46 results on '"T Touloumenidou"'
Search Results
2. PB2183: RELAPSE PREDICTS POOR OUTCOMES IN FLT3-MUTATED ACUTE MYELOID LEUKEMIA POST ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION
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E. Gavriilaki, A. Papalexandri, D. Mallouri, I. Batsis, A. Vardi, Z. Bousiou, C. Demosthenous, A. Panteliadou, N. Spyridis, G. Karavalakis, T. Touloumenidou, M. Masmanidou, G. Pistiolas, F. Mouladeniou, C. Vadikoliou, C. Lalayanni, E. Yannaki, A. Anagnostopoulos, and I. Sakellari
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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3. PB2226: THE ROLE OF COMPLEMENT IN THE IMMUNE RESPONSE OF SICKLE CELL DISEASE PATIENTS AFER COVID-19 VACCINATION
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C. Varelas, E. Gavriilaki, I. Sakellari, P. Klonizakis, E.-E. Koravou, I. Christodoulou, I. Mavrikou, A. Kourelis, F. Chatzopoulou, D. Chatzidimitriou, T. Touloumenidou, A. Papalexandri, A. Anagnostopoulos, and E. Vlachaki
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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4. Topic: AS01-Diagnosis/AS01c-Molecular aberrations (cytogenetic, genetic, gene expression): PATHOGENIC VARIANTS RELATED TO HEMATOLOGIC MALIGNANCIES CONTRIBUTE TO THE DIFFERENTIAL DIAGNOSIS OF CYTOPENIAS
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A. Papalexandri, V. Douka, M. Iskas, M. Papathanasiou, C. Demosthenous, C. Varelas, T. Touloumenidou, and I. Sakellari
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Cancer Research ,Oncology ,Hematology - Published
- 2023
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5. Correction: Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1
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Tomasz Sacha, Spencer Hermanson, Helen Vålerhaugen, Israel Bendit, Smadar Avigad, Carmen Chillón, Shalini C. Reshmi, Gareth Gerrard, Sandra Markovic, Martin C. Mueller, Gianni Cazzaniga, Hubert Serve, J. J. M. Van Dongen, Katarzyna Borg, Tomáš Jurček, Christa Homburg, Oliver G. Ottmann, Veli Kairisto, Fabrizio Pane, Jean-Michel Cayuela, T Touloumenidou, Beat W. Schäfer, Thoralf Lange, Heike Pfeifer, Loredana Elia, Eva Herrmann, Thomas Lion, Christine Damm-Welk, Susanna Akiki, Sandrine Hayette, Orietta Spinelli, Hélène Cavé, Giovanni Martinelli, Peter Vandenberghe, Susanne Schnittger, A. Juh, Lena Rai, Jan Zuna, and Vincent H.J. van der Velden
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Cancer Research ,business.industry ,Lymphoblastic Leukemia ,Philadelphia positive ,Quantitative Reverse Transcriptase PCR ,Hematology ,medicine.disease ,Minimal residual disease ,Leukemia ,Bcr abl1 ,Oncology ,medicine ,Cancer research ,business - Published
- 2020
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6. PS1192 INITIAL REPORT OF A NILOTINIB DISCONTINUATION PROJECT WITH 54 GREEK CML PATIENTS FOLLOWED IN ACCORDANCE TO THE APPROVED DISCONTINUATION INDICATION OF THE DRUG
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M. Angelopoulou, T. Iliakis, A. Symeonidis, A. Stefanou, P. Panayiotidis, A. Papalexandri, T. Touloumenidou, E. Staikou, M. Roumelioti, I. Adamopoulos, M. Dimou, and A. Kouraklis
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Drug ,medicine.medical_specialty ,Nilotinib ,business.industry ,media_common.quotation_subject ,Internal medicine ,medicine ,Hematology ,business ,media_common ,Discontinuation ,medicine.drug - Published
- 2019
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7. Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale
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Cross, N.C.P. White, H.E. Ernst, T. Welden, L. Dietz, C. Saglio, G. Mahon, F.-X. Wong, C.C. Zheng, D. Wong, S. Wang, S.-S. Akiki, S. Albano, F. Andrikovics, H. Anwar, J. Balatzenko, G. Bendit, I. Beveridge, J. Boeckx, N. Cerveira, N. Cheng, S.-M. Colomer, D. Czurda, S. Daraio, F. Dulucq, S. Eggen, L. El Housni, H. Gerrard, G. Gniot, M. Izzo, B. Jacquin, D. Janssen, J.J.W.M. Jeromin, S. Jurcek, T. Kim, D.-W. Machova-Polakova, K. Martinez-Lopez, J. McBean, M. Mesanovic, S. Mitterbauer-Hohendanner, G. Mobtaker, H. Mozziconacci, M.-J. Pajič, T. Pallisgaard, N. Panagiotidis, P. Press, R.D. Qin, Y.-Z. Radich, J. Sacha, T. Touloumenidou, T. Waits, P. Wilkinson, E. Zadro, R. Müller, M.C. Hochhaus, A. Branford, S.
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hemic and lymphatic diseases - Abstract
Molecular monitoring of chronic myeloid leukemia patients using robust BCR-ABL1 tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO) BCR-ABL1 reference panel was developed (MR 1 -MR 4), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR 4.5 level. The secondary panel was calibrated to IS using digital PCR with ABL1, BCR and GUSB as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of BCR-ABL1 assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR 4.5 sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms. © 2016 Macmillan Publishers Limited, part of Springer Nature.
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- 2016
8. Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale
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T. Pajič, J. Anwar, J. Beveridge, T Touloumenidou, Dolors Colomer, P. Waits, Tomáš Jurček, S. Czurda, Andreas Hochhaus, L. Welden, Israel Bendit, M J Mozziconacci, Jeroen Janssen, Tomasz Sacha, Francesco Albano, Dong-Kee Kim, M. Gniot, Jerry Radich, D. Zheng, E. Wilkinson, L. Eggen, Christian Dietz, S. M. Cheng, K. Machova-Polakova, S. Wong, Martin C. Müller, Gareth Gerrard, Stéphanie Dulucq, Nuno Cerveira, H El Housni, Barbara Izzo, Francois-Xavier Mahon, Filomena Daraio, Helen E. White, G. Mitterbauer-Hohendanner, D. Jacquin, Susanna Akiki, G. Balatzenko, Renata Zadro, Susan Branford, Niels Pallisgaard, Nicholas C.P. Cross, Ya-Zhen Qin, S. Jeromin, H. Mobtaker, M. McBean, S. S. Wang, S. Mesanovic, Panagiotis Panagiotidis, Wong Connie C, Nancy Boeckx, Richard D. Press, Thomas Ernst, Hajnalka Andrikovics, Joaquin Martinez-Lopez, Giuseppe Saglio, Cross, NCP, White, HE, Ernst, T, Welden, L, Branford, Susan, Cancer Center Amsterdam, Hematology, CCA - Biomarkers, Cross, N. C. P, White, H. E, Dietz, C, Saglio, G, Mahon, F. X, Wong, C. C, Zheng, D, Wong, S, Wang, S. S, Akiki, S, Albano, F, Andrikovics, H, Anwar, J, Balatzenko, G, Bendit, I, Beveridge, J, Boeckx, N, Cerveira, N, Cheng, S. M, Colomer, D, Czurda, S, Daraio, F, Dulucq, S, Eggen, L, El Housni, H, Gerrard, G, Gniot, M, Izzo, Barbara, Jacquin, D, Janssen, J. J. W. M, Jeromin, S, Jurcek, T, Kim, D. W, Machova Polakova, K, Martinez Lopez, J, Mcbean, M, Mesanovic, S, Mitterbauer Hohendanner, G, Mobtaker, H, Mozziconacci, M. J, Pajič, T, Pallisgaard, N, Panagiotidis, P, Press, R. D, Qin, Y. Z, Radich, J, Sacha, T, Touloumenidou, T, Waits, P, Wilkinson, E, Zadro, R, Müller, M. C, Hochhaus, A, and Branford, S.
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0301 basic medicine ,Cancer Research ,International scale ,bcr-abl ,Fusion Proteins, bcr-abl ,Genes, abl ,Bioinformatics ,World Health Organization ,Polymerase Chain Reaction ,World health ,Anesthésiologie ,03 medical and health sciences ,Bcr abl1 ,0302 clinical medicine ,Reference genes ,hemic and lymphatic diseases ,Statistics ,Calibration ,Secondary reference ,Medicine ,Humans ,Digital polymerase chain reaction ,business.industry ,Proto-Oncogene Proteins c-bcr ,Reference Standards ,Hematology ,Oncology ,abl ,leukemia ,Fusion Proteins ,BCR-ABL1 tests ,Cancérologie ,030104 developmental biology ,Genes ,molecular monitoring ,030220 oncology & carcinogenesis ,Correlation analysis ,Original Article ,business ,Hématologie - Abstract
Molecular monitoring of chronic myeloid leukemia patients using robust BCR-ABL1 tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO) BCR-ABL1 reference panel was developed (MR 1 -MR 4), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR 4.5 level. The secondary panel was calibrated to IS using digital PCR with ABL1, BCR and GUSB as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of BCR-ABL1 assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR 4.5 sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms., 0, SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2016
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9. The phylogeny of Monsonia L. (Geraniaceae)
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Focke Albers, Freek T. Bakker, and T. Touloumenidou
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Polytomy ,number ,Plant Science ,Pelargonium ,Biology ,biology.organism_classification ,mitochondrial ,taxonomic status ,Biosystematiek ,Monophyly ,chloroplast dna ,Cladogram ,Chloroplast DNA ,angiosperm phylogeny ,Genus ,sequence comparisons ,Botany ,evolution ,Biosystematics ,regions ,Clade ,Geraniaceae ,section ,Ecology, Evolution, Behavior and Systematics ,sarcocaulon - Abstract
The phylogeny of Monsonia L. (Geraniaceae) is examined. Analysis of nrDNA ITS and trnL (UAA) 5'exon-trnF (GAA) chloroplast DNA sequence data of 26 Monsonia and two outgroup Pelargonium species, suggests monophyly for the genus including the former genus Sarcocaulon (DC.) Sweet. The species of Monsonia sect. Sarcocaulon resolve as two subclades (ITS cladogram 80% and trnL-F cladogram 96%) and two additional species in an unresolved basal polytomy, in a clade with species of the sect. Olopetalum and M. senegalensis. All these species share the basic chromosome number x = 11. The remaining species have derived karyotypes of x = 12, 10, 9 or 8. Chromosome sizes vary considerably between the species, and polyploids are rare. The current infrageneric classification is discussed.
