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- Gkoliou, G, et al.
(författare)
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Differences in the immunoglobulin gene repertoires of IgG versus IgA multiple myeloma allude to distinct immunopathogenetic trajectories
- 2023
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Ingår i: Frontiers in oncology. - : Frontiers Media SA. - 2234-943X. ; 13, s. 1123029-
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Tidskriftsartikel (refereegranskat)abstract
- The analysis of the immunogenetic background of multiple myeloma (MM) has proven key to understanding disease ontogeny. However, limited information is available regarding the immunoglobulin (IG) gene repertoire in MM cases carrying different heavy chain isotypes. Here, we studied the IG gene repertoire in a series of 523 MM patients, of whom 165 and 358 belonged to the IgA and IgG MM groups, respectively. IGHV3 subgroup genes predominated in both groups. However, at the individual gene level, significant (p<0.05) differences were identified regarding IGHV3-21 (frequent in IgG MM) and IGHV5-51 (frequent in IgA MM). Moreover, biased pairings were identified between certain IGHV genes and IGHD genes in IgA versus IgG MM. Turning to the imprints of somatic hypermutation (SHM), the bulk of rearrangements (IgA: 90.9%, IgG: 87.4%) were heavily mutated [exhibiting an IGHV germline identity (GI) <95%]. SHM topology analysis disclosed distinct patterns in IgA MM versus IgG MM cases expressing B cell receptor IG encoded by the same IGHV gene: the most pronounced examples concerned the IGHV3-23, IGHV3-30 and IGHV3-9 genes. Furthermore, differential SHM targeting was also identified between IgA MM versus IgG MM, particularly in cases utilizing certain IGHV genes, alluding to functional selection. Altogether, our detailed immunogenetic evaluation in the largest to-date series of IgA and IgG MM patients reveals certain distinct features in the IGH gene repertoires and SHM. These findings suggest distinct immune trajectories for IgA versus IgG MM, further underlining the role of external drive in the natural history of MM.
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- Voskaridou, E., et al.
(författare)
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High Circulating Sclerostin is Present in Patients with Thalassemia-associated Osteoporosis and Correlates with Bone Mineral Density
- 2012
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 44:12, s. 909-913
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis is a severe complication of thalassemia. Sclerostin is a Wnt signaling inhibitor, which is produced by osteocytes and inhibits osteoblast function. Sclerostin is implicated in the pathogenesis of osteoporosis of different etiology. The aim of the study was to evaluate circulating sclerostin in 66 patients (median age 42 years) with thalassemia and osteoporosis who participated in a phase 2, randomized study (zoledronic acid vs. placebo) and the results were compared with those of 30 healthy controls (median age 44 years) without osteopenia/osteoporosis and 62 women with postmenopausal osteoporosis (median age 63 years). At baseline, thalassemic patients with osteoporosis had elevated circulating levels of sclerostin (median: 605 pg/ml, range: 22-1,227 pg/ml) compared to healthy controls without osteopenia/osteoporosis (250 pg/ml, 0-720 pg/ml, p<0.001) and reduced levels of sclerostin compared with postmenopausal women with osteoporosis (840 pg/ml, 181-1,704 pg/ml, p<0.001). Thalassemia patients had also increased serum dickkopf-1 (Dkk-1) and high bone turnover. Circulating sclerostin levels correlated with bone mineral density in lumbar spine (r=0.619, p<0.001), distal radius (r=0.401, p=0.001) and femoral neck (r=0.301, p=0.021). Zoledronic acid did not alter sclerostin levels after 12 months of therapy, although it reduced circulating Dkk-1. We conclude that circulating sclerostin is elevated in thalassemia patients with osteoporosis and correlated with their BMD, but it was not reduced post zoledronic acid administration. These findings suggest that high sclerostin may serve as a marker of increased osteocyte activity in thalassemia patients. Drugs targeting sclerostin may also be used in this difficult to treat disorder associated with bone loss.
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- Engert, Andreas, et al.
(författare)
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The European Hematology Association Roadmap for European Hematology Research : a consensus document
- 2016
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Ingår i: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
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Tidskriftsartikel (refereegranskat)abstract
- The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
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- Polyzos, S. A., et al.
