology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Human disease ,Biosynthesis ,Polysaccharides ,Neoplasms ,Glycosyltransferase ,medicine ,Humans ,Molecular Biology ,biology ,Cancer ,General Medicine ,medicine.disease ,carbohydrates (lipids) ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Molecular mechanism ,biology.protein ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Protein Processing, Post-Translational - Abstract
O-glycosylation is a highly frequent post-translation modification of proteins, with important functional implications in both physiological and disease contexts. The biosynthesis of O-glycans depends on several layers of regulation of the cellular glycosylation machinery, being organ-, tissue- and cell-specific. This review provides insights on the molecular mechanism underlying O-glycan biosynthesis and modification, and highlights illustrative examples of diseases that are triggered or modulated by aberrant cellular O-glycosylation. Particular relevance is given to genetic disorders of glycosylation, infectious diseases and cancer. Finally, we address the potential of O-glycans and their biosynthetic pathways as targets for novel therapeutic strategies.
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- 2021
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10. Cadherins Glycans in Cancer: Sweet Players in a Bitter Process
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Salomé S. Pinho, Celso A. Reis, Sandra Carvalho, and Instituto de Investigação e Inovação em Saúde
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0301 basic medicine ,Cancer Research ,Glycan ,Glycosylation ,Morphogenesis ,Cadherins/metabolism ,Biology ,Neoplasms/pathology ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,N-linked glycosylation ,Polysaccharides ,Neoplasms ,Biomarkers, Tumor ,Cell Adhesion ,medicine ,Animals ,Humans ,Polysaccharides/metabolism ,Cell adhesion ,Cadherin ,Cancer ,Cadherins ,medicine.disease ,Cell biology ,030104 developmental biology ,Oncology ,Biomarkers, Tumor/metabolism ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Neoplasms/metabolism - Abstract
Cadherins are key components in tissue morphogenesis and architecture, contributing to the establishment of cohesive cell adhesion. Reduced cellular adhesiveness as a result of cadherin dysfunction is a defining feature of cancer. During tumor development and progression, major changes in the glycan repertoire of cancer cells take place, affecting the stability, trafficking, and cell-adhesion properties of cadherins. Importantly, the different glycoforms of cadherins are promising biomarkers, with potential clinical application to improve the management of patients, and constitute targets for the development of new therapies. This review discusses the most recent insights on the impact of glycan structure on the regulation of cadherin function in cancer, and provides a perspective on how cadherin glycans constitute tumor biomarkers and potential therapeutic targets. IPATIMUP integrates the I3S Research Unit, which is partially supported by FCT, the Portuguese Foundation for Science and Technology (Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovação). This work was financed by FEDER – Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 – Operational Program for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through the FCT in the framework of the project ‘Institute for Research and Innovation in Health Sciences’ (POCI-01-0145-FEDER-007274), PTDC/DTP-PIC/0560/2014, and PTDC/BBB-EBI/0567/2014. S.C. also acknowledges funding from the FCT (SFRH/BD/77386/2011).
