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Article ; Online: Teplizumab in Relatives at Risk for Type 1 Diabetes.

Couri, Carlos E / Malmegrim, Kelen C R / Oliveira, M Carolina

2019 Volume 381, Issue 19, Page(s) 1879

MeSH term(s)	Antibodies, Monoclonal, Humanized ; Diabetes Mellitus, Type 1 ; Humans
Chemical Substances	Antibodies, Monoclonal, Humanized ; teplizumab (S4M959U2IJ)
Language	English
Publishing date	2019-10-29
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	207154-x
ISSN	1533-4406 ; 0028-4793
ISSN (online)	1533-4406
ISSN	0028-4793
DOI	10.1056/NEJMc1912500
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Article ; Online: Reconstitution of the immune system and clinical correlates after stem cell transplantation for systemic sclerosis.

Kawashima-Vasconcelos, Marianna Y / Santana-Gonçalves, Maynara / Zanin-Silva, Djúlio C / Malmegrim, Kelen C R / Oliveira, Maria Carolina

Frontiers in immunology

2022 Volume 13, Page(s) 941011

Abstract: Systemic sclerosis (SSc) is a chronic autoimmune disease that includes fibrosis, diffuse vasculopathy, inflammation, and autoimmunity. Autologous hematopoietic stem cell transplantation (auto-HSCT) is considered for patients with severe and progressive ... ...

Abstract	Systemic sclerosis (SSc) is a chronic autoimmune disease that includes fibrosis, diffuse vasculopathy, inflammation, and autoimmunity. Autologous hematopoietic stem cell transplantation (auto-HSCT) is considered for patients with severe and progressive SSc. In recent decades, knowledge about patient management and clinical outcomes after auto-HSCT has significantly improved. Mechanistic studies have contributed to increasing the comprehension of how profound and long-lasting are the modifications to the immune system induced by transplantation. This review revisits the immune monitoring studies after auto-HSCT for SSc patients and how they relate to clinical outcomes. This understanding is essential to further improve clinical applications of auto-HSCT and enhance patient outcomes.
MeSH term(s)	Autoimmunity ; Hematopoietic Stem Cell Transplantation ; Humans ; Immune System ; Scleroderma, Systemic ; Transplantation, Autologous
Language	English
Publishing date	2022-08-11
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.941011
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Article: New Horizons in the Treatment of Type 1 Diabetes: More Intense Immunosuppression and Beta Cell Replacement.

Couri, Carlos E B / Malmegrim, Kelen C R / Oliveira, Maria C

Frontiers in immunology

2018 Volume 9, Page(s) 1086

Abstract: ... independence in parallel with relevant increments in C-peptide levels during mixed meal tolerance test ... However, on long-term follow-up, almost all patients resumed exogenous insulin use, with subsequent decrease in C ...

Abstract	Since the discovery of autoimmunity as the main pathophysiologic process involved in type 1 diabetes, many attempts have tried to delay or stop beta cell destruction. Most research protocols in humans have investigated the effects of therapeutic agents targeting specific steps of the autoimmune response. In spite of safety and some degree of beta cell preservation, the clinical impact of such approaches was similar to placebo. Recently, research groups have analyzed the effects of a more intense and wider immunologic approach in newly diagnosed type 1 diabetic individuals with the "immunologic reset," i.e., high-dose immunosuppression followed by autologous hematopoietic stem cell transplantation. This more aggressive approach has enabled the majority of patients to experience periods of insulin independence in parallel with relevant increments in C-peptide levels during mixed meal tolerance test. However, on long-term follow-up, almost all patients resumed exogenous insulin use, with subsequent decrease in C-peptide levels. This has been at least in part explained by persistence of islet-specific T-cell auto-reactivity. Here, we discuss future steps to induce immune tolerance in individuals with type 1 diabetes, with emphasis on risks and possible benefits of a more intense transplant immunosuppressive regimen, as well as strategies of beta cell replacement not requiring immunomodulation.
MeSH term(s)	Animals ; Autoimmunity/drug effects ; Biomarkers ; Clinical Trials as Topic ; Diabetes Mellitus, Type 1/immunology ; Diabetes Mellitus, Type 1/metabolism ; Diabetes Mellitus, Type 1/therapy ; Hematopoietic Stem Cell Transplantation/adverse effects ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Immune Tolerance ; Immunosuppression/methods ; Immunosuppressive Agents/pharmacology ; Immunosuppressive Agents/therapeutic use ; Insulin-Secreting Cells/transplantation ; Islets of Langerhans Transplantation ; Transplantation, Autologous ; Treatment Outcome
Chemical Substances	Biomarkers ; Immunosuppressive Agents
Language	English
Publishing date	2018-05-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2018.01086
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Article ; Online: Autologous hematopoietic stem cell transplantation promotes connective tissue remodeling in systemic sclerosis patients.

