N-glycosylation of integrins plays an important role in cancer progression. Increased αvβ3 integrin expression during melanoma progression is well-documented but the role of its glycans in tumorigenesis is still poorly understood. In the present study we used the WM793 primary melanoma cell line and its highly metastatic variant, WM1205Lu, to examine αvβ3 glycosylation. Lectin precipitation, enzyme digestion and the use of swainsonine (SW) showed that αvβ3 integrin glycosylation differs significantly between primary and metastatic melanoma cells. High-mannose structures and complex glycans with bisecting N-acetylglucosamine (GlcNAc) were more abundant in both subunits of primary cells. We also observed a shift in the sialylation of αvβ3 integrin related to reduction of α2-6-linked sialic acid expression and an increase of α2-3 sialylation of both subunits in melanoma progression. Metastatic melanoma migration on vitronectin (VN) was reduced in the presence of antibody against αvβ3 and the lectins phytohemagglutinin-L (PHA-L), Sambucus nigra agglutinin (SNA) and Maackia amurensis (MAA) in woundhealing assays. Our results show that the acquisition of metastatic competence by melanoma cells is accompanied by alteration of αvβ3 integrin glycosylation and that both αvβ3 and β1-6-branched sialylated complex-type N-glycans promote metastatic melanoma migration on VN.
Galectin-3 (Gal-3) is a member of the β-galactoside-binding lectins family and has been implicated in angiogenesis, tumor invasion, and metastatic process in vitro and in vivo. As we showed recently that advanced melanoma patients presented high serum level of Gal-3, we investigated the association of this protein with the outcome of melanoma patients. Whether this protein could be a biomarker has not been assessed, and we compared the prognostic value of serum Gal-3 in multivariate analysis with lactate dehydrogenase, C-reactive protein and S100B. We conclude that Gal-3 could be of prognostic value in melanoma patients; more precisely, this protein has a strong independent prognostic signification with a cut-off value of 10 ng/ml. After these data, we believe that serum Gal-3 measurement can have an important role in the follow-up and management of advanced American Joint Commission on Cancer stage III and stage IV melanoma patients. Further studies will uncover whether Gal-3 will be able to open new therapeutic perspectives.
We have examined the diversity between primary uveal (92-1 and Mel202) and cutaneous (FM55P and IGR-39) melanoma cells in their interaction with vitronectin, and established the effect of integrins and β1,6-branched N-oligosaccharides on this process. The adhesion level of uveal melanoma cells to vitronectin was at least twice lower than that of cutaneous ones, but all cells tested repaired scratch wounds on vitronectin-coated surfaces with similar speed. Swainsonine treatment, by reducing the amount of β1,6-branches, significantly decreased cell attachment in all cases, but reduction of wound healing efficiency was compromised only in cutaneous melanoma cell. Functional blocking antibodies used in adhesion and migration assays revealed that integrin αvβ3 was strongly involved in adhesion and migration only in cutaneous melanoma cells, but its role here was less pronounced than that of integrin αvβ5. However, in uveal melanoma the specific anti-αvβ5 integrin antibody had no impact on migration speed. Therefore, the anti-α3β1 integrin antibody was used in order to explain the nature of uveal melanoma interaction with vitronectin, which caused a mild decrease in adhesion efficiency and reduced their motility. Expression of αvβ5 integrin differed between the cell lines, but there was no distinct pattern to distinguish uveal melanoma from cutaneous melanoma. In conclusion, αvβ5, but not αvβ3 integrin is heavily involved in uveal melanoma cell interaction with vitronectin. The role of β1,6-branched N-glycans in the adhesion, but not during migration, of all cells to vitronectin has been confirmed.
Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells glycosylation with AITD and the influence of genetic background in a case-control study with several independent cohorts and over 3,000 individuals in total. The study revealed an inverse association of IgG core fucosylation with TPOAb and AITD, as well as decreased peripheral blood mononuclear cells antennary α1,2 fucosylation in AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity previously associated with TPOAb levels. Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells glycosylation with AITD and the influence of genetic background in a case-control study with several independent cohorts and over 3,000 individuals in total. The study revealed an inverse association of IgG core fucosylation with TPOAb and AITD, as well as decreased peripheral blood mononuclear cells antennary α1,2 fucosylation in AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity previously associated with TPOAb levels. Autoimmune thyroid diseases (AITD) 1The abbreviations used are:AITDAutoimmune thyroid diseaseADCCantibody-dependent cell-mediated cytotoxicityFcãRsFcã-receptorsFUT8Fucosyltransferase 8 (Alpha (1,6) Fucosyltransferase)GDGraves' diseaseGlcNAcN-acetylglucosamineGWASgenome-wide association studiesHTHashimoto's thyroiditisIgGImmunoglobulin GIKZF1IKAROS Family Zinc Finger 1LDlinkage disequilibriumvNKNatural killer cellNSFN-Ethylmaleimide Sensitive FactorPBMCperipheral blood mononuclear cellsTgthyroglobulinTgAbthyroglobulin antibodiesTPOthyroid peroxidaseTPOAbThyroid peroxidase antibodiesTSAbantibodies against TSH receptorsTSHthyroid-stimulating hormoneTSHRTSH receptorTWAStranscriptome-wide association studies. 1The abbreviations used are:AITDAutoimmune thyroid diseaseADCCantibody-dependent cell-mediated cytotoxicityFcãRsFcã-receptorsFUT8Fucosyltransferase 8 (Alpha (1,6) Fucosyltransferase)GDGraves' diseaseGlcNAcN-acetylglucosamineGWASgenome-wide association studiesHTHashimoto's thyroiditisIgGImmunoglobulin GIKZF1IKAROS Family Zinc Finger 1LDlinkage disequilibriumvNKNatural killer cellNSFN-Ethylmaleimide Sensitive FactorPBMCperipheral blood mononuclear cellsTgthyroglobulinTgAbthyroglobulin antibodiesTPOthyroid peroxidaseTPOAbThyroid peroxidase antibodiesTSAbantibodies against TSH receptorsTSHthyroid-stimulating hormoneTSHRTSH receptorTWAStranscriptome-wide association studies. are a class of chronic, organ-specific autoimmune disorders that disturb the function of the thyroid gland. They affect close to 5% of the European population (with a gender disparity) and so, represent the most common group of autoimmune diseases (1Wang B. Shao X. Song R. Xu D. Zhang J.-A. The emerging role of epigenetics in autoimmune thyroid diseases.Front. Immunol. 2017; 8: 113-174PubMed Google Scholar). AITD encompass a spectrum of conditions including Hashimoto's thyroiditis (HT) and Graves' disease (GD). One of the features of AITD is the production of autoantibodies against components of thyroid cells that are also detected in the bloodstream. Autoimmune thyroid disease antibody-dependent cell-mediated cytotoxicity Fcã-receptors Fucosyltransferase 8 (Alpha (1,6) Fucosyltransferase) Graves' disease N-acetylglucosamine genome-wide association studies Hashimoto's thyroiditis Immunoglobulin G IKAROS Family Zinc Finger 1 linkage disequilibriumv Natural killer cell N-Ethylmaleimide Sensitive Factor peripheral blood mononuclear cells thyroglobulin thyroglobulin antibodies thyroid peroxidase Thyroid peroxidase antibodies antibodies against TSH receptors thyroid-stimulating hormone TSH receptor transcriptome-wide association studies. Autoimmune thyroid disease antibody-dependent cell-mediated cytotoxicity Fcã-receptors Fucosyltransferase 8 (Alpha (1,6) Fucosyltransferase) Graves' disease N-acetylglucosamine genome-wide association studies Hashimoto's thyroiditis Immunoglobulin G IKAROS Family Zinc Finger 1 linkage disequilibriumv Natural killer cell N-Ethylmaleimide Sensitive Factor peripheral blood mononuclear cells thyroglobulin thyroglobulin antibodies thyroid peroxidase Thyroid peroxidase antibodies antibodies against TSH receptors thyroid-stimulating hormone TSH receptor transcriptome-wide association studies. The