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- 2007
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10. Defining low and undetectable levels of disease in chronic myeloid leukemia:progress towards standardisation in Europe
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H. White, F. Lin, A. Aggerholm, H. Andrikovics, G. Barbany, N. Boeckx, J. M. Cayuela, D. Colomer, F. Daraio, S. Dulucq, H. El Housni, G. Gerrard, E. Gineikiene, S. Hayette, M. Jansson, P. Johnels, T. Jurcek19, V. Kairisto20, T. Lange21, T. Lion22, K. Machova23, G. Martinelli, PA Merle, G. Mitterbauer Hohendanner, M. Nagar Marciano, J. Nomdedeu, D. A. Nymoen, E. Oppliger Leibundgut, U. Ozbek, T. Pajic, C. Preudhomme33, K. Raudsepp34, T. Sacha35, R. Talmaci36, T. Touloumenidou, VHJ Van der Velden, R. Zadro, J. Ziermann, K. Zoi, MC Müller, A. Hochhaus, NCP Cross, IZZO, BARBARA, White H, H., White, F., Lin, A., Aggerholm, H., Andrikovic, G., Barbany, N., Boeckx, J. M., Cayuela, D., Colomer, F., Daraio, S., Dulucq, H., El Housni, G., Gerrard, E., Gineikiene, S., Hayette, Izzo, Barbara, M., Jansson, P., Johnel, T., Jurcek19, V., Kairisto20, T., Lange21, T., Lion22, K., Machova23, G., Martinelli, Pa, Merle, G., Mitterbauer Hohendanner, M., Nagar Marciano, J., Nomdedeu, D. A., Nymoen, E., Oppliger Leibundgut, U., Ozbek, T., Pajic, C., Preudhomme33, K., Raudsepp34, T., Sacha35, R., Talmaci36, T., Touloumenidou, VHJ Van der, Velden, R., Zadro, J., Ziermann, K., Zoi, Mc, Müller, A., Hochhau, and Ncp, Cross
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- 2013
11. A certified plasmid reference material for the standardisation of BCR-ABL1 mRNA quantification by real-time quantitative PCR
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J M Cayuela, BJ Milner, Stéphane Mazoua, Elisabeth Oppliger Leibundgut, Linda Fletcher, Heike Pfeifer, Tomáš Jurček, E Gineikienė, P. Waits, Susanna Akiki, G Wilson, J Farrugia, H El Housni, Ugur Ozbek, D Wren, F. Lin, Tomasz Sacha, Hajnalka Andrikovics, S Chudleigh, Letizia Foroni, Stefanie Trapmann, Petra Johnels, Gareth Gerrard, Thomas Lion, M. Jansson, Katerina Zoi, Hendrik Emons, K. Raudsepp, Gisela Barbany, D A Nymoen, H Schimmel, J Ziermann, Nancy Boeckx, Mark Catherwood, Sandrine Hayette, G Romeo, Helen E. White, R Ganderton, Filomena Daraio, G. Mitterbauer-Hohendanner, Philippe Corbisier, Claude Preudhomme, Andreas Hochhaus, Martin C. Müller, P A Merle, V H J van der Velden, M Nagar, Victoria J. Hall, Lihui Wang, Theis Lange, Tim Clench, T Pajič, Stéphanie Dulucq, D-W Kim, Nicholas C.P. Cross, Josep F. Nomdedeu, Rodica Talmaci, Kateřina Machová Poláková, A Bench, Liesbet Deprez, T Touloumenidou, G Nickless, Veli Kairisto, Barbara Izzo, Dolors Colomer, Aytug Kizilors, Giovanni Martinelli, Renata Zadro, Anni Aggerholm, S McCarron, E Wilkinson, Hematology, CCA - Disease profiling, White, H, Deprez, L, Corbisier, P, Hall, V, Lin, F, Mazoua, S, Trapmann, S, Aggerholm, A, Andrikovics, H, Akiki, S, Barbany, G, Boeckx, N, Bench, A, Catherwood, M, Cayuela, Jm, Chudleigh, S, Clench, T, Colomer, D, Daraio, F, Dulucq, S, Farrugia, J, Fletcher, L, Foroni, L, Ganderton, R, Gerrard, G, Gineikienė, E, Hayette, S, El Housni, H, Izzo, Barbara, Jansson, M, Johnels, P, Jurcek, T, Kairisto, V, Kizilors, A, Kim, Dw, Lange, T, Lion, T, Polakova, Km, Martinelli, G, Mccarron, S, Merle, Pa, Milner, B, Mitterbauer Hohendanner, G, Nagar, M, Nickless, G, Nomdedéu, J, Nymoen, Da, Leibundgut, Eo, Ozbek, U, Pajič, T, Pfeifer, H, Preudhomme, C, Raudsepp, K, Romeo, G, Sacha, T, Talmaci, R, Touloumenidou, T, Van der Velden, Vh, Waits, P, Wang, L, Wilkinson, E, Wilson, G, Wren, D, Zadro, R, Ziermann, J, Zoi, K, Müller, Mc, Hochhaus, A, Schimmel, H, Cross, Nc, Emons, H., Immunology, Radiology & Nuclear Medicine, Izzo, B, and Mitterbauer-Hohendanner, G
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EMTREE drug terms: plasmid DNA EMTREE medical terms: Article ,Cancer Research ,Fusion Proteins, bcr-abl ,Gene Dosage ,Membrane Transport Protein ,Plasmid ,RECOMMENDATIONS ,real time quantitative polymerase chain reaction ,K562 cell line ,law.invention ,law ,hemic and lymphatic diseases ,Escherichia coli Protein ,CANCER PROGRAM ,Digital polymerase chain reaction ,Cloning, Molecular ,Polymerase chain reaction ,MOLECULAR RESPONSE ,Medicine (all) ,Escherichia coli Proteins ,copy number variation ,breakpoint cluster region ,gene control ,Hematology ,Reference Standards ,gusb gene ,3. Good health ,Real-time polymerase chain reaction ,Certified reference materials ,priority journal ,Oncology ,real time polymerase chain reaction ,Calibration ,Proto-Oncogene Proteins c-bcr ,Original Article ,Life Sciences & Biomedicine ,Medical Genetics ,Plasmids ,EUROPE ,POLYMERASE-CHAIN-REACTION ,610 Medicine & health ,Biology ,Real-Time Polymerase Chain Reaction ,IMATINIB ,Gene dosage ,Anesthésiologie ,chronic myeloid leukemia ,TRANSCRIPTS ,TYROSINE KINASE INHIBITORS ,bcr abl gene ,Humans ,controlled study ,human ,ddc:610 ,RNA, Messenger ,CHRONIC MYELOID-LEUKEMIA ,gene ,certified plasmid reference material ,bcr-abl1 ,Medicinsk genetik ,freeze thawing ,Messenger RNA ,Science & Technology ,human cell ,reference value ,Membrane Transport Proteins ,HL 60 cell line ,DNA ,ta3122 ,Molecular biology ,Cancérologie ,Anesthesiology and Pain Medicine ,certified reference material ,minimal residual disease ,Reference Standard ,Hématologie - Abstract
Serial quantification of BCR-ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR-ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 10 6, 1.08±0.11 × 10 5, 1.03±0.10 × 10 4, 1.02±0.09 × 10 3, 1.04±0.10 × 10 2 and 10.0±1.5 copies/μl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR-ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR-ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a-f)., 0, SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2015
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12. Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR), Growth Differentiation Factor-15 (GDF-15), and Soluble C5b-9 (sC5b-9) Levels Are Significantly Associated with Endothelial Injury Indices in CAR-T Cell Recipients.