Zanin-Silva, Djúlio C / Santana-Gonçalves, Maynara / Kawashima-Vasconcelos, Marianna Y / Lima-Júnior, João R / Dias, Juliana B E / Moraes, Daniela A / Covas, Dimas T / Malmegrim, Kelen C R / Ramalho, Leandra / Oliveira, Maria Carolina

Arthritis research & therapy

2022 Volume 24, Issue 1, Page(s) 95

Abstract: Background: Autologous hematopoietic stem cell transplantation (AHSCT) treats patients with severe and progressive systemic sclerosis (SSc). However, basic mechanisms associated with the therapeutic efficacy of the procedure are not entirely understood. ...

Abstract	Background: Autologous hematopoietic stem cell transplantation (AHSCT) treats patients with severe and progressive systemic sclerosis (SSc). However, basic mechanisms associated with the therapeutic efficacy of the procedure are not entirely understood. We aimed to evaluate how AHSCT affects skin fibrosis in SSc patients. Methods: Clinical data, serum, and skin samples from 39 SSc patients who underwent AHSCT were retrospectively evaluated. Skin biopsies were analyzed by immunohistochemistry with anti-MMP-1, -MMP-2, -MMP-3, -MMP-9, -TIMP-1, -α-SMA, -TGF-β, and -NF-κB p65 antibodies, and stained with hematoxylin and eosin and picrosirius red to assess skin thickness and collagen density, respectively. Serum samples were evaluated by Multiplex Assay for COL1A1, COL4A1, FGF-1, MMP-1, MMP-3, MMP-12, MMP-13, PDGF-AA, PDGF-BB, S100A9, and TIMP-1 levels and compared to healthy controls. Results: After AHSCT, SSc patients showed clinical improvement in skin involvement, assessed by modified Rodnan's skin score (mRSS). Histologically, collagen density and skin thickness decreased after AHSCT. Immunohistochemical analyses showed increased expression of MMP-2, MMP-3, MMP-9, and TIMP-1 after AHSCT, whereas expression of NF-κB p65 decreased. At baseline, serum levels of COL4A1 and S100A9 were higher than in healthy controls. Serum levels of S100A9 normalized after AHCST in SSc patients compared to controls. Serum levels of PDGF-AA, PDGF-BB, TIMP-1, and MMP-1 decreased, while COL1A1 increased after AHSCT in SSc patients. No changes were detected in MMP-3, MMP-12, MMP-13, and FGF-1 serum levels after AHSCT. Conclusions: Our results suggest that the therapeutic effects of AHSCT on skin fibrosis are related to changes in molecules associated with connective tissue maintenance and inflammation in SSc.
MeSH term(s)	Becaplermin ; Connective Tissue/metabolism ; Connective Tissue/pathology ; Fibroblast Growth Factor 1 ; Fibrosis ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Matrix Metalloproteinase 1 ; Matrix Metalloproteinase 12 ; Matrix Metalloproteinase 13 ; Matrix Metalloproteinase 2 ; Matrix Metalloproteinase 3 ; Matrix Metalloproteinase 9/metabolism ; NF-kappa B ; Retrospective Studies ; Scleroderma, Systemic/surgery ; Tissue Inhibitor of Metalloproteinase-1
Chemical Substances	NF-kappa B ; Tissue Inhibitor of Metalloproteinase-1 ; Fibroblast Growth Factor 1 (104781-85-3) ; Becaplermin (1B56C968OA) ; Matrix Metalloproteinase 13 (EC 3.4.24.-) ; Matrix Metalloproteinase 3 (EC 3.4.24.17) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; Matrix Metalloproteinase 12 (EC 3.4.24.65) ; Matrix Metalloproteinase 1 (EC 3.4.24.7)
Language	English
Publishing date	2022-04-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2107602-9
ISSN	1478-6362 ; 1478-6354
ISSN (online)	1478-6362
ISSN	1478-6354
DOI	10.1186/s13075-022-02779-w
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Article: Autologous hematopoietic stem cell transplantation modifies specific aspects of systemic sclerosis-related microvasculopathy.