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- 2016
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11. Mechanisms of cisplatin resistance and targeting of cancer stem cells: Adding glycosylation to the equation
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Manuel Neves, Lúcio Lara Santos, Cristiana Gaiteiro, Yehuda G. Assaraf, Andreia F. Peixoto, Celso A. Reis, José Alexandre Ferreira, and Instituto de Investigação e Inovação em Saúde
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Neoplastic Stem Cells/drug effects ,0301 basic medicine ,Cisplatin/pharmacology ,Cancer Research ,Glycosylation ,Glycosylation/drug effects ,Antineoplastic Agents ,Biology ,Proteomics ,Bioinformatics ,Neoplasms/pathology ,Drug Resistance, Neoplasm/physiology ,03 medical and health sciences ,0302 clinical medicine ,Neoplastic Stem Cells/metabolism ,Cancer stem cell ,Neoplasms ,Biomarkers, Tumor ,medicine ,Humans ,Pharmacology (medical) ,Pharmacology ,Mesenchymal stem cell ,Cancer ,medicine.disease ,Precision medicine ,Neoplasms/drug therapy ,3. Good health ,Biomarker (cell) ,030104 developmental biology ,Infectious Diseases ,Oncology ,Drug Resistance, Neoplasm ,Biomarkers, Tumor/metabolism ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Cancer biomarkers ,Cisplatin ,Stem cell ,Antineoplastic Agents/pharmacology ,Neoplasms/metabolism - Abstract
Cisplatin-based chemotherapeutic regimens are the most frequently used (neo)adjuvant treatments for the majority of solid tumors. While platinum-based chemotherapeutic regimens have proven effective against highly proliferative malignant tumors, significant relapse and progression rates as well as decreased overall survival are still observed. Currently, it is known that sub-populations of chemoresistant cells share biological properties with cancer stem cells (CSC), which are believed to be responsible for tumor relapse, invasion and ultimately disease dissemination through acquisition of mesenchymal cell traits. In spite of concentrated efforts devoted to decipher the mechanisms underlying CSC chemoresistance and to design targeted therapeutics to these cells, proteomics has failed to unveil molecular signatures capable of distinguishing between malignant and non-malignant stem cells. This has hampered substantial developments in this complex field. Envisaging a novel rationale for an effective therapy, the current review summarizes the main cellular and molecular mechanisms underlying cisplatin resistance and the impact of chemotherapy challenge in CSC selection and clinical outcome. It further emphasizes the growing amount of data supporting a role for protein glycosylation in drug resistance. The dynamic and context-dependent nature of protein glycosylation is also comprehensively discussed, hence highlighting its potentially important role as a biomarker of CSC. As the paradigm of cancer therapeutics shifts towards precision medicine and patient-tailored therapeutics, we bring into focus the need to introduce glycomics and glycoproteomics in holistic pan-omics models, in order to integrate diverse, multimodal and clinically relevant information towards more effective cancer therapeutics. This work was supported by European Union funds (FEDER/COMPETE) and by national funds (FCT, the Portuguese Foundation for Science and Technology) under the projects with the references FCOMP-01-0124-FEDER 028188 (PTDC/BBB-EBI/0786/2012) and PTDC/BBB-EBI/0567/2014. C.R. acknowledges the support by Gastric Glyco Explorer Initial Training Network (Seventh Framework Programme grant no. 316929). IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT, (PEst-C/SAU/LA0003/2013). Grants were received from FCT: SFRH/BPD/111048/2015 to J.A.F and SFRH/BD/111242/2015 to A.P. FCT is co-financed by European Social Fund (ESF) under Human Potential Operation Programme (POPH) from National Strategic Reference Framework (NSRF).
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- 2016
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12. Probing the O-Glycoproteome of Gastric Cancer Cell Lines for Biomarker Discovery*
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Sergey Y. Vakhrushev, Daniela Freitas, J. Sousa, Catharina Steentoft, Luís Pedro Afonso, Catarina Gomes, Diana Campos, Ana Magalhães, Celso A. Reis, Malene Bech Vester-Christensen, Ulla Mandel, Lúcio Lara Santos, Henrik Clausen, Joana Gomes, José Alexandre Ferreira, and Instituto de Investigação e Inovação em Saúde
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Male ,N-Acetylgalactosaminyltransferases/blood ,Proteome ,Glycoproteins/metabolism ,Proximity ligation assay ,Biology ,Stomach Neoplasms/metabolism ,Biochemistry ,Analytical Chemistry ,03 medical and health sciences ,0302 clinical medicine ,Stomach Neoplasms ,Cell Line, Tumor ,Biomarkers, Tumor ,medicine ,N-Acetylgalactosaminyltransferases/metabolism ,Humans ,Biomarker discovery ,Glycoproteins/blood ,Molecular Biology ,Aged ,Glycoproteins ,030304 developmental biology ,Aged, 80 and over ,chemistry.chemical_classification ,0303 health sciences ,Research ,CD44 ,Cancer ,Middle Aged ,medicine.disease ,3. Good health ,chemistry ,Biomarkers, Tumor/blood ,Biomarkers, Tumor/metabolism ,030220 oncology & carcinogenesis ,Cancer cell ,Immunology ,Cancer research ,biology.protein ,Stomach Neoplasms/blood ,N-Acetylgalactosaminyltransferases ,Biomarker (medicine) ,Female ,Glycoprotein - Abstract