- Author
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Gavriilaki E, Demosthenous C, Evangelidis P, Bousiou Z, Batsis I, Vardi A, Mallouri D, Koravou EE, Spyridis N, Panteliadou A, Karavalakis G, Masmanidou M, Touloumenidou T, Papalexandri A, Poziopoulos C, Yannaki E, Sakellari I, Politou M, and Papassotiriou I
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- Humans, Male, Female, Middle Aged, Adult, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Aged, Growth Differentiation Factor 15 blood, Growth Differentiation Factor 15 metabolism, Receptors, Urokinase Plasminogen Activator blood, Receptors, Urokinase Plasminogen Activator metabolism, Biomarkers blood
- Abstract
Endothelial injury indices, such as Endothelial Activation and Stress Index (EASIX), modified EASIX (m-EASIX), and simplified EASIX (s-EASIX) scores, have been previously associated with chimeric antigen receptor-T (CAR-T) cell immunotherapy complications. Soluble urokinase-type plasminogen activator receptor (suPAR), growth differentiation factor-15 (GDF-15), and soluble C5b-9 (sC5b-9) have been described as markers of endothelial injury post-hematopoietic stem cell transplantation. In the current study, we examined whether suPAR, GDF-15, and sC5b-9 levels were associated with endothelial injury indices in adult CAR-T cell recipients. The levels of these markers were measured in patients before CAR-T cell infusion and in healthy individuals with immunoenzymatic methods. We studied 45 CAR-T cell recipients and 20 healthy individuals as the control group. SuPAR, GDF-15, and sC5b-9 levels were significantly higher in the patients' group compared to the healthy control group ( p < 0.001, in all comparisons). SuPAR levels at baseline were associated with the m-EASIX scores calculated at the same time point ( p = 0.020), while suPAR and GDF-15 concentrations were correlated with EASIX scores at day 14 post-infusion ( p < 0.001 in both comparisons). Moreover, sC5b-9 levels were correlated with the s-EASIX scores at infusion ( p = 0.008) and the EASIX scores at day 14 ( p = 0.005). In our study, sC5b9, suPAR, and GDF-15 levels were found to reflect endothelial injury in CAR-T cell recipients.
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- 2024
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13. Prospective study of complement activation and thromboinflammation within sickle cell disease and its complications.
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Varelas C, Vlachaki E, Klonizakis P, Pantelidou D, Minti F, Diamantidis M, Sabanis N, Koravou E, Christodoulou I, Papadopoulou D, Theodoridou S, Touloumenidou T, Papalexandri A, Sakellari I, Vakalopoulou S, Perifanis V, Vassilopoulos G, Mitroulis I, and Gavriilaki E
- Abstract
Competing Interests: Eleni Gavriilaki has consulted for Alexion, Omeros, and Sanofi Cooperation. The other authors declare no competing financial interest.
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- 2024
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14. Increased Complement Activation and Decreased ADAMTS13 Activity Are Associated with Genetic Susceptibility in Patients with Preeclampsia/HELLP Syndrome Compared to Healthy Pregnancies: An Observational Case-Controlled Study.
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Venou TM, Vetsiou E, Varelas C, Daniilidis A, Psarras K, Koravou EE, Koutra M, Touloumenidou T, Tsolakidis V, Papalexandri A, Minti F, Mandala E, Dinas K, Vlachaki E, and Gavriilaki E
- Abstract
Preeclampsia is a progressive multi-systemic disorder characterized by proteinuria, critical organ damage, and new-onset hypertension. It can be further complicated by HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), resulting in critical liver or renal damage, disseminated coagulation, and grand mal seizures. This study aimed to examine the involvement of ADAMTS13, von Willebrand, and the complement system in the pathogenesis of preeclampsia/HELLP syndrome. We studied 30 Caucasian preeclamptic pregnant women and a control group of 15 healthy pregnancies. Genetic sequencing of ADAMTS13 and complement regulatory genes (MiniSeq System, Illumina) was performed. The modified Ham test was used to check for complement activation, ADAMTS13 activity, von Willebrand antigen (vWFAg) levels, and soluble C5b-9 levels were measured. Patients with preeclampsia had a decreased ADAMTS13 activity and increased C5b-9 levels. The vWFAg was significantly correlated with ADAMTS13 activity (r = 0.497, p = 0.003). Risk-factor variants were found in the genes of ADAMTS13, C3, thrombomodulin, CFB, CFH, MBL2, and, finally, MASP2. A portion of pregnant women with preeclampsia showed a decline in ADAMTS13 activity, correlated with vWFAg levels. These patients also exhibited an elevated complement activation and high-risk genetic variants in regulatory genes. Further research is needed to determine if these factors can serve as reliable biomarkers., Competing Interests: The authors declare no conflicts of interest.
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- 2024
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15. Genetic justification of COVID-19 patient outcomes using DERGA, a novel data ensemble refinement greedy algorithm.
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Asteris PG, Gandomi AH, Armaghani DJ, Tsoukalas MZ, Gavriilaki E, Gerber G, Konstantakatos G, Skentou AD, Triantafyllidis L, Kotsiou N, Braunstein E, Chen H, Brodsky R, Touloumenidou T, Sakellari I, Alkayem NF, Bardhan A, Cao M, Cavaleri L, Formisano A, Guney D, Hasanipanah M, Khandelwal M, Mohammed AS, Samui P, Zhou J, Terpos E, and Dimopoulos MA
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- Humans, Artificial Intelligence, Algorithms, COVID-19 epidemiology, COVID-19 genetics
- Abstract
Complement inhibition has shown promise in various disorders, including COVID-19. A prediction tool including complement genetic variants is vital. This study aims to identify crucial complement-related variants and determine an optimal pattern for accurate disease outcome prediction. Genetic data from 204 COVID-19 patients hospitalized between April 2020 and April 2021 at three referral centres were analysed using an artificial intelligence-based algorithm to predict disease outcome (ICU vs. non-ICU admission). A recently introduced alpha-index identified the 30 most predictive genetic variants. DERGA algorithm, which employs multiple classification algorithms, determined the optimal pattern of these key variants, resulting in 97% accuracy for predicting disease outcome. Individual variations ranged from 40 to 161 variants per patient, with 977 total variants detected. This study demonstrates the utility of alpha-index in ranking a substantial number of genetic variants. This approach enables the implementation of well-established classification algorithms that effectively determine the relevance of genetic variants in predicting outcomes with high accuracy., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
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- 2024
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16. Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) and Growth Differentiation Factor-15 (GDF-15) Levels Are Significantly Associated with Endothelial Injury Indices in Adult Allogeneic Hematopoietic Cell Transplantation Recipients.
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Gavriilaki E, Bousiou Z, Batsis I, Vardi A, Mallouri D, Koravou EE, Konstantinidou G, Spyridis N, Karavalakis G, Noli F, Patriarcheas V, Masmanidou M, Touloumenidou T, Papalexandri A, Poziopoulos C, Yannaki E, Sakellari I, Politou M, and Papassotiriou I
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- Adult, Humans, Receptors, Urokinase Plasminogen Activator, Growth Differentiation Factor 15, Biomarkers, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease etiology, Thrombotic Microangiopathies
- Abstract
Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) and graft-versus-host disease (GvHD) represent life-threatening syndromes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In both conditions, endothelial dysfunction is a common denominator, and development of relevant biomarkers is of high importance for both diagnosis and prognosis. Despite the fact that soluble urokinase plasminogen activator receptor (suPAR) and growth differentiation factor-15 (GDF-15) have been determined as endothelial injury indices in various clinical settings, their role in HSCT-related complications remains unexplored. In this context, we used immunoenzymatic methods to measure suPAR and GDF-15 levels in HSCT-TMA, acute and/or chronic GVHD, control HSCT recipients, and apparently healthy individuals of similar age and gender. We found considerably greater SuPAR and GDF-15 levels in HSCT-TMA and GVHD patients compared to allo-HSCT and healthy patients. Both GDF-15 and suPAR concentrations were linked to EASIX at day 100 and last follow-up. SuPAR was associated with creatinine and platelets at day 100 and last follow-up, while GDF-15 was associated only with platelets, suggesting that laboratory values do not drive EASIX. SuPAR, but not GDF-15, was related to soluble C5b-9 levels, a sign of increased HSCT-TMA risk. Our study shows for the first time that suPAR and GDF-15 indicate endothelial damage in allo-HSCT recipients. Rigorous validation of these biomarkers in many cohorts may provide utility for their usefulness in identifying and stratifying allo-HSCT recipients with endothelial cell impairment.
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- 2023
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17. Pre-Emptive Use of Rituximab in Epstein-Barr Virus Reactivation: Incidence, Predictive Factors, Monitoring, and Outcomes.
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Papalexandri A, Gavriilaki E, Vardi A, Kotsiou N, Demosthenous C, Constantinou N, Touloumenidou T, Zerva P, Kika F, Iskas M, Batsis I, Mallouri D, Yannaki E, Anagnostopoulos A, and Sakellari I
- Subjects
- Humans, Rituximab therapeutic use, Herpesvirus 4, Human physiology, Incidence, Viral Load, DNA, Viral genetics, Retrospective Studies, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections drug therapy, Hematopoietic Stem Cell Transplantation adverse effects, Lymphoproliferative Disorders drug therapy, Lymphoproliferative Disorders etiology, Graft vs Host Disease etiology
- Abstract
Post-transplant lymphoproliferative disease (PTLD) is a fatal complication of hematopoietic cell transplantation (HCT) associated with the Epstein-Barr virus (EBV). Multiple factors such as transplant type, graft-versus-host disease (GVHD), human leukocyte antigens (HLA) mismatch, patient age, and T-lymphocyte-depleting treatments increase the risk of PTLD. EBV reactivation in hematopoietic cell transplant recipients is monitored through periodic quantitative polymerase chain reaction (Q-PCR) tests. However, substantial uncertainty persists regarding the clinically significant EBV levels for these patients. Guidelines recommend initiating EBV monitoring no later than four weeks post-HCT and conducting it weekly. Pre-emptive therapies, such as the reduction of immunosuppressive therapy and the administration of rituximab to treat EBV viral loads are also suggested. In this study, we investigated the occurrence of EBV-PTLD in 546 HCT recipients, focusing on the clinical manifestations and risk factors associated with the disease. We managed to identify 67,150 viral genomic copies/mL as the cutoff point for predicting PTLD, with 80% sensitivity and specificity. Among our cohort, only 1% of the patients presented PTLD. Anti-thymocyte globulin (ATG) and GVHD were independently associated with lower survival rates and higher treatment-related mortality. According to our findings, prophylactic measures including regular monitoring, pre-emptive therapy, and supportive treatment against infections can be effective in preventing EBV-related complications. This study also recommends conducting EBV monitoring at regular intervals, initiating pre-emptive therapy when viral load increases, and identifying factors that increase the risk of PTLD. Our study stresses the importance of frequent and careful follow-ups of post-transplant complications and early intervention in order to improve survival rates and reduce mortality.
