| 3041. |
- Salvagno, G. L., et al.
(författare)
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Impact of different inhibitor reactivities with commercial factor VIII concentrates on thrombin generation
- 2007
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 13:1, s. 51-56
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Tidskriftsartikel (refereegranskat)abstract
- In order to describe the haemostatic role of a variation in inhibitor reactivity with different factor VIII (FVIII) concentrates, we have compared inhibitor titres against a panel of FVIII concentrates and correlated titre with the capacity to inhibit thrombin generation. Three plasma-derived concentrates were tested in vitro in mixing experiments with inhibitor plasmas from 11 patients with severe haemophilia A: Fanhdi, which contains von Willebrand factor (VWF) with a final ratio of approximately 1:1 (VWF IU per IU FVIII:Q; Haemate-P with a ratio of 2.5:1 and Hemofil-M containing only trace amounts of VWF. In addition, the recombinant FVIII concentrate Kogenate Bayer containing no VWF was included. Inhibitor titres and the capacity to generate thrombin were measured. A statistically significant difference in measured titres was found with the highest titres recorded against Hemofil-M. The inhibitor titres needed to inhibit 50% maximum thrombin generation were the lowest for Kogenate Bayer and the highest and similar for Fanhdi and Haemate-P with intermediate titres needed for inhibition of Hemofil-M. In this study, the thrombin generation assay provides additional indications for the role of VWF in the treatment of patients with inhibitors. The VWF-containing concentrates Fanhdi and Haemate-P, added to FVIII-deficient plasma with the presence of inhibitor, generate more thrombin than do the purified concentrates Hemofil-M and Kogenate Bayer.
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| 3042. |
- Salvagno, G. L., et al.
(författare)
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Thrombin generation assay: a useful routine check-up tool in the management of patients with haemophilia?
- 2009
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 15:1, s. 290-296
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Tidskriftsartikel (refereegranskat)abstract
- Severity assessment of patients with haemophilia A (HA) is traditionally based on FVIII activity (FVIII:C). Clinical phenotype of HA patients often differs between individuals with the same FVIII:C determined with clotting and chromogenic assays. The aim of this study was to assess the influence of the FVIII:C on thrombin generation (TG) assay parameters both in vitro and ex-vivo postinfusion plasma. For in-vitro approach, influence of FVIII:C was evaluated on TG parameters in several dilutions of a normal plasma pool with commercial FVIII-depleted-plasma (FVIIIDP) and in others experiments, adding increasing amounts of different commercial FVIII concentrates (Fanhdi, Haemate-P, Hemofil-M and Kogenate Bayer) to FVIIIDP. In a series of 50 postinfusion samples, from HA patients of different severity, we assayed TG and FVIII:C (chromogenic and clotting). In vitro experiments, the 50% of maximum TG peak (TGMP) was achieved using only 5% FVIII:C and the TGMP was obtained with 40% of normal VIII:C. Impaired response compared with normal plasma was found in FVIIIDP using addition of increasing amounts of different commercial FVIII concentrates. An overall good correlation between the two FVIII assays was observed (y = 0.9115x - 0.273, r = 0.975, P < 0.001); TGMP and the Lag-Phase-Time (LPT) provided some discrepant results when compared with the total range of FVIII:C measurements. In contrast, correlations for TGMP, LPT and endogenous thrombin potential were improved in samples restricted to FVIII:C < 5%. We conclude that TG parameters tentatively could be a tool to tailor the global haemostatic capacity in haemophilic patients.
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| 3043. |
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| 3044. |
- Samuelson Bannow, Bethany, et al.