(författare)
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Serum sclerostin levels positively correlate with lumbar spinal bone mineral density in postmenopausal women—the six-month effect of risedronate and teriparatide
- 2011
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Ingår i: Osteoporosis International. - : Springer. - 0937-941X .- 1433-2965. ; 23:3, s. 1171-1176
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Tidskriftsartikel (refereegranskat)abstract
- Summary: Sclerostin is expressed by osteocytes and inhibits bone formation by osteoblasts. In this study, serum sclerostin was positively correlated with either lumbar spinal bone mineral density or T-score. Furthermore, serum sclerostin was increased after 6 months treatment with risedronate, whereas remained unchanged after 6 months teriparatide treatment.Introduction: The primary aim of this study was the evaluation of serum sclerostin levels in postmenopausal women and their association with bone mineral density (BMD) and bone turnover markers. The secondary aim was the evaluation of treatment with either teriparatide (TPTD) or risedronate (RIS) on serum sclerostin levels in women with postmenopausal osteoporosis.Methods: Women with postmenopausal osteoporosis, assigned to receive either TPTD (TPTD group, n = 13) or RIS (RIS group, n = 36) for 6 months, and non-osteoporotic early postmenopausal women (NOEP group, n = 13) were recruited. Main outcome measure was serum sclerostin levels.Results: Serum sclerostin was higher in the NOEP group at baseline compared with either TPTD group (p = 0.007) or RIS group (p = 0.049). Sclerostin was positively correlated with both lumbar spinal (LS) BMD (r = 0.353; p = 0.005) and T-score (r = 0.501; p < 0.001) and negatively correlated with intact parathyroid hormone (r = −0.343; p = 0.024) at baseline. Multiple regression analysis showed that either LS BMD (Beta = 0.653; p = 0.018) or T-score (Beta = 0.711; p = 0.005) were independent predictors of serum sclerostin levels. No significant correlation was observed between serum sclerostin and bone turnover markers or estradiol at baseline. Sclerostin was significantly increased 6 months post-treatment in RIS group (p = 0.002), whereas remained statistically unaffected in the TPTD group.Conclusions: Serum sclerostin is decreased in women with postmenopausal osteoporosis compared with non-osteoporotic early postmenopausal women and is positively correlated to either LS BMD or LS T-score. Furthermore, serum sclerostin was increased after 6 months treatment with RIS, whereas remained essentially unchanged after 6 months TPTD treatment.
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- Terpos, E., et al.
(författare)
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Early effects of IL-6 receptor inhibition on bone homeostasis: a pilot study in women with rheumatoid arthritis
- 2011
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Ingår i: Clinical and Experimental Rheumatology. - Pisa, Italy : Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 29:6, s. 921-925
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: A critical role of interleukin-6 (IL-6) in bone homeostasis has been suggested in experimental studies. We examined whether inhibition of IL-6 receptor in patients with rheumatoid arthritis (RA) results in early alterations of circulating markers of bone remodelling.Methods: Circulating levels of osteoprotegerin, receptor activator of nuclear factor-kappaB ligand (RANKL), Wnt signalling pathway inhibitors Dickkopf-1 (Dkk-1) and sclerostin, markers of bone resorption (C-terminal cross-linking telopeptide of collagen type-I (CTX), tartrate-resistant acid phosphatase isoform-5b) and bone formation (bone-specific alkaline-phosphatase, osteocalcin) were examined in 22 women with active RA before and after two monthly infusions of tocilizumab (8mg/kg each); 'healthy', non-osteopenic, 1:1 age-matched women served as controls.Results: At baseline, osteoprotegerin/RANKL ratio in patients was lower than controls by 5-fold; circulating osteoprotegerin correlated negatively with corresponding 28-joint-count disease activity scores and circulating RANKL correlated positively with C-reactive protein. Also, Dkk-1, sclerostin, CTX and osteocalcin levels were higher in RA than controls. After two months, osteoprotegerin/RANKL ratio increased, Dkk-1 decreased and sclerostin increased comparing to baseline; other markers did not change significantly. Increases of osteoprotegerin/RANKL ratio were more prominent in 10 patients who achieved remission or low disease activity after tocilizumab than in 12 patients who did not. In contrast, the significant alterations of both Wnt inhibitors were comparable between these patient subgroups.Conclusions: Anti-IL-6 therapy induced suppression of the inflammatory response affects rapidly the disrupted bone homeostasis in active RA. An additional, possibly specific, effect of IL-6 receptor inhibition on bone remodelling in humans should be further examined.
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