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- 2023
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18. Caplacizumab for immune thrombotic thrombocytopenic purpura: real-world multicenter data.
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Gavriilaki E, Nikolousis E, Koravou EE, Dimou-Besikli S, Kartsios C, Papakonstantinou A, Mpanti A, Pontikoglou C, Kalpadaki C, Bitsani A, Tassi I, Touloumenidou T, Chatziconstantinou T, Papathanasiou M, Syrigou A, Ztriva E, Kaiafa G, Mandala E, Mellios Z, Karakasis D, Kourakli A, Symeonidis A, Kapsali E, Papadaki HH, Lalayanni C, and Sakellari I
- Abstract
Given the limited real-world data of caplacizumab, our multicenter real-world study was designed to assess the safety and efficacy of caplacizumab in immune thrombotic thrombocytopenic pupura (iTTP), compared to historic controls. We have studied 70 patients: 23 in the caplacizumab and 47 in the historic control group. Plasma exchange was applied in all episodes except for two patients that denied plasma exchange. Rituximab as first-line treatment was more common in the caplacizumab group compared to historic control. Caplacizumab (10 mg daily) was given at a median on day 7 (1-43) from initial diagnosis for 32 (6-47) dosages. In the caplacizumab group, a median of 12 (8-23) patients required plasma exchange sessions versus 14 (6-32) in the control group. Caplacizumab administration did not produce any grade 3 complications or major hemorrhagic events. After a median of 19.0 (2.6-320) months since the iTTP diagnosis, 5 deaths occurred (4 in the control group and 1 in the caplacizumab group, p = 0.310). Caplacizumab patients achieved early platelet normalization and ADAMTS13 activity normalization at the end of treatment. Relapse was observed only in 2/23 (9%) caplacizumab patients, compared to 29/47 (62%) historic controls ( p < 0.001). Overall, caplacizumab is safe and effective in treating iTTP, including cases refractory to plasma exchange, re-administration, and cases without previous plasma exchange treatment. No major hemorrhagic events were observed. Cessation of dosing guided by ADAMTS13 has ensured a low relapse rate., Competing Interests: AntS and ArgS have received grants, honoraria or travel support from Abbvie, Amgen, Bei-Gene, BMS, Gilead, Glaxo, Janssen, MSD, Pfizer, Roche, Sanofi, Servier, SOBI, Takeda. ChaK and ChrK have received honoraria from Pfizer, BMS, Bayer, Takeda. EG and CP have received honoraria from Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gavriilaki, Nikolousis, Koravou, Dimou-Besikli, Kartsios, Papakonstantinou, Mpanti, Pontikoglou, Kalpadaki, Bitsani, Tassi, Touloumenidou, Chatziconstantinou, Papathanasiou, Syrigou, Ztriva, Kaiafa, Mandala, Mellios, Karakasis, Kourakli, Symeonidis, Kapsali, Papadaki, Lalayanni and Sakellari.)
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- 2023
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19. Targeted genotyping of COVID-19 patients reveals a signature of complement C3 and factor B coding SNPs associated with severe infection.
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Tsiftsoglou SA, Gavriilaki E, Touloumenidou T, Koravou EE, Koutra M, Papayanni PG, Karali V, Papalexandri A, Varelas C, Chatzopoulou F, Chatzidimitriou M, Chatzidimitriou D, Veleni A, Rapti E, Kioumis I, Kaimakamis E, Bitzani M, Boumpas DT, Tsantes A, Sotiropoulos D, Papadopoulou A, Sakellari I, Kokoris S, and Anagnostopoulos A
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- Male, Female, Humans, Complement Factor B genetics, Complement C3 genetics, Polymorphism, Single Nucleotide, Genotype, Complement Factor H genetics, SARS-CoV-2, Complement C2 genetics, Macular Degeneration genetics, COVID-19
- Abstract
We have attempted to explore further the involvement of complement components in the host COVID-19 (Coronavirus disease-19) immune responses by targeted genotyping of COVID-19 adult patients and analysis for missense coding Single Nucleotide Polymorphisms (coding SNPs) of genes encoding Alternative pathway (AP) components. We have identified a small group of common coding SNPs in Survivors and Deceased individuals, present in either relatively similar frequencies (CFH and CFI SNPs) or with stark differences in their relative abundance (C3 and CFB SNPs). In addition, we have identified several sporadic, potentially protective, coding SNPs of C3, CFB, CFD, CFH, CFHR1 and CFI in Survivors. No coding SNPs were detected for CD46 and CD55. Our demographic analysis indicated that the C3 rs1047286 or rs2230199 coding SNPs were present in 60 % of all the Deceased patients (n = 25) (the rs2230199 in 67 % of all Deceased Males) and in 31 % of all the Survivors (n = 105, p = 0.012) (the rs2230199 in 25 % of all Survivor Males). When we analysed these two major study groups using the presence of the C3 rs1047286 or rs2230199 SNPs as potential biomarkers, we noticed the complete absence of the protective CFB rs12614 and rs641153 coding SNPs from Deceased Males compared to Females (p = 0.0023). We propose that in these individuals, C3 carrying the R102G and CFB lacking the R32W or the R32Q amino acid substitutions, may contribute to enhanced association dynamics of the C3bBb AP pre-convertase complex assembly, thus enabling the exploitation of the activation of the Complement Alternative pathway (AP) by SARS-CoV-2., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)
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- 2023
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20. Neutralizing antibody and T cell responses to SARS-CoV-2 vaccination in hematopoietic cell transplant recipients.
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Gavriilaki E, Papadopoulou A, Touloumenidou T, Stavridou F, Koravou EE, Giannaki M, Papalexandri A, Karavalakis G, Batsis I, Kourelis A, Chatzopoulou F, Chatzidimitriou D, Sotiropoulos D, Yannaki E, Sakellari I, and Anagnostopoulos A
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- Antibodies, Neutralizing, Antibodies, Viral, COVID-19 Vaccines, Humans, SARS-CoV-2, T-Lymphocytes, Transplant Recipients, Vaccination, COVID-19 prevention & control, Hematopoietic Stem Cell Transplantation
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- 2022
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21. Standardization of molecular monitoring of CML: results and recommendations from the European treatment and outcome study.
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White HE, Salmon M, Albano F, Andersen CSA, Balabanov S, Balatzenko G, Barbany G, Cayuela JM, Cerveira N, Cochaux P, Colomer D, Coriu D, Diamond J, Dietz C, Dulucq S, Engvall M, Franke GN, Gineikiene-Valentine E, Gniot M, Gómez-Casares MT, Gottardi E, Hayden C, Hayette S, Hedblom A, Ilea A, Izzo B, Jiménez-Velasco A, Jurcek T, Kairisto V, Langabeer SE, Lion T, Meggyesi N, Mešanović S, Mihok L, Mitterbauer-Hohendanner G, Moeckel S, Naumann N, Nibourel O, Oppliger Leibundgut E, Panayiotidis P, Podgornik H, Pott C, Rapado I, Rose SJ, Schäfer V, Touloumenidou T, Veigaard C, Venniker-Punt B, Venturi C, Vigneri P, Vorkinn I, Wilkinson E, Zadro R, Zawada M, Zizkova H, Müller MC, Saussele S, Ernst T, Machova Polakova K, Hochhaus A, and Cross NCP
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- Fusion Proteins, bcr-abl genetics, Humans, Reference Standards, Treatment Outcome, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
- Abstract
Standardized monitoring of BCR::ABL1 mRNA levels is essential for the management of chronic myeloid leukemia (CML) patients. From 2016 to 2021 the European Treatment and Outcome Study for CML (EUTOS) explored the use of secondary, lyophilized cell-based BCR::ABL1 reference panels traceable to the World Health Organization primary reference material to standardize and validate local laboratory tests. Panels were used to assign and validate conversion factors (CFs) to the International Scale and assess the ability of laboratories to assess deep molecular response (DMR). The study also explored aspects of internal quality control. The percentage of EUTOS reference laboratories (n = 50) with CFs validated as optimal or satisfactory increased from 67.5% to 97.6% and 36.4% to 91.7% for ABL1 and GUSB, respectively, during the study period and 98% of laboratories were able to detect MR
4.5 in most samples. Laboratories with unvalidated CFs had a higher coefficient of variation for BCR::ABL1IS and some laboratories had a limit of blank greater than zero which could affect the accurate reporting of DMR. Our study indicates that secondary reference panels can be used effectively to obtain and validate CFs in a manner equivalent to sample exchange and can also be used to monitor additional aspects of quality assurance., (© 2022. The Author(s).)- Published
- 2022
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22. Targeted Genotyping of MIS-C Patients Reveals a Potential Alternative Pathway Mediated Complement Dysregulation during COVID-19 Infection.