Santana-Gonçalves, Maynara / Zanin-Silva, Djúlio / Henrique-Neto, Álvaro / Moraes, Daniela A / Kawashima-Vasconcelos, Marianna Y / Lima-Júnior, João R / Dias, Juliana B E / Bragagnollo, Vinícius / de Azevedo, Júlia T C / Covas, Dimas T / Malmegrim, Kelen C R / Ramalho, Leandra / Oliveira, Maria Carolina

Therapeutic advances in musculoskeletal disease

2022 Volume 14, Page(s) 1759720X221084845

Abstract: Objective: Autologous hematopoietic stem cell transplantation (AHSCT) is a therapeutic option for patients with severe and progressive systemic sclerosis (SSc). Here, we aimed to investigate how AHSCT affects the vasculopathy of SSc patients.: Methods! ...

Abstract	Objective: Autologous hematopoietic stem cell transplantation (AHSCT) is a therapeutic option for patients with severe and progressive systemic sclerosis (SSc). Here, we aimed to investigate how AHSCT affects the vasculopathy of SSc patients. Methods: Twenty-seven SSc patients were retrospectively assessed, before and after AHSCT, for vessel morphology (nailfold capillaroscopy), skin expression of endothelial markers and serum levels of markers of inflammation, angiogenesis and endothelial activation. Skin biopsies were analyzed by immunohistochemistry (IHC) for expression of CD31, VE-cadherin, E-selectin, angiopoietin-1 (Ang1), angiopoietin-2 (Ang2), Tie-2, vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), and endothelin-1 before and 12 months post-AHSCT. Serum samples from SSc patients were assessed before and up to 36 months after AHSCT for IL-6, von Willebrand factor (vWF), CXC Motif Chemokine Ligand 8 (CXCL8), Endothelin-1, epidermal growth factor (EGF), VEGFA, Pentraxin-3, Intercellular Adhesion Molecule 1 (ICAM-1), E-selectin, P-selectin, Thrombomodulin and IL-18 levels, and compared to healthy control samples. Results: On nailfold capillaroscopy, the number of capillaries increased at 1 year, while giant capillaries decreased at 6 months and 1 year after AHSCT. In the skin biopsies, expression of E-selectin notably decreased and Ang1 increased after AHSCT. At baseline, all vascular markers evaluated in the serum were significantly higher in SSc patients when compared to healthy controls, except for ICAM-1. When compared at different time points after AHSCT, Thrombomodulin, Pentraxin-3, vWF, and IL-18 levels remained generally stable at high levels until 36 months after AHSCT. Conclusion: Our results suggest that AHSCT contributes to improvements of the vessel morphology and dermal microvasculopathy, but does not normalize elevated levels of serum vascular markers in SSc patients. Additional vascular therapeutic approaches might contribute to more effectively treat the endothelial injury.
Language	English
Publishing date	2022-03-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2516075-8
ISSN	1759-7218 ; 1759-720X
ISSN (online)	1759-7218
ISSN	1759-720X
DOI	10.1177/1759720X221084845
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Article ; Online: Autologous haematopoietic stem cell transplantation restores the suppressive capacity of regulatory B cells in systemic sclerosis patients.