autoantibodies are produced against the three core thyroid proteins: thyroid peroxidase (TPO), thyroglobulin (Tg), and the thyroid-stimulating hormone receptor (TSHR). Except for antibodies against TSH receptors (TSAb), which are known to stimulate the production of thyroid hormones by binding TSH receptors in GD (2De Groot L. Graves' disease and the manifestations of thyrotoxicosis.in: Feingold K.R. Anawalt B. Boyce A. Chrousos G. Dungan K. Grossman A. Hershman J.M. Kaltsas G. Koch C. Kopp P. Korbonits M. McLachlan R. Morley J.E. New M. Perreault L. Purnell J. Rebar R. Singer F. Trence D.L. Vinik A. Wilson D.P. Thyroid Disease Manager. MDText.com, Inc., South Dartmouth, MA2015Google Scholar), little is known about the role of two other thyroid autoantibodies, thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies (TgAb). Circulating TPOAb is the most common and diagnostically useful marker of AITD, detectable in the serum of most HT (95%) and GD (85%) patients (3Mariotti S. Caturegli P. Piccolo P. Barbesino G. Pinchera A. Antithyroid peroxidase autoantibodies in thyroid diseases.J. Clin. Endocrinol. Metabolism. 1990; 71: 661-669Crossref PubMed Scopus (247) Google Scholar). In recent years, using TPOAb as a marker has been challenged because it appears in ∼10% of apparently healthy individuals (4Hollowell J.G. Staehling N.W. Flanders W.D. Hannon W.H. Gunter E.W. Spencer C.A. Braverman L.E. Serum TSH, T sub4/sub, and Thyroid Antibodies in the United States Population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III).J. Clin. Endocrinol. Metabolism. 2002; 87: 489-499Crossref PubMed Scopus (2939) Google Scholar). Even though autoantibodies are often a hallmark of autoimmune disorders, they can appear years before the first symptoms (5Seeling M. Brückner C. Nimmerjahn F. Differential antibody glycosylation in autoimmunity: sweet biomarker or modulator of disease activity?.Nat. Rev. Rheumatol. 2017; 13: 621-630Crossref PubMed Scopus (108) Google Scholar), which poses the question about their causative role. Some evidence exists that autoantibodies can trigger autoimmunity, and IgG isotype seems to be connected with the development of autoimmune diseases potentially through regulation of IgG effector functions by alternative glycosylation (5Seeling M. Brückner C. Nimmerjahn F. Differential antibody glycosylation in autoimmunity: sweet biomarker or modulator of disease activity?.Nat. Rev. Rheumatol. 2017; 13: 621-630Crossref PubMed Scopus (108) Google Scholar). However, it is yet to be determined if anti-thyroid antibodies cause AITD, or whether additional control mechanisms, such as post-translational modifications, are required to trigger the disease onset. The most abundant and diverse form of post-translational modification is glycosylation, the attachment of sugar moieties to proteins, and various glycans are involved in virtually all physiological processes (6Kobata A. The N-linked sugar chains of human immunoglobulin G: their unique pattern, and their functional roles.Biochim. Biophys. Acta. 2008; 1780: 472-478Crossref PubMed Scopus (88) Google Scholar). Glycans attached to Immunoglobulin G (IgG) are indispensable for its effector function and control of inflammation (7Shade K.-T. Anthony R. Antibody glycosylation and inflammation.Antibodies. 2013; 2: 392-414Crossref Scopus (79) Google Scholar, 8Novokmet M. Lukić E. Vučković F. Đurić Ž Keser T. Rajšl K. Remondini D. Castellani G. Gašparović H. Gornik O. Lauc G. Changes in IgG and total plasma protein glycomes in acute systemic inflammation.Sci. Reports. 2014; 4: 4347Crossref PubMed Scopus (97) Google Scholar, 9Marth J.D. Grewal P.K. Mammalian glycosylation in immunity.Nat. Rev. Immunol. 2008; 8: 874-887Crossref PubMed Scopus (526) Google Scholar, 10Maverakis E. Kim K. Shimoda M. Gershwin M.E. Patel F. Wilken R. Raychaudhuri S. Ruhaak L.R. Lebrilla C.B. Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review.J. 