Circulating O-glycoproteins shed from cancer cells represent important serum biomarkers for diagnostic and prognostic purposes. We have recently shown that selective detection of cancer-associated aberrant glycoforms of circulating O-glycoprotein biomarkers can increase specificity of cancer biomarker assays. However, the current knowledge of secreted and circulating O-glycoproteins is limited. Here, we used the COSMC KO "Simple- Cell" (SC) strategy to characterize the O-glycoproteome of two gastric cancer SimpleCell lines (AGS, MKN45) as well as a gastric cell line (KATO III) which naturally expresses at least partially truncated O-glycans. Overall, we identified 499 O-glycoproteins and 1236 O-glycosites in gastric cancer SimpleCells, and a total 47 O-glycoproteins and 73 O-glycosites in the KATO III cell line. We next modified the glycoproteomic strategy to apply it to pools of sera from gastric cancer and healthy individuals to identify circulating O-glycoproteins with the STn glycoform. We identified 37 O-glycoproteins in the pool of cancer sera, and only nine of these were also found in sera from healthy individuals. Two identified candidate O-glycoprotein biomarkers (CD44 and GalNAc-T5) circulating with the STn glycoform were further validated as being expressed in gastric cancer tissue. A proximity ligation assay was used to show that CD44 was expressed with the STn glycoform in gastric cancer tissues. The study provides a discovery strategy for aberrantly glycosylated O-glycoproteins and a set of O-glycoprotein candidates with biomarker potential in gastric cancer. This work was supported by The Danish Research Councils, The Mizutani Foundation, The Danish National Research Foundation (DNRF107) and Fundacão para a Ciência e a Tecnologia (FCT) and COMPETE (Programa Operacional Temático Factores de Competitividade, comparticipado pelo fundo comunitário europeu FEDER) in the framework of the projects: PTDC/BBB-EBI/0786/2012; EXPL/CTM-BIO/0762/2013. Grants were received from FCT (SFRH/BD/73717/2010 to DC), (SFRH/BPD/75871/2011 to AM), (SFRH/BPD/96510/2013 to CG) and (SFRH/BPD/66288/2009 to JAF). IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education, and is partially supported by FCT.
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- 2015
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13. Machine learning methodology applied to characterize subgroups of gastric cancer patients using an integrated large biomarker dataset
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D. Morley, M. Afshar, Karol Polom, Frédérique Lisacek, Daniele Marrelli, F. Roviello, Qiujin Shen, Mariana Guergova-Kuras, Y. Tognetti, Celso A. Reis, Alessia D'Ignazio, Masood Kamali-Moghaddam, Stefan Mereiter, Niclas G. Karlsson, Coralie Williams, Barbara Adamczyk, and F. Parmentier
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Biomarker (medicine) ,Cancer ,Surgery ,General Medicine ,medicine.disease ,business - Published
- 2019
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14. Quantitative MUC5AC and MUC6 mucin estimations in gastric mucus by a least-squares minimization method
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Pradeep K. Luther, Miguel J. Guerreiro, John M. Squire, Julian Wiseman, Celso A. Reis, and Ramon L. Sidebotham
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Adult ,Molar ,medicine.medical_specialty ,Gastric mucus ,Biophysics ,Mucin 5AC ,Biochemistry ,Gastroenterology ,fluids and secretions ,Internal medicine ,Least squares minimization ,medicine ,Humans ,Stomach Ulcer ,Mucin-6 ,Molecular Biology ,Aged ,chemistry.chemical_classification ,biology ,Chemistry ,Mucin ,Cell Biology ,Anatomy ,Middle Aged ,respiratory system ,Helicobacter pylori ,biology.organism_classification ,Mucus ,digestive system diseases ,Duodenal ulcer ,Duodenal Ulcer ,Glycoprotein - Abstract
We have determined the molar proportions of the MUC5AC and MUC6 mucus glycoproteins (mucins) in mucus from the normal and pathological human gastric antrum using a least-squares minimization analysis applied to amino acid compositions. We noted that the content of MUC5AC mucin in mucus from individuals without gastroduodenal disease was very high, suggesting that the integrity and barrier properties of the adherent gastric mucus layer are normally maintained by building-block structures formed from this mucin alone. We observed that the molar content of MUC6 mucin doubled (without significance) in mucus from patients with duodenal ulcer, and increased five times (with high significance) in mucus from patients with gastric ulcer, when compared with that in mucus from individuals without gastroduodenal disease.