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Gavriilaki E, Tsiftsoglou SA, Touloumenidou T, Farmaki E, Panagopoulou P, Michailidou E, Koravou EE, Mavrikou I, Iosifidis E, Tsiatsiou O, Papadimitriou E, Papadopoulou-Alataki E, Papayanni PG, Varelas C, Kokkoris S, Papalexandri A, Fotoulaki M, Galli-Tsinopoulou A, Zafeiriou D, Roilides E, Sakellari I, Anagnostopoulos A, and Tragiannidis A
- Abstract
Complement dysregulation has been documented in adults with COVID-19 and implicated in relevant pediatric inflammatory responses against SARS-CoV-2. We propose that signatures of complement missense coding SNPs associated with dysregulation could also be identified in children with multisystem inflammatory syndrome (MIS-C). We investigated 71 pediatric patients with RT-PCR validated SARS-CoV-2 hospitalized in pediatric COVID-19 care units (November 2020-March 2021) in three major groups. Seven (7) patients suffered from MIS-C (MIS-C group), 32 suffered from COVID-19 and were hospitalized (admitted group), whereas 32 suffered from COVID-19, but were sent home. All patients survived and were genotyped for variations in the C3 , C5 , CFB , CFD , CFH , CFHR1 , CFI , CD46 , CD55 , MASP1 , MASP2 , MBL2 , COLEC11 , FCN1 , and FCN3 genes. Upon evaluation of the missense coding SNP distribution patterns along the three study groups, we noticed similarities, but also considerably increased frequencies of the alternative pathway (AP) associated with SNPs rs12614 CFB , rs1061170, and rs1065489 CFH in the MIS-C patients. Our analysis suggests that the corresponding substitutions potentially reduce the C3b-inactivation efficiency and promote slower and weaker AP C3bBb pre-convertase assembly on virions. Under these circumstances, the complement AP opsonization capacity may be impaired, leading to compromised immune clearance and systemic inflammation in the MIS-C syndrome.
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- 2022
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23. Genetic and Functional Evidence of Complement Dysregulation in Multiple Myeloma Patients with Carfilzomib-Induced Thrombotic Microangiopathy Compared to Controls.
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Gavriilaki E, Dalampira D, Theodorakakou F, Liacos CI, Kanellias N, Eleutherakis-Papaiakovou E, Terpos E, Gavriatopoulou M, Verrou E, Triantafyllou T, Sevastoudi A, Koravou EE, Touloumenidou T, Varelas C, Papalexandri A, Sakellari I, Dimopoulos MA, Kastritis E, and Katodritou E
- Abstract
Background: Carfilzomib, an irreversible proteasome inhibitor approved for the treatment of relapsed/refractory Multiple Myeloma (MM) has been associated with Thrombotic Microangiopathy (TMA). Several pathogenetic mechanisms of carfilzomib-induced TMA have been proposed; however, recently, there has been a shift of focus on the potential contribution of complement dysregulation. Our aim was to explore whether patients with carfilzomib-induced TMA harbor germline variants of complement-related genes, which have been characterized as risk factors for TMA., Methods: We retrospectively recruited consecutive MM patients with carfilzomib-induced TMA and compared them to MM patients who received ≥4 cycles of carfilzomib and did not develop signs/symptoms of TMA, in a 1:2 ratio. Genomic DNA from peripheral blood was analyzed using next generation sequencing (NGS) with a complement-related gene panel; ADAMTS13 activity and soluble C5b-9 were measured using ELISA., Results: Complement-related variants were more common in patients with carfilzomib-induced TMA compared to non-TMA controls, regardless of patient and treatment characteristics; ADAMTS13 activity and C5b-9 were compatible with the phenotype of complement-related TMA., Conclusions: We confirmed the previous findings that implicated complement-related genes in the pathogenesis of carfilzomib-induced TMA. Most importantly, by incorporating a control group of non-TMA MM patients treated with carfilzomib-based regimens and functional complement assays, we enhanced the credibility of our findings.
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- 2022
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24. Genetic prediction of ICU hospitalization and mortality in COVID-19 patients using artificial neural networks.
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Asteris PG, Gavriilaki E, Touloumenidou T, Koravou EE, Koutra M, Papayanni PG, Pouleres A, Karali V, Lemonis ME, Mamou A, Skentou AD, Papalexandri A, Varelas C, Chatzopoulou F, Chatzidimitriou M, Chatzidimitriou D, Veleni A, Rapti E, Kioumis I, Kaimakamis E, Bitzani M, Boumpas D, Tsantes A, Sotiropoulos D, Papadopoulou A, Kalantzis IG, Vallianatou LA, Armaghani DJ, Cavaleri L, Gandomi AH, Hajihassani M, Hasanipanah M, Koopialipoor M, Lourenço PB, Samui P, Zhou J, Sakellari I, Valsami S, Politou M, Kokoris S, and Anagnostopoulos A
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- COVID-19 epidemiology, Complement Activation genetics, Complement Factor H genetics, Complement System Proteins genetics, Female, Greece epidemiology, Hospitalization statistics & numerical data, Humans, Intensive Care Units statistics & numerical data, Male, Middle Aged, Models, Genetic, Morbidity, Polymorphism, Single Nucleotide, Thrombomodulin genetics, COVID-19 genetics, COVID-19 mortality, Neural Networks, Computer
- Abstract
There is an unmet need of models for early prediction of morbidity and mortality of Coronavirus disease-19 (COVID-19). We aimed to a) identify complement-related genetic variants associated with the clinical outcomes of ICU hospitalization and death, b) develop an artificial neural network (ANN) predicting these outcomes and c) validate whether complement-related variants are associated with an impaired complement phenotype. We prospectively recruited consecutive adult patients of Caucasian origin, hospitalized due to COVID-19. Through targeted next-generation sequencing, we identified variants in complement factor H/CFH, CFB, CFH-related, CFD, CD55, C3, C5, CFI, CD46, thrombomodulin/THBD, and A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS13). Among 381 variants in 133 patients, we identified 5 critical variants associated with severe COVID-19: rs2547438 (C3), rs2250656 (C3), rs1042580 (THBD), rs800292 (CFH) and rs414628 (CFHR1). Using age, gender and presence or absence of each variant, we developed an ANN predicting morbidity and mortality in 89.47% of the examined population. Furthermore, THBD and C3a levels were significantly increased in severe COVID-19 patients and those harbouring relevant variants. Thus, we reveal for the first time an ANN accurately predicting ICU hospitalization and death in COVID-19 patients, based on genetic variants in complement genes, age and gender. Importantly, we confirm that genetic dysregulation is associated with impaired complement phenotype., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
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- 2022
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25. Immune Response of Adult Sickle Cell Disease Patients after COVID-19 Vaccination: The Experience of a Greek Center.
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Varelas C, Gavriilaki E, Sakellari I, Klonizakis P, Koravou EE, Christodoulou I, Mavrikou I, Kourelis A, Chatzopoulou F, Chatzidimitriou D, Touloumenidou T, Papalexandri A, Anagnostopoulos A, and Vlachaki E
- Abstract
Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are essential weapons to control the spread of the coronavirus disease-19 (COVID-19) pandemic and protect immunocompromised patients. With a greater susceptibility to infection, sickle cell disease (SCD) patients are considered as "high risk" patients during the current COVID-19 pandemic. In our study, we try to determine the immune response of adult SCD patients monitored at our center after the first and second dose of the qualified mRNA vaccines available and correlate them to several disease-specific markers, as well as complement activation. The results demonstrate that the levels of neutralizing antibodies (nAbs) against SARS-CoV-2 were adequate for most patients studied after the second dose and there seemed to be a certain association with complement activation. Further studies are critical to determine the durability of this immune response and the potential benefit of a third dose.
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- 2022
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26. Predictors of Transplant-Associated Thrombotic Microangiopathy in Patients With Overlap or Chronic Graft-vs-Host-Disease.
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Gavriilaki E, Sakellari I, Chatzikonstantinou T, Bousiou Z, Mallouri D, Masmanidou M, Vardi A, Koravou EE, Kika F, Touloumenidou T, Papalexandri A, Yannaki E, Batsis I, and Anagnostopoulos A
- Subjects
- Humans, Retrospective Studies, Graft vs Host Disease diagnosis, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects, Thrombotic Microangiopathies etiology, Transplants
- Abstract
Background: Recent data suggest that novel biologic agents are associated with increased risk of thrombotic microangiopathy (TMA). Ruxolitinib, an approved treatment for graft-vs-host-disease (GVHD), has been associated with thrombocytopenia of unclear etiology., Methods: We investigated factors and outcomes associated with transplant-associated thrombotic microangiopathy (TA-TMA) in patients with GVHD. We retrospectively enrolled consecutive allogeneic hematopoietic cell transplantation recipients with overlap or chronic GVHD at our Joint Accreditation Committee ISCT-Europe & EBMT-accredited unit (January 2016-June 2019). Ruxolitinib has been administered off-label since 2016., Results: Among 160 patients with GVHD, 18 were diagnosed with TA-TMA. TA-TMA developed at a median of 150 posttransplant days (range, 98-3013). Among pre- and posttransplant factors, TA-TMA was associated only with ruxolitinib administration and severe GVHD. Interestingly, these 2 variables did not correlate with each other. In the multivariate analysis, both were independent predictors of TA-TMA. Time-dependent analysis confirmed ruxolitinib's association with TA-TMA. With a follow-up of 38.4 months (4.6-83.9) in surviving patients, 5-year overall survival was 52.9%, independently predicted by TA-TMA, severe acute GVHD, and CD34+ cells infused. Ruxolitinib was not associated with survival outcomes., Conclusions: Our data suggest that ruxolitinib and GVHD severity are associated with TA-TMA. Given the expanding use of ruxolitinib in GVHD and ongoing trials on chronic GVHD, further studies are warranted to confirm these findings., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2021
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27. Genetic justification of severe COVID-19 using a rigorous algorithm.