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Additional N-glycosylation sites are present in ∼20% of IgG fragment antigen binding (Fab) and play a role in immunity, such as the affinity of epitope-binding site (13Bondt A. Rombouts Y. Selman M.H.J. Hensbergen P.J. Reiding K.R. Hazes J.M.W. Dolhain R.J.E.M. Wuhrer M. Immunoglobulin G (IgG) Fab glycosylation analysis using a new mass spectrometric high-throughput profiling method reveals pregnancy-associated changes.Mol. Cell. Proteomics. 2014; 13: 3029-3039Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 14Spiegelberg H.L. Abel C.A. Grey H.M. Fishkin B.G. Localization of the carbohydrate within the variable region of light and heavy chains of human γG myeloma proteins.Biochemistry. 1970; 9: 4217-4223Crossref PubMed Scopus (87) Google Scholar, 15Abel C.A. Spiegelberg H.L. Grey H.M. Carbohydrate content of fragments and polypeptide chains of human .gamma.G-myeloma proteins of different heavy-chain subclasses.Biochemistry. 1968; 7: 1271-1278Crossref PubMed Scopus (90) Google Scholar, 16van de Bovenkamp F.S. Hafkenscheid L. Rispens T. Rombouts Y. The emerging importance of IgG Fab glycosylation in immunity.J. Immunol. 2016; 196: 1435-1441Crossref PubMed Scopus (166) Google Scholar). Previous analysis of IgG glycosylation with other autoimmune diseases showed a reduction of IgG galactosylation and sialylation, which trigger inflammatory response (17Jennewein M.F. Alter G. The immunoregulatory roles of antibody glycosylation.Trends Immunol. 2017; 38: 358-372Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, 18Vučkovic F. Krištic J. Gudelj I. Teruel M. Keser T. Pezer M. Pučic-Bakovic M. Štambuk Trbojevic-Akmačic J.I. Barrios C. Pavić T. Menni C. Wang Y. Zhou Y. Cui L. Song H. Zeng Q. Guo X. Pons-Estel B.A. McKeigue P. Leslie Patrick A. Gornik O. Spector T.D. Harjaček M. Alarcon-Riquelme M. Molokhia M. Wang W. Lauc G. Association of systemic lupus erythematosus with decreased immunosuppressive potential of the IgG glycome.Arthritis Rheumatol. 2015; 67: 2978-2989Crossref PubMed Scopus (165) Google Scholar, 19Trbojević-Akmačić I. Ventham N.T. Theodoratou E. Vučković F. Kennedy N.A. Krištić J. Nimmo E.R. Kalla R. Drummond H. Štambuk Dunlop J.M.G. Novokmet M. Aulchenko Y. Gornik O. Campbell H. Pučić Baković M. Satsangi J. Lauc G. Consortium IBD-BIOM Inflammatory bowel disease associates with proinflammatory potential of the immunoglobulin G glycome.Inflammatory Bowel Dis. 2015; 21: 1Crossref PubMed Scopus (130) Google Scholar, 20Harre U. Lang S.C. Pfeifle R. Rombouts Y. Fruhbeisser S. Amara K. Bang H. Lux A. Koeleman C.A. Baum W. Dietel K. Grohn F. Malmstrom V. Klareskog L. Kronke G. Kocijan R. Nimmerjahn F. Toes R.E.M. Herrmann M. Scherer H.U. Schett G. Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss.Nat. Commun. 2015; 6: 6651Crossref PubMed Scopus (189) Google Scholar). In relation to AITD, two small studies (62 and 146 patients respectively) looked at the TgAb glycosylation and reported differences between AITD, papillary thyroid cancers, and controls (21Yuan S. Li Q. Zhang Y. Huang C. Wu H. Li Y. Liu Y. Yu N. Zhang H. Lu G. Gao Y. Gao Y. Guo X. Changes in anti-thyroglobulin IgG glycosylation patterns in Hashimoto's thyroiditis patients.J. Clin. Endocrinol. Metabolism. 2015; 100: 717-724Crossref PubMed Scopus (29) Google Scholar, 22Zhao L. Liu M. Gao Y. Huang Y. Lu G. Gao Y. Guo X. She B. Glycosylation of sera thyroglobulin antibody in patients with thyroid diseases.Eur. J. Endocrinol. 2013; 168: 585-592Crossref PubMed Scopus (15) Google Scholar). First, TgAb IgG from HT patients showed higher levels of core fucose than the control group, as well as of terminal sialic acid and mannose (21Yuan S. Li Q. Zhang Y. Huang C. Wu H. Li Y. Liu Y. Yu N. Zhang H. Lu G. Gao Y. Gao Y. Guo X. Changes in anti-thyroglobulin IgG glycosylation patterns in Hashimoto's thyroiditis patients.J. Clin. Endocrinol. Metabolism. 2015; 100: 717-724Crossref PubMed Scopus (29) Google Scholar). On the other hand, it was observed that among HT, GD, and papillary thyroid cancer groups, HT patients had significantly lower core fucose content on TgAb than the other two groups (22Zhao L. Liu M. Gao Y. Huang Y. Lu G. Gao Y. Guo X. She B. Glycosylation of sera thyroglobulin antibody in patients with thyroid diseases.Eur. J. Endocrinol. 