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- 2013
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15. BJcuL, a lectin purified from Bothrops jararacussu venom, induces apoptosis in human gastric carcinoma cells accompanied by inhibition of cell adhesion and actin cytoskeleton disassembly
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Selene Elifio-Esposito, Celso A. Reis, Danusa de Castro Damasio, Ana Magalhães, Maria Cristina Roque-Barreira, Luciana Zischler, Stefanie Nolte, Andrea N Moreno-Amaral, Joana Gomes, Adriana Cristina Baréa, and Patrícia Maria Stuelp-Campelo
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Programmed cell death ,Matrigel ,Pathology ,medicine.medical_specialty ,Antineoplastic Agents ,Apoptosis ,Biology ,Toxicology ,Actin cytoskeleton ,Cell biology ,Actin Cytoskeleton ,Stomach Neoplasms ,Cell culture ,Cell Line, Tumor ,Crotalid Venoms ,Cell Adhesion ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Bothrops ,Lectins, C-Type ,Viability assay ,Cytoskeleton ,Cell adhesion - Abstract
We show that BJcuL, a lectin purified from Bothrops jararacussu venom, exerts cytotoxic effects to gastric carcinoma cells MKN45 and AGS. This effect was due to the direct interaction with specific glycans on the cells surface and was observed by cell viability decrease, disorganization of actin filaments and apoptosis. In addition, BJcuL was able to reduce tumor cell adhesion to matrigel, what was inhibited by specific carbohydrate or partially inhibited when cells were pre-incubated with matrigel. Our results suggest that BJcuL was able to promote apoptosis in both tumor cells lines and therefore has a prospect for potential use in cancer therapy.
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- 2012
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16. Solvent properties governing protein partitioning in polymer/polymer aqueous two-phase systems
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Larissa M. Mikheeva, Pedro P. Madeira, Boris Y. Zaslavsky, Arnon Chait, Celso A. Reis, and Alírio E. Rodrigues
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Biochemistry ,Analytical Chemistry ,Polarizability ,Animals ,Ficoll ,Humans ,chemistry.chemical_classification ,Aqueous solution ,Chromatography ,Hydrogen bond ,Osmolar Concentration ,Organic Chemistry ,Solvatochromism ,Proteins ,Dextrans ,Hydrogen Bonding ,General Medicine ,Polymer ,Solvent ,Partition coefficient ,Models, Chemical ,chemistry ,Linear Models ,Solvents ,Solvent effects ,Hydrophobic and Hydrophilic Interactions ,Algorithms ,Chromatography, Liquid - Abstract
Distribution coefficients of various proteins were measured in aqueous Dextran–Ficoll, Dextran–PES, and Ficoll–PES two-phase systems, containing 0.15 M NaCl in 0.01 M phosphate buffer, pH 7.4. The acquired data were combined with data for the same proteins in different systems reported previously [29] , [30] and known solvatochromic solvent properties of the systems [17] to characterize the protein–solvent interactions. The relative susceptibilities of proteins to solvent dipolarity/polarizability, solvent hydrogen bond acidity, solvent hydrogen bond basicity, and solvent ability to participate in ion–ion and ion–dipole interactions were characterized. These parameters, which are representative of solute–solvent interactions, adequately described the partitioning of the proteins in each system. It was found that the relative susceptibilities of proteins to solvent dipolarity/polarizability are interrelated with their relative susceptibilities to solvent hydrogen bond acidity and solvent hydrogen bond basicity similarly to those established previously for small nonionic organic compounds.