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Gavriilaki E, Asteris PG, Touloumenidou T, Koravou EE, Koutra M, Papayanni PG, Karali V, Papalexandri A, Varelas C, Chatzopoulou F, Chatzidimitriou M, Chatzidimitriou D, Veleni A, Grigoriadis S, Rapti E, Chloros D, Kioumis I, Kaimakamis E, Bitzani M, Boumpas D, Tsantes A, Sotiropoulos D, Sakellari I, Kalantzis IG, Parastatidis ST, Koopialipoor M, Cavaleri L, Armaghani DJ, Papadopoulou A, Brodsky RA, Kokoris S, and Anagnostopoulos A
- Subjects
- Aged, Algorithms, COVID-19 physiopathology, Complement Activation, Complement Factor H genetics, Critical Care, Female, Genetic Testing, High-Throughput Nucleotide Sequencing, Hospitalization statistics & numerical data, Humans, Intensive Care Units, Male, Middle Aged, Risk Factors, Severity of Illness Index, Thrombotic Microangiopathies genetics, ADAMTS13 Protein genetics, COVID-19 genetics, Complement C3 genetics, Genetic Predisposition to Disease genetics, Thrombomodulin genetics
- Abstract
Recent studies suggest excessive complement activation in severe coronavirus disease-19 (COVID-19). The latter shares common characteristics with complement-mediated thrombotic microangiopathy (TMA). We hypothesized that genetic susceptibility would be evident in patients with severe COVID-19 (similar to TMA) and associated with disease severity. We analyzed genetic and clinical data from 97 patients hospitalized for COVID-19. Through targeted next-generation-sequencing we found an ADAMTS13 variant in 49 patients, along with two risk factor variants (C3, 21 patients; CFH,34 patients). 31 (32%) patients had a combination of these, which was independently associated with ICU hospitalization (p = 0.022). Analysis of almost infinite variant combinations showed that patients with rs1042580 in thrombomodulin and without rs800292 in complement factor H did not require ICU hospitalization. We also observed gender differences in ADAMTS13 and complement-related variants. In light of encouraging results by complement inhibitors, our study highlights a patient population that might benefit from early initiation of specific treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2021
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28. Endothelial and Complement Activation As Predictors of Survival in Adult Allogeneic Hematopoietic Cell Transplantation.
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Gavriilaki E, Sakellari I, Chatzikonstantinou T, Mallouri D, Batsis I, Vardi A, Bousiou Z, Koravou EE, Masmanidou M, Touloumenidou T, Papalexandri A, Athanasiadou A, Yannaki E, and Anagnostopoulos A
- Abstract
Competing Interests: EG has consulted for Alexion and Omeros Pharmaceuticals. The remaining authors have no conflicts of interest.
- Published
- 2020
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29. Correction: Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.
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Pfeifer H, Cazzaniga G, van der Velden VHJ, Cayuela JM, Schäfer B, Spinelli O, Akiki S, Avigad S, Bendit I, Borg K, Cavé H, Elia L, Reshmi SC, Gerrard G, Hayette S, Hermanson M, Juh A, Jurcek T, Chillón MC, Homburg C, Martinelli G, Kairisto V, Lange T, Lion T, Mueller MC, Pane F, Rai L, Damm-Welk C, Sacha T, Schnittger S, Touloumenidou T, Valerhaugen H, Vandenberghe P, Zuna J, Serve H, Herrmann E, Markovic S, van Dongen JJM, and Ottmann OG
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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30. Pretransplant Genetic Susceptibility: Clinical Relevance in Transplant-Associated Thrombotic Microangiopathy.
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Gavriilaki E, Touloumenidou T, Sakellari I, Batsis I, Mallouri D, Psomopoulos F, Tsagiopoulou M, Koutra M, Yannaki E, Papalexandri A, Taylor P, Nikolousis E, Stamouli M, Holbro A, Baltadakis I, Liga M, Spyridonidis A, Tsirigotis P, Charchalakis N, Tsakiris DA, Brodsky RA, Passweg J, Stamatopoulos K, and Anagnostopoulos A
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- ADAMTS13 Protein genetics, Adult, Aged, Female, Genetic Predisposition to Disease, Genome, Hematologic Neoplasms mortality, Hematologic Neoplasms therapy, Humans, Male, Middle Aged, Survival Analysis, Thrombotic Microangiopathies etiology, Transplantation, Homologous, Young Adult, Genotype, Hematologic Neoplasms genetics, Hematopoietic Stem Cell Transplantation, Postoperative Complications genetics, Thrombotic Microangiopathies genetics, Untranslated Regions genetics
- Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic cell transplantation (HCT). We hypothesized that pretransplant genetic susceptibility is evident in adult TA-TMA and further investigated the association of TMA-associated variants with clinical outcomes. We studied 40 patients with TA-TMA, donors of 18 patients and 40 control non-TMA HCT recipients, without significant differences in transplant characteristics. Genomic DNA from pretransplant peripheral blood was sequenced for TMA-associated genes. Donors presented significantly lower frequency of rare variants and variants in exonic/splicing/untranslated region (UTR) regions, compared with TA-TMA patients. Controls also showed a significantly lower frequency of rare variants in ADAMTS13 , CD46 , CFH , and CFI. The majority of TA-TMA patients (31/40) presented with pathogenic or likely pathogenic variants. Patients refractory to conventional treatment (62%) and patients that succumbed to transplant-related mortality (65%) were significantly enriched for variants in exonic/splicing/UTR regions. In conclusion, increased incidence of pathogenic, rare and variants in exonic/splicing/UTR regions of TA-TMA patients suggests genetic susceptibility not evident in controls or donors. Notably, variants in exonic/splicing/UTR regions were associated with poor response and survival. Therefore, pretransplant genomic screening may be useful to intensify monitoring and early intervention in patients at high risk for TA-TMA., Competing Interests: R.A.B. is currently serving as an Alexion Pharmaceuticals Scientific Advisory Board member and an Achillion Pharmaceuticals Scientific Advisor (or consultant). The other authors declare no competing financial interest., (Georg Thieme Verlag KG Stuttgart · New York.)
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- 2020
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31. Linking Complement Activation, Coagulation, and Neutrophils in Transplant-Associated Thrombotic Microangiopathy.
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Gavriilaki E, Chrysanthopoulou A, Sakellari I, Batsis I, Mallouri D, Touloumenidou T, Papalexandri A, Mitsios A, Arampatzioglou A, Ritis K, Brodsky RA, Mitroulis I, and Anagnostopoulos A
- Subjects
- Adult, Aged, Antithrombin III, Biomarkers metabolism, Blood Coagulation, Case-Control Studies, Complement Activation, Complement Membrane Attack Complex metabolism, Female, Humans, Male, Middle Aged, Peptide Hydrolases blood, Thrombomodulin blood, Thrombotic Microangiopathies etiology, Young Adult, Endothelium, Vascular pathology, Extracellular Traps metabolism, Graft vs Host Disease immunology, Hematopoietic Stem Cell Transplantation, Neutrophils immunology, Postoperative Complications immunology, Thrombotic Microangiopathies immunology
- Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe and life-threatening complication of hematopoietic cell transplantation (HCT) that often coincides with graft-versus-host-disease (GVHD). Although endothelial damage seems to be the common denominator for both disorders, the role of complement system, neutrophils, and coagulation has not been clarified. In an effort to distinguish the pathogenesis of TA-TMA from GVHD, we evaluated markers of complement activation, neutrophil extracellular trap (NET) release, endothelial damage, and activation of coagulation cascade in the circulation of patients with these two disorders, as well as control HCT recipients without TA-TMA or GVHD. We observed that the terminal complement product C5b-9 levels, the levels of markers of NET formation, and thrombin-antithrombin complex levels were significantly increased in the TA-TMA group compared with patients without complications, whereas there was no significant difference between the GVHD and the control group. On the other hand, the levels of circulating thrombomodulin, an endothelial damage marker, were significantly increased in both TA-TMA and GVHD patients. These findings propose a role for the interplay between complement system, neutrophil activation through NET release, and activation of the coagulation cascade in TA-TMA., Competing Interests: R.A.B. is currently serving as an Alexion Pharmaceuticals Scientific Advisory Board member, an Achillion Pharmaceuticals Scientific Advisor (or consultant), and an Apellis Pharmaceuticals Scientific Advisor (or consultant). Other authors declare no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)
- Published
- 2019
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32. Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.