2013; 168: 585-592Crossref PubMed Scopus (15) Google Scholar). Furthermore, because recent genome-wide association studies (GWAS) identified novel loci associated with IgG glycosylation, which were known to be strongly associated with autoimmune conditions (23Lauc G. Huffman J.E. Pučić M. Zgaga L. Adamczyk B. Mužinić A. Novokmet M. Polašek O. Gornik O. Krištić J. Keser T. Vitart V. Scheijen B. Uh H.W. Molokhia M. Patrick A.L. McKeigue P. Kolčić I. Lukić I.K. Swann O. van Leeuwen F.N. Ruhaak L.R. Houwing-Duistermaat J.J. Slagboom P.E. Beekman M. de Craen A.J. Deelder A.M. Zeng Q. Wang W. Hastie N.D. Gyllensten U. Wilson J.F. Wuhrer M. Wright A.F. Rudd P.M. Hayward C. Aulchenko Y. Campbell H. Rudan I. Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers.PLoS Genet. 2013; 9: e1003225Crossref PubMed Scopus (188) Google Scholar, 24Shen X. Klarić L. Sharapov S. Mangino M. Ning Z. Di Wu Trbojević-Akmačić I. Pučić-Baković M. Rudan I. Polašek O. Hayward C. Spector T.D. Wilson J.F. Lauc G. Aulchenko Y.S. Multivariate discovery and replication of five novel loci associated with Immunoglobulin G N-glycosylation.Nat. Communications. 2017; 8: 447Crossref PubMed Scopus (47) Google Scholar) and the heritability of AITD is estimated to 55–75% (25Brix T.H. Kyvik K.O. Hegedüs L. A population-based of chronic autoimmune hypothyroidism in Danish twins.JCEM. 2000; 85: 536-539Crossref PubMed Scopus (208) Google Scholar, 26Brix T.H. Kyvik K.O. Christensen K. Hegedüs L. Evidence for a major role of heredity in Graves' disease: a population-based study of two Danish twin cohorts.J. Clin. Endocrinol. Metabolism. 2001; 86: 930-934Crossref PubMed Scopus (409) Google Scholar, 27Hansen P.S. Brix T.H. Bennedbæk F.N. Bonnema S.J. Iachine I. Kyvik K.O. Hegedüs L. The relative importance of genetic and environmental factors in the aetiology of thyroid nodularity: A study of healthy Danish twins.Clin. Endocrinol. 2006; 62: 380-386Crossref Scopus (21) Google Scholar), the next logical step was to examine if there was any common genetic background between those features. No data is currently available on common genetic variants associated with IgG glycosylation traits and AITD, and no large study on associations of the glycosylation of total IgG with the level of thyroid autoantibodies or with AITD has been performed. Our goal was to determine if there are any IgG or peripheral blood mononuclear cells glycan structures associated with the AITD or TPOAb positivity and examine if there are any common heritable factors between AITD and glycan structures. We investigated the association of total serum or plasma IgG glycome composition with TPOAb level in two cohorts: TwinsUK discovery cohort of 2297 individuals (988 controls, 1309 TPOAb positive) and Croatian replication cohort (73 controls, 90 TPOAb positive). We then focused our analysis of the IgG glycosylation on individuals with AITD in discovery cohort (988 controls, 203 AITD), and compared them to Polish replication cohort (114 control, 105 HT). In a fraction of the samples from Polish cohort we analyzed peripheral blood mononuclear cells glycosylation. Additionally, we looked for possible common genetic background between AITD and N-glycans, and at the gene expression of relevant genes. In total, we found an association between the decreased level of IgG core fucosylation and PBMCs antennary α1,2 fucosylation with TPOAb level as well as with AITD. We observed the association of significantly affected IgG N-glycan traits with FUT8 and IKZF1 genes (responsible for IgG fucosylation), but we could not identify SNPs or a general dysregulation of gene expression in whole blood; suggesting a restricted dysregulation of glycosylation in a subpopulation of B cells. The discovery sample consisted of twins from the UK Adult Twin Registry (TwinsUK cohort). The TwinsUK cohort is comprised of virtually 12,000 monozygotic and dizygotic twins unselected for any disease or trait. The cohort is from Northern European/UK ancestry and has been shown to be representative of singleton populations and the UK population in general (29Spector T.D. Williams F.M. The UK Adult Twin Registry (TwinsUK).Twin Res Hum Genet. 