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- 2011
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17. PO-248 Novel insights on the role of glycosylation in cancer: molecular functions and clinical applications
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Henrique O Duarte, Daniela Freitas, Diana Campos, Celso A. Reis, Catarina Gomes, José R. B. Gomes, Meritxell Balmaña, Ana Magalhães, and S. Meriter
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Cancer Research ,Glycan ,Glycosylation ,biology ,Cancer ,medicine.disease ,Receptor tyrosine kinase ,Glycoproteomics ,carbohydrates (lipids) ,Glycomics ,chemistry.chemical_compound ,Oncology ,chemistry ,Cancer cell ,Cancer research ,medicine ,biology.protein ,Gastrointestinal cancer - Abstract
Introduction Glycosylation alterations are frequently found in cancer and specific aberrant glycan structures are associated with tumour development and progression.1 The characterisation of glycosylation modifications occurring in cancer is of high interest and represents a source of putative new biomarkers for cancer detection, therapeutic intervention and patient stratification. Material and methods Glycomics, glycoproteomics, glycoprofiling, and in situ Proximity Ligation Assays of glycoengineered cancer cell models and tissue samples from gastrointestinal cancer patients were performed. Results and discussions This presentation reports the recent discoveries applying several novel approaches for: (A) the characterisation of glycosylation changes in the cancer cells; (B) the identification of the aberrant expression of specific glycan structures in cancer, like terminal sialylated glycans, which lead to the activation of tyrosine kinase receptors, such as HER2, MET, and RON;2,3,4,5 (C) the identification of altered glycosylated proteins, carrying simple mucin-type carbohydrate structures, in engineered cancer cell models and in sera of cancer patients.5,6 Conclusion These results demonstrate aberrant glycan structures as key functional players in tumour biology and highlight their potential as novel biomarkers and as therapeutic targets in the clinical management of cancer patients.1,5,6
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- 2018
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18. PO-174 ErbB2 glycosylation landscape in gastric cancer cells – a novel functional target?
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Stefan Mereiter, Celso A. Reis, Henrique O Duarte, José R. B. Gomes, António Polónia, Meritxell Balmaña, Hugo Osório, and L.L. Santos
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Cancer Research ,Glycan ,Glycosylation ,biology ,Proximity ligation assay ,Sialyl-Lewis A ,Receptor tyrosine kinase ,Cell biology ,chemistry.chemical_compound ,Oncology ,chemistry ,Cell culture ,Cancer cell ,biology.protein ,Neoplastic transformation ,skin and connective tissue diseases ,neoplasms - Abstract
Introduction Aberrant expression and hyperactivation of the human epidermal growth factor receptor 2 (ErbB2) constitute crucial molecular events underpinning gastric neoplastic transformation. Despite the extracellular domain of this cancer-relevant receptor tyrosine kinase (RTK) being a well-known target for extensive glycosylation, its detailed glycosylation profile and the molecular mechanisms through which it actively tunes ErbB2 towards malignancy in gastric cancer (GC) cells remain elusive. Material and methods The expression of relevant glycosyltransferase-coding genes, and the expression and activation of the ErbB receptors were assessed in four GC cell lines. ErbB2-overexpressing NCI-N87 cells were selected for further glycan characterisation. ErbB2 was immunoprecipitated and validated by MALDI/TOF-TOF tandem mass spectrometry. Receptor’s glycosylation was confirmed by Peptide-N-Glycosidase F digestion and profiled with carbohydrate-binding lectins and monoclonal antibodies (mAbs). The expression of genes controlling the biosynthesis of cancer-associated glycans in association to ErbB2 status were studied. Expression and activation of ErbB2 were assessed in ErbB2-overexpressing cells submitted to in vitro deglycosylation and mAb-mediated glycan blocking. ErbB2-glycan in situ proximity ligation assay (PLA) was performed in tissue samples from ErbB2-positive GC patients. Results and discussions Cellular- and receptor-specific glycan profiling of ErbB2-overexpressing NCI-N87 cells unveiled a heterogeneous glycosylation pattern harbouring the tumor-associated sialyl Lewis a (SLea) antigen. The expression of SLea and key enzymes of its biosynthetic pathway were strongly upregulated in this GC cell line. An association between the expression of ERBB2 and FUT3, a central gene in SLea biosynthesis, was additionally established in GC patients. Moreover, cellular deglycosylation and CA 19.9 antibody-mediated blocking of SLea drastically disrupted both receptor’s expression and activation in NCI-N87 cells. PLA staining disclosed ErbB2 as an in situ carrier of SLea in over 50% of the cases harbouring ErbB2 and SLea positive gastric carcinoma, further highlighting the crosstalk between ErbB2 and SLea expression. Conclusion Our results show that the disclosed glycosylation profile of ErbB2 in GC cells has a major functional impact on receptor’s biology with potential clinical applications. Furthermore, NCI-N87 cell model constitutes an appealing in vitro system to address glycan-mediated regulation of ErbB2 in GC.