- Author
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Pfeifer H, Cazzaniga G, van der Velden VHJ, Cayuela JM, Schäfer B, Spinelli O, Akiki S, Avigad S, Bendit I, Borg K, Cavé H, Elia L, Reshmi SC, Gerrard G, Hayette S, Hermanson M, Juh A, Jurcek T, Chillón MC, Homburg C, Martinelli G, Kairisto V, Lange T, Lion T, Mueller MC, Pane F, Rai L, Damm-Welk C, Sacha T, Schnittger S, Touloumenidou T, Valerhaugen H, Vandenberghe P, Zuna J, Serve H, Herrmann E, Markovic S, Dongen JJMV, and Ottmann OG
- Subjects
- Consensus, Humans, Neoplasm, Residual, RNA, Messenger analysis, Fusion Proteins, bcr-abl genetics, Philadelphia Chromosome, Practice Guidelines as Topic, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Real-Time Polymerase Chain Reaction methods
- Abstract
Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10
-3 and 36/67 (53%) and 53/67 (79%) at 10-4 BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.- Published
- 2019
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33. Skewing of the T-cell receptor repertoire in patients receiving rituximab after allogeneic hematopoietic cell transplantation: what lies beneath?
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Papalexandri A, Karypidou M, Stalika E, Kotta K, Touloumenidou T, Zerva P, Paleta A, Mallouri D, Batsis I, Sakellari I, Kotsianidis I, Anagnostopoulos A, Hadzidimitriou A, Margaritis D, and Stamatopoulos K
- Subjects
- Adolescent, Adult, Antineoplastic Agents, Immunological adverse effects, Female, Follow-Up Studies, Gene Rearrangement, T-Lymphocyte genetics, Graft vs Host Disease etiology, Graft vs Host Disease pathology, Hematologic Neoplasms therapy, Humans, Leukemia, Large Granular Lymphocytic chemically induced, Leukemia, Large Granular Lymphocytic immunology, Male, Middle Aged, Prognosis, Retrospective Studies, Survival Rate, Transplantation, Homologous, Virus Activation drug effects, Young Adult, Clonal Evolution, Gene Rearrangement, T-Lymphocyte immunology, Graft vs Host Disease drug therapy, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Large Granular Lymphocytic pathology, Receptors, Antigen, T-Cell, alpha-beta immunology, Rituximab adverse effects
- Abstract
Rituximab is known to affect T cell immune responses. We and others have reported expansions of T large granular lymphocytes (T-LGLs) in lymphoma patients after Rituximab. We report here the immunogenetic profiling of the T cell receptor (TR) gene repertoire in 14 patients who received Rituximab post allo-HCT and explore clinicobiological correlations. All experienced antigenic triggers, CMV, EBV re-activation and chronic GvHD and had been treated with Rituximab. Skewing of TRBV genes was observed: 3 TRBV genes accounted for half of the repertoire. Oligoclonal pattern with expanded clonotypes was common. Patients with oligoclonality exhibited frequently cGvHD. Longitudinal samples in one revealed distinct clonotypes, suggesting clonal drift. T-LGL leukemia of donor origin with mixed chimerism eventually developed. In conclusion, we report development of oligoclonal T-LGLs after Rituximab post allo-HCT, alluding to antigen selection. Persistence of this phenomenon likely reflects strong antigenic stimulation by viruses and/or cGVHD aggravated by Rituximab.
- Published
- 2019
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34. Blast Crisis of CML After TKI Discontinuation in a Patient With Previous Stable Deep Molecular Response: Is It Safe to Stop?
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Papalexandri A, Saloum R, Touloumenidou T, Papathanasiou M, Lalayanni C, Baldoumi E, Demosthenous C, Zerva P, Koutra MG, Athanasiadou A, and Anagnostopoulos A
- Published
- 2018
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35. Pre- and Post-transfusion Complement Activation in Transfusion-dependent β-thalassaemia.
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Gavriilaki E, Christodoulou I, Koravou EE, Paleta A, Koutra M, Zerva P, Touloumenidou T, Papalexandri A, Apostolou C, Klonizakis P, Anagnostopoulos A, and Vlachaki E
- Published
- 2018
- Full Text
- View/download PDF
36. Donor EBV at the time of hematopoietic cell transplantation: Is it time to adopt molecular assays?
- Author
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Sakellari I, Papalexandri A, Mallouri D, Batsis I, Iskas M, Xochelli A, Marvaki A, Gavriilaki E, Vardi A, Zerva P, Touloumenidou T, and Anagnostopoulos A
- Subjects
- Adolescent, Adult, Antineoplastic Agents, Immunological pharmacology, Antineoplastic Agents, Immunological therapeutic use, Epstein-Barr Virus Infections drug therapy, Female, Humans, Male, Middle Aged, Rituximab pharmacology, Rituximab therapeutic use, Virus Activation drug effects, Young Adult, DNA, Viral blood, Epstein-Barr Virus Infections virology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation adverse effects, Tissue Donors
- Published
- 2018
- Full Text
- View/download PDF
37. In vitro evidence of complement activation in patients with sickle cell disease.
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Gavriilaki E, Mainou M, Christodoulou I, Koravou EE, Paleta A, Touloumenidou T, Papalexandri A, Athanasiadou A, Apostolou C, Klonizakis P, Anagnostopoulos A, and Vlachaki E
- Subjects
- Adult, Biomarkers analysis, Female, Humans, Male, Middle Aged, Anemia, Sickle Cell immunology, Complement Activation
- Published
- 2017
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- View/download PDF
38. GLASS: assisted and standardized assessment of gene variations from Sanger sequence trace data.
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Pal K, Bystry V, Reigl T, Demko M, Krejci A, Touloumenidou T, Stalika E, Tichy B, Ghia P, Stamatopoulos K, Pospisilova S, Malcikova J, and Darzentas N
- Subjects
- Alternative Splicing, Humans, Polymorphism, Genetic, Tumor Suppressor Protein p53 genetics, Genotyping Techniques methods, Sequence Analysis, DNA methods, Sequence Analysis, RNA methods, Software
- Abstract
Motivation: Sanger sequencing is still being employed for sequence variant detection by many laboratories, especially in a clinical setting. However, chromatogram interpretation often requires manual inspection and in some cases, considerable expertise., Results: We present GLASS, a web-based Sanger sequence trace viewer, editor, aligner and variant caller, built to assist with the assessment of variations in 'curated' or user-provided genes. Critically, it produces a standardized variant output as recommended by the Human Genome Variation Society., Availability and Implementation: GLASS is freely available at http://bat.infspire.org/genomepd/glass/ with source code at https://github.com/infspiredBAT/GLASS., Contact: nikos.darzentas@gmail.com or malcikova.jitka@fnbrno.cz., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)
- Published
- 2017
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39. Tp53 gene p72R polymorphism in chronic lymphocytic leukemia: incidence and clinical significance amongst cases with unmutated immunoglobulin receptors.
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Gemenetzi K, Galigalidou C, Vlachonikola E, Stalika E, Xochelli A, Baliakas P, Karypidou M, Touloumenidou T, Minga E, Douka V, Iskas M, Athanasiadou A, Makris A, Stavroyianni N, Anagnostopoulos A, Hadzidimitriou A, and Stamatopoulos K
- Subjects
- Amino Acid Substitution, Codon, Gene Rearrangement, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Variable Region genetics, Incidence, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Mutation, Phenotype, Alleles, Genes, p53, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Polymorphism, Single Nucleotide
- Published
- 2017
- Full Text
- View/download PDF
40. Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale.
- Author
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Cross NC, White HE, Ernst T, Welden L, Dietz C, Saglio G, Mahon FX, Wong CC, Zheng D, Wong S, Wang SS, Akiki S, Albano F, Andrikovics H, Anwar J, Balatzenko G, Bendit I, Beveridge J, Boeckx N, Cerveira N, Cheng SM, Colomer D, Czurda S, Daraio F, Dulucq S, Eggen L, El Housni H, Gerrard G, Gniot M, Izzo B, Jacquin D, Janssen JJ, Jeromin S, Jurcek T, Kim DW, Machova-Polakova K, Martinez-Lopez J, McBean M, Mesanovic S, Mitterbauer-Hohendanner G, Mobtaker H, Mozziconacci MJ, Pajič T, Pallisgaard N, Panagiotidis P, Press RD, Qin YZ, Radich J, Sacha T, Touloumenidou T, Waits P, Wilkinson E, Zadro R, Müller MC, Hochhaus A, and Branford S
- Subjects
- Calibration, Fusion Proteins, bcr-abl standards, Genes, abl, Humans, Polymerase Chain Reaction, Proto-Oncogene Proteins c-bcr genetics, Reference Standards, World Health Organization, Fusion Proteins, bcr-abl analysis
- Abstract
Molecular monitoring of chronic myeloid leukemia patients using robust BCR-ABL1 tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO) BCR-ABL1 reference panel was developed (MR(1)-MR(4)), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR(4.5) level. The secondary panel was calibrated to IS using digital PCR with ABL1, BCR and GUSB as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of BCR-ABL1 assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR(4.5) sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms., Competing Interests: This study was designed and funded by Novartis Pharmaceuticals Corporation. CW, DZ, SW and SSW are employed by Novartis Pharmaceuticals Corporation. None of the co-authors, participating laboratories or institutions received any payments for participating in this study. All authors have read and agreed with the contents of the manuscript. All other authors declare no conflicts of interest.
