| 1. |
- Flygare, Johan, et al.
(författare)
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Deficiency of ribosomal protein S19 in CD34+ cells generated by siRNA blocks erythroid development and mimics defects seen in Diamond-Blackfan anemia
- 2005
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 105:12, s. 4627-4634
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Tidskriftsartikel (refereegranskat)abstract
- Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia in which 25% of the patients have a mutation in the ribosomal protein S19 (RPS19) gene. To study effects of RPS19 deficiency in hematopoiesis we transduced CD34+ umbilical cord blood (CB) and bone marrow (BM) cells with 3 lentiviral vectors expressing small interfering RNA (siRNA) against RPS19 and 1 scrambled control vector. All vectors also express green fluorescent protein (GFP). Transduction with the siRNA vectors reduced RPS19 mRNA levels to various degrees, which resulted in erythroid defects, correlating to the degree of RPS19 down-regulation, and was rescued by expression of an siRNA-resistant RPS19 transcript. Erythroid colony formation capacity conjointly decreased with RPS19 levels in CD34+ CB and BM cells. In liquid culture supporting erythroid differentiation, RPS19-silenced as well as DBA patient CD34+ cells exhibited reduced proliferative capacity and impaired erythroid differentiation resulting in fewer erythroid colony-forming units (CFU-Es). When assaying myeloid development, a less pronounced influence on proliferation was seen. This study shows for the first time that RPS19 silencing decreases the proliferative capacity of hematopoietic progenitors and leads to a defect in erythroid development.
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| 2. |
- Flygare, Johan, et al.
(författare)
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Gene therapy of Diamond Blackfan anemia CD34(+) cells leads to improved erythroid development and engraftment following transplantation.
- 2008
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Ingår i: Experimental Hematology. - : Elsevier BV. - 1873-2399 .- 0301-472X. ; 36, s. 1428-1435
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia caused by mutations in ribosomal protein (RP) genes. Our aim is to develop gene therapy for DBA patients with mutations in RPS19. We previously demonstrated that RPS19 gene transfer partially corrects erythroid development in vitro. In this study, we asked if RPS19 gene transfer corrects erythroid development in unsorted cells transplanted to immunodeficient mice and if the RPS19-corrected fraction has a proliferative advantage after transplantation. We further determined if high level of RPS19 expression is required for correction. MATERIAL AND METHODS: Mobilized peripheral blood CD34(+) cells were transduced by oncoretroviral vector particles pseudotyped with the feline endogenous retrovirus envelope. Vectors containing two different promoters with different RPS19 transgene expression levels were compared. Transduced cells were transplanted to immunocompromised nonobese diabetic/severe combined immunodeficient-beta2 microglobulin null mice in order to assess therapeutic effects of RPS19 gene transfer in vivo. RESULTS: We show that correction of erythroid development requires high RPS19 expression. The corrected fraction of unselected DBA cells have a survival advantage in vivo, suggesting that successful gene therapy may only require correction of a fraction of the patient cells. CONCLUSION: Our findings are fundamental for development of clinical gene therapy for DBA because they demonstrate increased engraftment of RPS19-transduced cells without selection of gene-corrected cells prior to transplantation, an essential prelude to studying long-term therapeutic effects in emerging animal models for DBA.
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| 3. |
- Hamaguchi, Isao, et al.