2006; 9: 899-906Crossref PubMed Google Scholar) (30Moayyeri A. Hammond C.J. Valdes A.M. Spector T.D. Cohort Profile: TwinsUK and Healthy Ageing Twin Study.Int. J. Epidemiol. 2013; 42: 76-85Crossref PubMed Scopus (174) Google Scholar). The project was approved by the local Ethics Committee, and informed consent was obtained from all participants. A more detailed description of the subjects and analyses performed on the TwinsUK cohort can be found in the supplemental Table S1. TwinsUK glycomic, transcriptomic, genetic data and GWAS results are publicly available upon request on the department website (http://www.twinsuk.ac.uk/data-access/accessmanagement/). The blood collected for the detection of different biological markers (TPOAb levels, plasma IgG N-glycan traits, transcriptomic data, and genetic variants) may have come from different time points for the same individuals between 1997 and 2013. As aging is an important modulator of IgG glycosylation (31Krištić J. Vučković F. Menni C. Klarić L. Keser T. Beceheli I. Pučić-Baković M. Novokmet M. Mangino M. Thaqi K. Rudan P. Novokmet N. Sarac J. Missoni S. Kolčić I. Polašek O. Rudan I. Campbell H. Hayward C. Aulchenko Y. Valdes A. Wilson J.F. Gornik O. Primorac D. Zoldoš V. Spector T. Lauc G. Glycans are a novel biomarker of chronological and biological ages.J. Gerontol. 2013; 69: 779-789Crossref Scopus (206) Google Scholar) and evolution of AITD, we restricted our sample collection/selection protocol in such a way that the largest absolute time difference between different samples collected from the same individuals is five years. This was performed in order to have enough subjects, but with a weak, potential aging effect between two samples. The criteria are not used on genomic data as it is almost stable relative to aging. For the current study, only twins who have phenotype data collected within the same year as the collection of plasma used for the IgG glycosylation profiling were selected in order to account for the potential effects of aging. Consequently, only 2,297 twins have glycan data and TPOAb level measured by Roche immunoassay and 392 twins from Abbott immunoassay (Table I.1 in supplemental Table S1). The blood to assess gene expression has been collected between 2009 and 2011. For the current analysis, only twins who have phenotype data collected within a 5-year range around the collection of blood used for the gene expression were selected in order to account for the potential effects of aging. Consequently, gene expression data was collected in only 180 twins that have gene expression data and AITD status, 199 twins with TPOAb level and 326 twins with IgG N-glycan traits (Table I.2 in supplemental Table S1). Two other cohorts were used to test the findings obtained in the TwinsUK cohort. Both cohorts are described in the Table I.1 in supplemental Table S1. The recruitment in the two replicated cohorts was performed to have age and gender-matched population between cases and controls. Croatian replication cohort includes 73 control individuals and 90 case individuals from Croatia. Individuals were considered as a control if they have TPOAb and TgAb levels within reference ranges (0–4.11 IU/ml for TPOAb and 0–5.61 IU/ml for TgAb). On the other hand, subjects were considered as case individuals if they have a high level of TPOAb or TgAb (with the antibody level at least double the upper limit of its reference range) and with normal complete blood count. The blood was collected via venous puncture for the detection of different biological markers from March to June 2015. The study was approved by the Ethics Committee of Genos Ltd. Informed consent for participation in the study was obtained from all participants. The second replication cohort consisted of patients from the Endocrinology Department of the University Hospital in Krakow and Jagiellonian University staff, Poland, and included 219 individuals (105 HT patients and 114 healthy donors)—a cohort of mainly females (103 HT and 106 in control group) with an average age of 36 (Table