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- 2018
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19. Topographic expression of MUC5AC and MUC6 in the gastric mucosa infected by Helicobacter pylori and in associated diseases
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Celso A. Reis, Terezinha Marques, Ana Margarida M. F. Nogueira, and Leonor David
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Pathology ,medicine.medical_specialty ,Adenocarcinoma ,Mucin 5AC ,Polymerase Chain Reaction ,digestive system ,Gastroenterology ,Helicobacter Infections ,Pathology and Forensic Medicine ,Pathogenesis ,Bacterial Proteins ,Stomach Neoplasms ,Internal medicine ,Gastric mucosa ,Humans ,Medicine ,CagA ,Stomach Ulcer ,Mucin-6 ,Antrum ,Antigens, Bacterial ,Helicobacter pylori ,biology ,business.industry ,Mucin ,Mucins ,Cell Biology ,bacterial infections and mycoses ,biology.organism_classification ,Immunohistochemistry ,Urease ,digestive system diseases ,medicine.anatomical_structure ,Gastric Mucosa ,Duodenal Ulcer ,Gastritis ,medicine.symptom ,business - Abstract
We investigated the topographic expression of MUC5AC and MUC6 in relationship with gastric diseases. The immunoexpression of MUC5AC and MUC6 was evaluated in 75 adults presenting Helicobacter pylori gastritis (n = 22; 11 cagA positive), duodenal ulcer (DU, n = 11), gastric ulcer (GU, n = 9), gastric carcinoma (GC, n = 20), and normal mucosa (H. pylori negative, n = 13). Five gastric areas (antral and corporeal lesser and greater curvatures and incisura) were studied. H. pylori was detected by carbolfuchsin, urease, and culture; cagA was determined by PCR. All patients with DU (eight with GU and 13 with GC) were H. pylori-positive. In H. pylori gastritis, MUC5AC expression was higher in the antrum than in the corpus; no difference was observed with respect to cagA status. MUC5AC expression was higher in the antrum of gastritis than in DU, and it was lower in the incisura among GU patients compared to DU. MUC6 expression was higher in the antrum of H. pylori gastritis compared to DU and to uninfected patients. No difference was observed in the topographic pattern of expression of MUC5AC and MUC6 among GC cases. The topographic over- and under-expression of mucins in H. pylori-associated gastritis and peptic disease suggest a role for these mucins in the pathogenesis of H. pylori infection and associated diseases.
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- 2005
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20. A bivalent conjugate vaccine in the treatment of biochemically relapsed prostate cancer: a study of glycosylated MUC-2-KLH and Globo H-KLH conjugate vaccines given with the new semi-synthetic saponin immunological adjuvant GPI-0100 OR QS-21
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Celso A. Reis, Matthew P. Jefferson, Philip O. Livingston, Andrew Wilton, Govind Ragupathi, Maria Spassova, Susan F. Slovin, Shemeeakah Powell, Samuel J. Danishefsky, Henrick Clausen, Howard I. Scher, Meghan Diani, and Celina Fernandez
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Male ,medicine.medical_treatment ,Dose-Response Relationship, Immunologic ,Enzyme-Linked Immunosorbent Assay ,Cancer Vaccines ,Adjuvants, Immunologic ,Recurrence ,Conjugate vaccine ,Humans ,Medicine ,Immunization Schedule ,Aged ,Vaccines, Conjugate ,General Veterinary ,General Immunology and Microbiology ,biology ,business.industry ,Public Health, Environmental and Occupational Health ,Antibody titer ,Prostatic Neoplasms ,Immunotherapy ,Middle Aged ,Prostate-Specific Antigen ,Saponins ,Flow Cytometry ,QS21 ,carbohydrates (lipids) ,Vaccination ,Infectious Diseases ,Immunology ,Toxicity ,biology.protein ,Molecular Medicine ,business ,Adjuvant ,Keyhole limpet hemocyanin - Abstract
GPI-0100 is a semi-synthetic saponin with modifications designed to augment stability and diminish toxicity. Two batches of GPI-0100 (the second with higher purity) were tested with doses ranging between 100 and 5000 microg in groups of five treated prostate cancer patients who had no evidence of disease except for rising PSA levels. GPI-0100 was mixed with a bivalent vaccine containing the glycolipid Globo H and the glycosylated mucin MUC2 conjugated to keyhole limpet hemocyanin (KLH). All doses were well tolerated and antibody titers against Globo H and MUC-2 escalated with the increasing dose levels. At the 5000 microg dose level in this patient population, toxicity remained minimal with only occasional grade II local toxicity at vaccination sites and occasional sporadic grade I elevations in ALT. Compared with a subsequent trial with the same bivalent vaccine plus QS-21 at the maximal tolerated dose of 100 microg, the 5000 microg dose of GPI-0100 produced comparable antibody titers.