(författare)
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Proliferation deficiency of multipotent hematopoietic progenitors in ribosomal protein S19 (RPS19)-deficient Diamond-Blackfan anemia improves following RPS19 gene transfer
- 2003
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Ingår i: Molecular Therapy. - 1525-0024. ; 7:5, s. 613-622
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Tidskriftsartikel (refereegranskat)abstract
- Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a specific deficiency in erythroid progenitors. Since some patients with DBA develop a reduction in thrombocytes and granulocytes with age, we asked whether multipotent hematopoietic progenitors from DBA patients had normal proliferative capacity in liquid expansion cultures. CD34(+) cells derived from DBA patients showed deficient proliferation in liquid culture containing IL-3, IL-6, and SCF. Single CD34(+) CD38(-) cells from DBA patients exhibited deficient proliferation recruitment in a limiting dilution assay containing IL-3, IL-6, SCF, Tpo, FIL, and G-CSF or containing IL-3, IL-6, and SCF. Our findings suggest that the underlying hematopoietic defect in DBA may not be limited to the erythroid lineage. Since a fraction of DBA patients have a deficiency in ribosomal protein S19 (RPS19), we constructed lentiviral vectors containing the RPS19 gene for overexpression in hematopoietic progenitors from RPS19-deficient DBA patients. Enforced expression of the RPS19 transgene improved the proliferation of CD34(+) cells from DBA patients with RPS19 mutation. Similarly, enforced expression of RPS19 improved erythroid development of RPS19-deficient hematopoietic progenitors as determined by colony assays and erythroid differentiation cultures. These findings suggest that gene therapy for RPS19-deficient DBA is feasible.
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| 4. |
- Jaako, Pekka, et al.
(författare)
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Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia.
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118, s. 6087-6096
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Tidskriftsartikel (refereegranskat)abstract
- Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Among these genes, ribosomal protein S19 (RPS19) is mutated most frequently. Generation of animal models for diseases like DBA is challenging since the phenotype is highly dependent on the level of RPS19 downregulation. We report the generation of mouse models for RPS19-deficient DBA using transgenic RNA interference that allows an inducible and graded downregulation of Rps19. Rps19-deficient mice develop a macrocytic anemia together with leukocytopenia and variable platelet count that with time leads to the exhaustion of hematopoietic stem cells and bone marrow failure. Both RPS19 gene transfer and the loss of p53 rescue the DBA phenotype implying the potential of the models for testing novel therapies. This study demonstrates the feasibility of transgenic RNA interference to generate mouse models for human diseases caused by haploinsufficient expression of a gene.
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| 5. |
- Kuzmenko, Volodymyr, 1987, et al.
(författare)
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Cellulose-derived carbon nanofibers/graphene composite electrodes for powerful compact supercapacitors
- 2017
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Ingår i: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 7:73, s. 45968-45977
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Tidskriftsartikel (refereegranskat)abstract
- Herein, we demonstrate a unique supercapacitor composite electrode material that is originated from a sustainable cellulosic precursor via simultaneous one-step carbonization/reduction of cellulose/graphene oxide mats at 800 degrees C. The resulting freestanding material consists of mechanically stable carbon nanofibrous (CNF, fiber diameter 50-500 nm) scaffolds tightly intertwined with highly conductive reduced graphene oxide (rGO) sheets with a thickness of 1-3 nm. The material is mesoporous and has electrical conductivity of 49 S cm(-1), attributed to the well-interconnected graphene layers. The electrochemical evaluation of the CNF/graphene composite electrodes in a supercapacitor device shows very promising volumetric values of capacitance, energy and power density (up to 46 F cm(-3), 1.46 W h L-1 and 1.09 kW L-1, respectively). Moreover, the composite electrodes retain an impressive 97% of the initial capacitance over 4000 cycles. With these superior properties, the produced composite electrodes should be the "looked-for" components in compact supercapacitors used for increasingly popular portable electronics and hybrid vehicles.
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| 6. |
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| 7. |
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| 8. |
- Miyake, Koichi, et al.