Lima-Júnior, João R / Arruda, Lucas C M / Gonçalves, Maynara S / Dias, Juliana B E / Moraes, Daniela A / Covas, Dimas T / Simões, Belinda P / Oliveira, Maria Carolina / Malmegrim, Kelen C R

Rheumatology (Oxford, England)

2021 Volume 60, Issue 12, Page(s) 5538–5548

Abstract: Objectives: The rationale of autologous haematopoietic stem cell transplantation (AHSCT) for autoimmune diseases is that high-dose immunosuppression eradicates autoreactive T and B cells and the infused autologous haematopoietic stem cells promote ... ...

Abstract	Objectives: The rationale of autologous haematopoietic stem cell transplantation (AHSCT) for autoimmune diseases is that high-dose immunosuppression eradicates autoreactive T and B cells and the infused autologous haematopoietic stem cells promote reconstitution of a naïve and self-tolerant immune system. The aim of this study was to evaluate the reconstitution of different B cell subsets, both quantitatively and functionally, in SSc patients treated with AHSCT. Methods: Peripheral blood was harvested from 22 SSc patients before transplantation and at 30, 60, 120, 180 and 360 days post-AHSCT. Immunophenotyping of B cell subsets, B cell cytokine production, signalling pathways and suppressive capacity of regulatory B cells (Bregs) were assessed by flow cytometry. Results: Naïve B cell frequencies increased from 60 to 360 days post-AHSCT compared with pre-transplantation. Conversely, memory B cell frequencies decreased during the same period. Plasma cell frequencies transiently decreased at 60 days post-AHSCT. IL-10-producing Bregs CD19+CD24hiCD38hi and CD19+CD24hiCD27+ frequencies increased at 180 days. Moreover, the phosphorylation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase increased in B cells reconstituted post-AHSCT. Notably, CD19+CD24hiCD38hi Bregs recovered their ability to suppress production of Th1 cytokines by CD4+ T cells at 360 days post-AHSCT. Finally, IL-6 and TGF-β1-producing B cells decreased following AHSCT. Conclusion: Taken together, these results suggest improvements in immunoregulatory and anti-fibrotic mechanisms after AHSCT for SSc, which may contribute to re-establishment of self-tolerance and clinical remission.
MeSH term(s)	Adolescent ; Adult ; B-Lymphocytes, Regulatory/immunology ; B-Lymphocytes, Regulatory/pathology ; Cells, Cultured ; Cytokines/metabolism ; Female ; Flow Cytometry ; Follow-Up Studies ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Immunophenotyping ; Lymphocyte Count ; Male ; Memory B Cells/immunology ; Memory B Cells/pathology ; Middle Aged ; Retrospective Studies ; Scleroderma, Systemic/immunology ; Scleroderma, Systemic/pathology ; Scleroderma, Systemic/therapy ; Time Factors ; Transplantation, Autologous ; Treatment Outcome ; Young Adult
Chemical Substances	Cytokines
Language	English
Publishing date	2021-03-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1464822-2
ISSN	1462-0332 ; 1462-0324
ISSN (online)	1462-0332
ISSN	1462-0324
DOI	10.1093/rheumatology/keab257
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Article ; Online: CMV-specific clones may lead to reduced TCR diversity and relapse in systemic sclerosis patients treated with AHSCT.

Arruda, Lucas C M / Clave, Emmanuel / Douay, Corinne / Lima-Júnior, João R / Slavov, Svetoslav N / Malmegrim, Kelen C R / Alberdi, Antônio José / Oliveira, Maria Carolina / Toubert, Antoine

Rheumatology (Oxford, England)

2020 Volume 59, Issue 9, Page(s) e38–e40

MeSH term(s)	Adult ; Antigenic Variation ; Clone Cells/immunology ; Clone Cells/virology ; Cytomegalovirus/immunology ; Female ; Hematopoietic Stem Cell Transplantation ; Humans ; Male ; Middle Aged ; Pilot Projects ; Receptors, Antigen, T-Cell/immunology ; Recurrence ; Scleroderma, Systemic/immunology ; Scleroderma, Systemic/therapy ; Scleroderma, Systemic/virology ; Transplantation, Autologous ; Young Adult
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2020-02-11
Publishing country	England
Document type	Case Reports ; Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	1464822-2
ISSN	1462-0332 ; 1462-0324
ISSN (online)	1462-0332
ISSN	1462-0324
DOI	10.1093/rheumatology/keaa001
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Article ; Online: Correction to: Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies.