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- 2005
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21. Role of site-specific promoter hypomethylation in aberrant MUC2 mucin expression in mucinous gastric carcinomas
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Celso A. Reis, Christoph Hanski, Patrícia Mesquita, Raquel Seruca, Filipe Silva, Antonio Peixoto, Raquel Almeida, and Leonor David
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Cancer Research ,Molecular Sequence Data ,Biology ,Stomach Neoplasms ,Gene expression ,medicine ,Humans ,Gene silencing ,Promoter Regions, Genetic ,Gene ,Mucin-2 ,Base Sequence ,Stomach ,Mucin ,Mucins ,Promoter ,Methylation ,DNA Methylation ,Adenocarcinoma, Mucinous ,Molecular biology ,digestive system diseases ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Oncology ,CpG site ,Gastric Mucosa ,Cancer research ,CpG Islands - Abstract
In the present work we investigated the methylation levels of mucin gene (MUC)2 promoter region in normal gastric mucosa and mucinous gastric carcinoma in order to access if the observed de novo expression of the intestinal mucin MUC2 in mucinous gastric carcinoma is associated with changes in MUC2 promoter methylation status. The results obtained by methylation-sensitive single nucleotide primer extension suggest that MUC2 expression in gastric cells is regulated by promoter methylation and further indicate that two specific cytosine guaine dinucleotide (CpG) sites may play a particularly important regulatory role.
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- 2003
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22. Sialyl-Tn identifies muscle-invasive bladder cancer basal and luminal subtypes facing decreased survival, being expressed by circulating tumor cells and metastases
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Ricardo Ribeiro, Janine Soares, Cristiana Gaiteiro, Ana P. M. Tavares, Elisabete Fernandes, Manuel Neves, Ana Castro, Lúcio Lara Santos, Andreia F. Peixoto, Celso A. Reis, Rita Azevedo, Dylan Ferreira, Marta I. Oliveira, José Alexandre Ferreira, Rui Freitas, Avelino Fraga, Manuel Cardoso de Oliveira, Diana Montezuma, Lorena Diéguez, and Luís Lima
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Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Urology ,Urinary Bladder ,Context (language use) ,Kaplan-Meier Estimate ,Keratin-20 ,Metastasis ,03 medical and health sciences ,Basal (phylogenetics) ,0302 clinical medicine ,Circulating tumor cell ,Antigen ,Internal medicine ,medicine ,Humans ,Antigens, Tumor-Associated, Carbohydrate ,Neoplasm Invasiveness ,Clinical significance ,Aged ,Retrospective Studies ,Aged, 80 and over ,Bladder cancer ,business.industry ,Muscles ,Keratin-14 ,Middle Aged ,Neoplastic Cells, Circulating ,medicine.disease ,Immunohistochemistry ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Urinary Bladder Neoplasms ,030220 oncology & carcinogenesis ,Keratin-5 ,Female ,business - Abstract
Objectives To evaluate the potential of sialyl-Tn (STn), a cancer-associated glycan antigen present in membrane glycoproteins, to improve a recent molecular model for stratification and prognostication of advanced stage bladder tumors based on keratins ( KRT14 , 5 , and 20 ) expression. In addition, determine the association between STn and disease dissemination based on the evaluation of circulating tumor cells (CTCs) and the metastasis, which is a critical matter to improve patient management. Patients and methods A retrospective series of 80 muscle-invasive primary bladder tumors and associated metastasis were screened for KRT 14, 5, and 20 and STn by real-time polymerase chain reaction and immunohistochemistry. Peripheral blood was collected in a patients’ subset, CTCs were isolated through a size-based microfluidic chip and screened for KRT s and STn. Results Basal-like lesions presented worse cancer-specific and disease-free survival compared to luminal tumors. STn antigen inclusion discriminated patients with worst survival in each subgroup ( P = 0.047 for luminal; P = 0.027 for basal-like tumors). STn expression in CTCs and distant metastasis was also demonstrated. Conclusion This work reinforces the potential of the KRT -based model for bladder cancer management and the association of STn with aggressiveness, supporting its inclusion in predictive molecular models toward patient-tailored precision medicine. Moreover, we describe for the first time that CTCs and the metastasis present a basal phenotype and express the STn antigen, highlighting its link with disease dissemination. Future studies should focus on determining the biological and clinical significance of these observations in the context of liquid biopsies. Given the membrane nature of STn, highly specific targeted therapeutics may also be envisaged.