(författare)
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RPS19 Deficiency Leads to Reduced Proliferation and Increased Apoptosis but Does Not Affect Terminal Erythroid Differentiation in a Cell Line Model of Diamond-Blackfan Anemia
- 2008
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 26:2, s. 323-329
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Tidskriftsartikel (refereegranskat)abstract
- Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia in which 25% of the patients have a mutation in the ribosomal protein (RP) S19 gene. It is not known how the RPS19 deficiency impairs erythropoiesis and proliferation of hematopoietic progenitors. To elucidate molecular mechanisms in RPS19 deficient DBA, we analyzed the effects of RPS19 deficiency on EPO induced signal transduction, cell cycle, and apoptosis in RPS19-deficient TF-1 cells. We did not find any abnormality in EPO induced signal transduction. However, RPS19 deficient-TF-1 cells showed G0/G1 arrest (82% vs 58%, p<0.05) together with accumulation of p21 and p27. The fraction of apoptotic cells detected by Annexin-V analysis also increased compared to control cells (13% vs 3.1%, p<0.05). Western blot analysis of apoptotic related proteins showed that the level of bcl-2 and Bad was decreased and Bax was increased in RPS19-deficient TF1 cells. Moreover, primary CD34 positive cells from DBA patients detected by Annexin-V analysis also generated a higher number of apoptotic cells compared to normal CD34 positive cells during in vitro culture (38% vs 8.9%, n=5, p<0.001). Finally, we show that while RPS19 silencing reduces EPO induced development of erythroid progenitors expressing Glycophorin A (GPA), RPS19 silencing in cells already expressing GPA does not affect GPA expression. These findings indicate that RPS19 deficiency causes apoptosis and accelerated loss of erythroid progenitors in RPS19 deficient DBA.
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| 9. |
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Agrarhistoria på många sätt : 28 studier om människan och jorden. Festskrift till Janken Myrdal på hans 60-årsdag
- 2009
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Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- Den överväldigande majoriteten av alla människor har varit verksamma i arbetet med jord och skog. Än idag är detta helt nödvändigt för vår överlevnad. Idag ställs även krav på landskapets biologiska och estetiska värden. Allt talar för att vi är i stort behov av agrarhistorisk kunskap. Boken ökar vår kunskap om dess kärna - om jorden, djuren och redskapen - men även de sociala, kulturella och politiska förhållandena som påverkat jordbruket. Bokens alla författare, både svenska och utländska, gör oss medvetna om mängden av agrarhistoriska källor och metoder. denna stora antologi är tillägnad Janken Myrdal, agrarhistoriens främste representant i Sverige, som låtit de mest skiftande och överraskande källmaterial och metoder komma till användning i sitt arbete.
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| 10. |
- Alattar, Abdul Ghani, et al.
(författare)
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Recombinant alpha(1)-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a Lu-177-DOTATATE Mouse Radiation Model
- 2023
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Ingår i: Biomolecules. - 2218-273X. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Lu-177-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although Lu-177-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal toxicity are still side effects that should be considered. Amino acids are often used to minimize renal radiotoxicity, however, they are associated with nausea and vomiting in patients. alpha (1)-microglobulin (A1M) is an antioxidant with heme- and radical-scavenging abilities. A recombinant form (rA1M) has previously been shown to be renoprotective in preclinical models, including in PRRT-induced kidney damage. Here, we further investigated rA1M's renal protective effect in a mouse Lu-177-DOTATATE model in terms of administration route and dosing regimen and as a combined therapy with amino acids (Vamin). Moreover, we investigated the protective effect of rA1M on peripheral blood and bone marrow cells, as well as circulatory biomarkers. Intravenous (i.v.) administration of rA1M reduced albuminuria levels and circulatory levels of the oxidative stress-related protein fibroblast growth factor-21 (FGF-21). Dual injections of rA1M (i.e., at 0 and 24 h post-Lu-177-DOTATATE administration) preserved bone marrow cellularity and peripheral blood reticulocytes. Administration of Vamin, alone or in combination with rA1M, did not show any protection of bone marrow cellularity or peripheral reticulocytes. In conclusion, this study suggests that rA1M, administered i.v. for two consecutive days in conjunction with Lu-177-DOTATATE, may reduce hematopoietic and kidney toxicity during PRRT with Lu-177-DOTATATE.
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