Noronha, Nádia de Cássia / Mizukami, Amanda / Caliári-Oliveira, Carolina / Cominal, Juçara Gastaldi / Rocha, José Lucas M / Covas, Dimas Tadeu / Swiech, Kamilla / Malmegrim, Kelen C R

Stem cell research & therapy

2019 Volume 10, Issue 1, Page(s) 132

Abstract: The original article [1] contained an error in the presentation of the first author's name, Nádia de Cássia Noronha. This has now been corrected. ...

Abstract	The original article [1] contained an error in the presentation of the first author's name, Nádia de Cássia Noronha. This has now been corrected.
Language	English
Publishing date	2019-05-17
Publishing country	England
Document type	Published Erratum
ZDB-ID	2548671-8
ISSN	1757-6512 ; 1757-6512
ISSN (online)	1757-6512
ISSN	1757-6512
DOI	10.1186/s13287-019-1259-0
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Article ; Online: Correction to

Nádia de Cássia Noronha / Amanda Mizukami / Carolina Caliári-Oliveira / Juçara Gastaldi Cominal / José Lucas M. Rocha / Dimas Tadeu Covas / Kamilla Swiech / Kelen C. R. Malmegrim

Stem Cell Research & Therapy, Vol 10, Iss 1, Pp 1-

Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies

2019 Volume 1

Abstract: The original article [1] contained an error in the presentation of the first author’s name, Nádia de Cássia Noronha. This has now been corrected. ...

Abstract	The original article [1] contained an error in the presentation of the first author’s name, Nádia de Cássia Noronha. This has now been corrected.
Keywords	Medicine (General) ; R5-920 ; Biochemistry ; QD415-436
Language	English
Publishing date	2019-05-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies.

Noronha, Nádia de Cássia / Mizukami, Amanda / Caliári-Oliveira, Carolina / Cominal, Juçara Gastaldi / Rocha, José Lucas M / Covas, Dimas Tadeu / Swiech, Kamilla / Malmegrim, Kelen C R

Stem cell research & therapy

2019 Volume 10, Issue 1, Page(s) 131

Abstract: Multipotent mesenchymal stromal cells (MSC) have been widely explored for cell-based therapy of immune-mediated, inflammatory, and degenerative diseases, due to their immunosuppressive, immunomodulatory, and regenerative potentials. Preclinical studies ... ...

Abstract	Multipotent mesenchymal stromal cells (MSC) have been widely explored for cell-based therapy of immune-mediated, inflammatory, and degenerative diseases, due to their immunosuppressive, immunomodulatory, and regenerative potentials. Preclinical studies and clinical trials have demonstrated promising therapeutic results although these have been somewhat limited. Aspects such as low in vivo MSC survival in inhospitable disease microenvironments, requirements for ex vivo cell overexpansion prior to infusions, intrinsic differences between MSC and different sources and donors, variability of culturing protocols, and potency assays to evaluate MSC products have been described as limitations in the field. In recent years, priming approaches to empower MSC have been investigated, thereby generating cellular products with improved potential for different clinical applications. Herein, we review the current priming approaches that aim to increase MSC therapeutic efficacy. Priming with cytokines and growth factors, hypoxia, pharmacological drugs, biomaterials, and different culture conditions, as well as other diverse molecules, are revised from current and future perspectives.
Language	English
Publishing date	2019-05-02
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2548671-8
ISSN	1757-6512 ; 1757-6512
ISSN (online)	1757-6512
ISSN	1757-6512
DOI	10.1186/s13287-019-1224-y
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