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- 2017
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23. E-cadherin Dysfunction in Canine Gastric Cancer
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Fátima Gärtner, Celso A. Reis, J. Carvalho, Alexandra Rêma, Carlos Augusto Fernandes de Oliveira, A.L. Saraiva, Marian Taulescu, Augusto Faustino, and Irina Amorim
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General Veterinary ,Cadherin ,business.industry ,medicine ,Cancer research ,Cancer ,medicine.disease ,business ,Pathology and Forensic Medicine - Published
- 2014
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24. 597 Using an in Vitro Model of Epithelial-Mesenchymal-Epithelial Transitions to Uncover Novel Biological Mechanisms
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Salomé S. Pinho, Pedro Oliveira, Carla Oliveira, Celso A. Reis, David G. Huntsman, Joana Carvalho, J. Lima, Maria M. Azevedo, Valdemar Máximo, and A. Moussavi
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Cancer Research ,Oncology ,Chemistry ,Mesenchymal stem cell ,In vitro model ,Cell biology - Published
- 2012
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25. Mo1556 High-Risk Host Genotype and H. pylori Strains in First Degree Relatives of Patients With Early-Onset Gastric Cancer
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Ceu Figueiredo, Isabel Pedroto, José Carlos Machado, Rui M. Ferreira, Mário Dinis-Ribeiro, Ricardo Marcos-Pinto, Xiaogang Wen, Jorge Areias, Carlos Lopes, Celso A. Reis, Fátima Carneiro, and José Alexandre Ferreira
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Hepatology ,business.industry ,Immunology ,Gastroenterology ,Medicine ,Cancer ,First-degree relatives ,business ,medicine.disease ,Host genotype ,Early onset - Published
- 2012
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26. MS237 SERUM ATHEROGENIC LIPID MARKERS IN SUBJECTS FROM THREE ISLANDS OF THE AZORES' ARCHIPELAGO (PORTUGAL) – A COMPARISON STUDY
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Cristina Correia, Rita Ferin, Celso A. Reis, Tállita Meciany Farias Vieira, Maria Leonor Pavão, Mafalda Raposo, Ana Rita Castro, and Bruno Gonçalves
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medicine.diagnostic_test ,Internal Medicine ,medicine ,Comparison study ,Azores archipelago ,Zoology ,General Medicine ,Biology ,Cardiology and Cardiovascular Medicine ,Lipid profile - Published
- 2010
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27. Solitary Fibrous Tumor of the Pleura: Review of 19 Cases From a Single Surgical Grou
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Carlos Eduardo Teixeira Lima, Mario Celso Martins Reis, Rui Haddad, Heitor C. Paiva, Tadeu Diniz Ferreira, Carlos Henrique Ribeiro Boasquevisque, and Fernando D'Imperio Teixeira
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Pulmonary and Respiratory Medicine ,Pleural Solitary Fibrous Tumor ,Solitary fibrous tumor ,Pathology ,medicine.medical_specialty ,business.industry ,Medicine ,Cardiology and Cardiovascular Medicine ,Critical Care and Intensive Care Medicine ,business ,medicine.disease - Published
- 2003
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28. Primary signet-ring cell carcinomas of the lung
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Manuel Sobrinho-Simões, José Carlos Machado, Celso A. Reis, and Fátima Carneiro
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Pathology ,medicine.medical_specialty ,Primary (chemistry) ,Lung ,medicine.anatomical_structure ,Signet ring cell ,medicine ,Biology ,Pathology and Forensic Medicine - Published
- 2000
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