- Published
- 2016
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41. ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset #2 is associated with markedly short telomeres.
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Navrkalova V, Young E, Baliakas P, Radova L, Sutton LA, Plevova K, Mansouri L, Ljungström V, Ntoufa S, Davis Z, Juliusson G, Smedby KE, Belessi C, Panagiotidis P, Touloumenidou T, Davi F, Langerak AW, Ghia P, Strefford JC, Oscier D, Mayer J, Stamatopoulos K, Pospisilova S, Rosenquist R, and Trbusek M
- Subjects
- Cohort Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Sequence Analysis, DNA, Survival Analysis, Telomere ultrastructure, Ataxia Telangiectasia Mutated Proteins genetics, Leukemia, Lymphocytic, Chronic, B-Cell classification, Mutation, Telomere Shortening
- Published
- 2016
- Full Text
- View/download PDF
42. A certified plasmid reference material for the standardisation of BCR-ABL1 mRNA quantification by real-time quantitative PCR.
- Author
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White H, Deprez L, Corbisier P, Hall V, Lin F, Mazoua S, Trapmann S, Aggerholm A, Andrikovics H, Akiki S, Barbany G, Boeckx N, Bench A, Catherwood M, Cayuela JM, Chudleigh S, Clench T, Colomer D, Daraio F, Dulucq S, Farrugia J, Fletcher L, Foroni L, Ganderton R, Gerrard G, Gineikienė E, Hayette S, El Housni H, Izzo B, Jansson M, Johnels P, Jurcek T, Kairisto V, Kizilors A, Kim DW, Lange T, Lion T, Polakova KM, Martinelli G, McCarron S, Merle PA, Milner B, Mitterbauer-Hohendanner G, Nagar M, Nickless G, Nomdedéu J, Nymoen DA, Leibundgut EO, Ozbek U, Pajič T, Pfeifer H, Preudhomme C, Raudsepp K, Romeo G, Sacha T, Talmaci R, Touloumenidou T, Van der Velden VH, Waits P, Wang L, Wilkinson E, Wilson G, Wren D, Zadro R, Ziermann J, Zoi K, Müller MC, Hochhaus A, Schimmel H, Cross NC, and Emons H
- Subjects
- Calibration, Cloning, Molecular, DNA, Escherichia coli Proteins genetics, Gene Dosage, Humans, Membrane Transport Proteins genetics, Proto-Oncogene Proteins c-bcr genetics, RNA, Messenger metabolism, Reference Standards, Fusion Proteins, bcr-abl genetics, Fusion Proteins, bcr-abl metabolism, Plasmids genetics, Real-Time Polymerase Chain Reaction standards
- Abstract
Serial quantification of BCR-ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR-ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 10(6), 1.08±0.11 × 10(5), 1.03±0.10 × 10(4), 1.02±0.09 × 10(3), 1.04±0.10 × 10(2) and 10.0±1.5 copies/μl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR-ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR-ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a-f).
- Published
- 2015
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43. Molecular evidence for repertoire skewing of T large granular lymphocyte proliferation after allogeneic hematopoietic SCT: report of two cases.
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Papalexandri A, Stalika E, Iskas M, Karypidou M, Zerva P, Touloumenidou T, Tachynopoulou V, Batsis I, Papadaki T, Sakellari I, Anagnostopoulos A, and Stamatopoulos K
- Subjects
- Adolescent, Adult, Female, Humans, Leukemia, Large Granular Lymphocytic immunology, Leukemia, Large Granular Lymphocytic pathology, Lymphocyte Activation, Male, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta immunology, Transplantation Conditioning methods, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation methods, Leukemia, Large Granular Lymphocytic genetics, Leukemia, Large Granular Lymphocytic therapy
- Published
- 2013
- Full Text
- View/download PDF
44. Sequential transient novel chromosomal translocations in a patient with chronic myelogenous leukemia in complete cytogenetic remission after therapy with imatinib mesylate.
- Author
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Papaioannou G, Athanasiadou A, Voutiadou G, Gaitatzi M, Batsis I, Touloumenidou T, and Anagnostopoulos A
- Subjects
- Adult, Antineoplastic Agents adverse effects, Benzamides, Clonal Evolution, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Male, Philadelphia Chromosome, Piperazines adverse effects, Protein Kinase Inhibitors adverse effects, Pyrimidines adverse effects, Remission Induction, Antineoplastic Agents therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Piperazines therapeutic use, Protein Kinase Inhibitors therapeutic use, Pyrimidines therapeutic use, Translocation, Genetic
- Published
- 2011
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- View/download PDF
45. Toll-like receptor signaling pathway in chronic lymphocytic leukemia: distinct gene expression profiles of potential pathogenic significance in specific subsets of patients.
- Author
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Arvaniti E, Ntoufa S, Papakonstantinou N, Touloumenidou T, Laoutaris N, Anagnostopoulos A, Lamnissou K, Caligaris-Cappio F, Stamatopoulos K, Ghia P, Muzio M, and Belessi C
- Subjects
- B-Lymphocytes pathology, Female, Gene Expression Profiling, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Neoplasm Proteins genetics, Oligonucleotide Array Sequence Analysis, Toll-Like Receptors genetics, B-Lymphocytes metabolism, Gene Expression Regulation, Leukemic, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, MAP Kinase Signaling System, Neoplasm Proteins biosynthesis, Toll-Like Receptors biosynthesis
- Abstract
Background: Signaling through the B-cell receptor appears to be a major contributor to the pathogenesis of chronic lymphocytic leukemia. Toll-like receptors bridge the innate and adaptive immune responses by acting as co-stimulatory signals for B cells. The available data on the expression of Toll-like receptors in chronic lymphocytic leukemia are limited and derive from small series of patients., Design and Methods: We profiled the expression of genes associated with Toll-like receptor signaling pathways in 192 cases of chronic lymphocytic leukemia and explored potential associations with molecular features of the clonotypic B-cell receptors., Results: Chronic lymphocytic leukemia cells express all Toll-like receptors expressed by normal activated B cells, with high expression of TLR7 and CD180, intermediate expression of TLR1, TLR6, TLR10 and low expression of TLR2 and TLR9. The vast majority of adaptors, effectors and members of the NFKB, JNK/p38, NF/IL6 and IRF pathways are intermediately-to-highly expressed, while inhibitors of Toll-like receptor activity are generally low-to-undetectable, indicating that the Toll-like receptor-signaling framework is competent in chronic lymphocytic leukemia. Significant differences were identified for selected genes between cases carrying mutated or unmutated IGHV genes or assigned to different subsets with stereotyped B-cell receptors. The differentially expressed molecules include receptors, NFκB/MAPK signaling molecules and final targets of the cascade., Conclusions: The observed variations are suggestive of distinctive activation patterns of the Toll-like receptor signaling pathway in subgroups of cases of chronic lymphocytic leukemia defined by the molecular features of B-cell receptors. Additionally, they indicate that different or concomitant signals acting through receptors other than the B-cell receptor can affect the behavior of the malignant clone.
- Published
- 2011
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- View/download PDF
46. Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors.
- Author
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Kostareli E, Hadzidimitriou A, Stavroyianni N, Darzentas N, Athanasiadou A, Gounari M, Bikos V, Agathagelidis A, Touloumenidou T, Zorbas I, Kouvatsi A, Laoutaris N, Fassas A, Anagnostopoulos A, Belessi C, and Stamatopoulos K
- Subjects
- Aged, B-Lymphocytes immunology, B-Lymphocytes pathology, Case-Control Studies, Cohort Studies, Disease Progression, Female, Genome, Viral, Humans, Male, Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, Somatic Hypermutation, Immunoglobulin, Time Factors, Virus Activation, Cytomegalovirus physiology, Herpesvirus 4, Human physiology, Immunoglobulin Heavy Chains genetics, Immunoglobulin Variable Region genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell virology, Receptors, Antigen, B-Cell genetics
- Abstract
The chronic lymphocytic leukemia (CLL) immunoglobulin repertoire is uniquely characterized by the presence of stereotyped B-cell receptors (BCRs). A major BCR stereotype in CLL is shared by immunoglobulin G-switched cases utilizing the immunoglobulin heavy-chain variable 4-34 (IGHV4-34) gene. Increased titers of IGHV4-34 antibodies are detected in selective clinical conditions, including infection by B-cell lymphotropic viruses, particularly Epstein-Barr virus (EBV) and cytomegalovirus (CMV). In this context, we sought evidence for persistent activation by EBV and CMV in CLL cases expressing the IGHV4-34 gene. The study group included 93 CLL cases with an intentional bias for the IGHV4-34 gene. On the basis of real-time PCR results for CMV/EBV DNA, cases were assigned to three groups: (1) double-negative (59/93); (2) single-positive (CMV- or EBV-positive; 25/93); (3) double-positive (9/93). The double-negative group was characterized by heterogeneous IGHV gene repertoire. In contrast, a bias for the IGHV4-34 gene was observed in the single-positive group (9/25 cases; 36%). Remarkably, all nine double-positive cases utilized the IGHV4-34 gene; seven of nine cases expressed the major BCR stereotype as described above. In conclusion, our findings indicate that the interactions of CLL progenitor cells expressing distinctive IGHV4-34 BCRs with viral antigens/superantigens might facilitate clonal expansion and, eventually, leukemic transformation. The exact type, timing and location of these interactions remain to be determined.
- Published
- 2009
- Full Text
- View/download PDF
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