I.1 supplemental Table S1). All HT patients have been on levothyroxine sodium substitutive therapy and were diagnosed based on a high TSH level and the TPOAb and/or TgAb positivity. Moreover, patients do not have any other concomitant autoimmune diseases, other thyroid diseases and history of cancers. The control group consisted of 114 individuals with a negative history of HT, other autoimmune diseases, other thyroid diseases and cancers with negative/low antibody titers of TPOAb, TgAb and anti-TSHR and TSH level within the reference range. Having a small number of men in this cohort, we ran an analysis of IgG N-glycan traits with only data from women. After quality control of data obtained after IgG glycome analysis, 106 control subjects and 103 HT patients were analyzed concerning IgG glycosylation profiling and to keep the age and gender match. 24 blood samples from 219 collected from the Polish replication cohort were also used to analyze PBMC glycosylation: 11 patients with HT and 13 healthy donors. The groups were matched for sex and age. Informed consent for participation in the study was obtained from all participants. The blood was collected via venous puncture for the detection of different biological markers from May 2014 to July 2015. The study was approved by the Ethics Committee of the Jagiellonian University Medical College in Krakow. The study was performed using TPOAb level as a continuous variable and a clinical AITD definition as a binary trait. Not having a clinical diagnostic for all twins, TPOAb level, and TSH level were used to define individuals with AITD and healthy groups. Individuals were considered to have AITD if they had a positive TPOAb titer (3 times more than the threshold set by the manufacturer (18 IU/ml for Abbott assay and 100 IU/ml for Roche assay)) or had a TSH level more than 10 mIU/L. We considered subjects to have HT when they have a TSH level ≥10 mIU/L or a positive TPOAb titer as decribed previously with TSH level more than 4 mIU/L. We considered individuals as heathy controls if they had a TSH level in the normal range and a negative TPOAb titer, with no previous clinical diagnosis of thyroid disease and not treated with thyroid medications or steroids. Individuals with a history of thyroid cancer or thyroid surgery (because of benign conditions) were excluded. The sera to assess TPOAb and TSH levels have been collected by a trained nurse or phlebotomist using venipuncture and a SafetyLokTM Blood Collection Kit (21G3/4 Needles) and plain 10 ml serum-separating tube vacutainer (no additives) during twin visits. After collection from the study subject, whole blood was held at 22 °C for 50 min at room temperature for a clot to form and serum separated within 60 min of collection. Processing of blood was performed using a refrigerated (4 °C) clinical centrifuge at 3000 × g for 10 min with the serum supernatant subsequently collected, transferred to a 2 ml screw capped Nunc Cryotubes and immediately frozen at −80 °C and kept frozen in 2 ml screw capped Nunc Cryotube at −80 °C until use. The quantitative determination of TSH and TPOAb (only IgG class) levels was done on the sera by a chemiluminescent microparticle immunoassay (ARCHITECT® Anti-TPO or TSH (ABBOTT Diagnostics Division, Wiesbaden, Germany, 2005)) (a TPOAb titer >6 IU/ml considered positive; normal range of TSH level is between 0.4 mIU/L and 4 mIU/L). For samples analyzed by an electrochemiluminescence immunoassay "ECLIA" (Elecsys and cobas e analyzers, (Roche Diagnostics, Indianapolis, lN, 2010)) (a TPOAb titer >34 IU/ml considered positive; normal range of TSH level is between 0.4 mIU/L and 4 mIU/L). Sera samples for Croatian cohort were collected via venous puncture from March to June 2015 into 10 ml serum-separating vacutainer tube without additives, centrifuged at 3500 rpm for 10 min, after which the serum was transferred to 2 ml Eppendorf tubes and kept frozen at −20 °C until use. Quantitative determination of TSH, free T3, free T4, TPOAb and TgAb was performed by a chemiluminescent micro-particle immunoassay (ARCHITECT® TSH, free T3, free T4, Anti-TPO or Anti-Tg (ABBOTT Diagnostics Division, Wiesbaden, Germany, 2015)). Sera and PBMCs for Polish cohort were collected via venous puncture for the detection of different biological markers from May 2014 to July 2015 using S-Monovette Serum Tubes 2.7 ml that contains Clotting Activator/Serum (Sarstedt, 05.1557.001) for collection. Blood samples were left at room temperature for five hours for blood coagulation and centrifuged at 1200 × g for 10 min at 4 °C. Serum samples were stored in deep freezing in Safe Lock Tubes 2 ml (Eppendorf, 0030123.344). The TSH level in sera samples were determined by immunoradiometric assay (IRMA) (DIAsource TSH-IRMA Kit (DIAsource ImmunoAssays S.A., Louvain-la-Neuve, Belgium)). Anti-TPO and anti-Tg levels were measured by radioimmunoassays (RIAs) (BRAHMS anti-TPOn RIA, BRAHMS anti-Tgn RIA (BRAHMS GmbH, Hennigsdorf, Germany)). The sera, as well as PBMC samples, were kept frozen at −70 °C until the analysis of glycosylation. The IgG glycosylation profiling was applied on total IgG glycome from blood (combined Fc and Fab glycans and all IgG subclasses). It is noted that glycosylation patterns of total IgG reflect mostly IgG Fc glycans because of the small proportion of IgG Fab glycans in the total IgG N-glycan structures (16van de Bovenkamp F.S. Hafkenscheid L. Rispens T. Rombouts Y. The emerging importance of IgG Fab glycosylation in immunity.J. Immunol. 2016; 196: 1435-1441Crossref PubMed Scopus (166) Google Scholar). It was performed in Genos Glycoscience Research Laboratory in Croatia using UPLC analysis of 2AB-labeled glycans. The IgG glycosylation of the discovery cohort was performed in four batches whereas the replications cohorts were performed in one batch per cohort. However, the protocol for replication cohorts followed the same protocol than the protocol used for the two last batches of the discovery cohort and described below. Effects of technical confounders (96-well plate and run-day batch effects) are minimized by careful experimental design (blocking on case-control status, sex and age, whereas the rest was randomized) (32Ugrina I. Campbell H. Vučkovic F. Laboratory experimental design for a glycomic study.Methods Mol. Biol. 2017; 1503: 13-19Crossref PubMed Scopus (5) Google Scholar). Additionally, batch-effects are controlled by introducing in-house plasma standards to each 96-well plate (32Ugrina I. Campbell H. Vučkovic F. Laboratory experimental design for a glycomic study.Methods Mol. Biol. 2017; 1503: 13-19Crossref PubMed Scopus (5) Google Scholar). The IgG was isolated using 96-well protein G monolithic plates (BIA Separations, Ljubljana, Slovenia) as described previously (33Pučić M. Knežević A. Vidič J. Adamczyk B. Novokmet M. Polašek O. Gornik O. Šupraha Goreta -S. Wormald M.R. Redžić I. Campbell H. Wright A. Hast
Cancer is a common cause of death in developed countries.There are several methods of cancer therapy.Plant-derived compounds such as Vinca alkaloids, paclitaxel or camptothecin and podophyllotoxin derivatives are also used in the treatment of this disease.Vinblastine and vincristine are the examples of Vinca alkaloids.Their mechanism of action is based on their interaction with microtubules.They are used in the treatment of Hodgkin's and non-Hodgkin's lymphoma among others.Microtubules are also the target for paclitaxel which was isolated from Taxus brevifolia.Paclitaxel is used in the therapy of such tumors as ovarian cancer and breast cancer.There are also plant compounds whose derivatives are used in the treatment of some types of cancer, for example camptothecin which occurs in Camptotheca acuminata and podophyllotoxin (from Podophyllum peltatum and P. emodi).There are some problems connected with the use of the aforementioned compounds in cancer treatment, including side effects.Nevertheless, Vinca alkaloids, paclitaxel, camptothecin and podophyllotoxin derivatives are the examples of plant-derived compounds which are successfully used in cancer therapy.In addition, various plant compounds are being investigated for their anticancer potential.
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