(författare)
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Factor VIII : Long-established role in haemophilia A and emerging evidence beyond haemostasis
- 2019
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Ingår i: Blood Reviews. - : Elsevier BV. - 0268-960X. ; 35, s. 43-50
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Forskningsöversikt (refereegranskat)abstract
- Factor VIII protein (FVIII) as a coagulation replacement factor has for decades been used as the standard of care for management of people with haemophilia A. It is effective for treatment of bleeding events, as prophylaxis to prevent bleeding events and preserve joint function, and to support surgery in people with haemophilia A. Despite long experience in treating haemophilia A, we are only beginning to understand the functions of FVIII beyond its established role as a coenzyme to factor IXa to expedite thrombin generation through the intrinsic pathway of coagulation. Here, we review the current role of FVIII coagulant (FVIII:C) in haemophilia A management and emerging evidence for the role of FVIII across multiple systems, including the cardiovascular system, angiogenesis and maintenance of bone health. For instance, supraphysiological FVIII levels are a risk factor for venous thromboembolism. von Willebrand factor (VWF), which forms a non-covalent complex with circulating FVIII, is an established marker and regulator of angiogenesis. In a mouse model of haemophilia, treatment with FVIII decreased expression of receptor activator of nuclear factor kappa-Β ligand (RANKL), a marker for bone turnover. Longitudinal follow-up data in people with haemophilia A are needed to confirm and extend these observations.
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| 3045. |
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| 3046. |
- Sánchez-García, I, et al.
(författare)
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Functional diversity of LIM proteins : amino-terminal activation domains in the oncogenic proteins RBTN1 and RBTN2
- 1995
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Ingår i: Oncogene. - 0950-9232. ; 10:7, s. 6-1301
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Tidskriftsartikel (refereegranskat)abstract
- The RBTN1 and RBTN2 genes are activated by distinct translocations involving chromosome 11 in some T cell acute leukaemias. The RBTN proteins belong to the LIM family which comprises proteins with one, two or three cysteine-rich LIM domains, sometimes together with homeodomains or protein kinase domains. The RBTN1 and RBTN2 proteins comprise only tandem LIM domains. We report that RBTN1 and RBTN2 proteins are capable of supporting transcriptional transactivation of specific reporter genes in transfection assays. The results, using intact proteins or fusions with the homeodomain of the heterologous protein Isl-1, show that this transcriptional activation ability resides in the NH2-terminal parts of both proteins. The use of yeast assays with RBTN2 shows that RBTN2 forms homodimers and that the NH2-terminal 27 amino acids are sufficient to facilitate transcriptional transactivation. These data expand the functional diversity of the LIM-domain protein family and they augment the previously defined relationship between chromosomal translocations and transcriptional activation.
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| 3047. |
- Sandén, Carl
(författare)
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Molecular Mechanisms of the DEK Protein in Leukemia
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The DEK gene is upregulated in a growing number of cancers and translocated to form the DEK-NUP214 fusion gene in a subset of acute myeloid leukemia. In this thesis, we studied the cellular and molecular functions of the DEK and DEK-NUP214 proteins. We found that the expression of DEK is increased by the leukemia-associated fusion protein NUP98-HOXA9, suggesting that DEK may be a downstream mediator of its leukemogenic function. We also determined the genome-wide binding of the DEK protein, showing that DEK binds specifically to the trans-cription start sites of predominantly highly and ubiquitously expressed genes. Furthermore, we demonstrated that DEK can serve to either promote or repress the transcription of these genes. Finally, we discovered that the DEK-NUP214 fusion protein promotes cellular proliferation through increased expression of mTOR and enhanced activity of mTORC1. Pharmacological inhibition of mTOR selectively reversed the proliferative effect, suggesting that patients with the fusion gene may benefit from treatment with mTOR inhibitors. These findings elucidate the roles of DEK and DEK-NUP214 in cancer with implications for the treatment of the associated malignancies.
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| 3048. |
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| 3049. |
- Sandén, Per, et al.
(författare)
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Warfarin treatment complications do not correlate to cTTR when above 70.
- 2015
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Ingår i: Thrombosis Research. - : Elsevier BV. - 1879-2472 .- 0049-3848. ; 136:6, s. 1185-1189
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Tidskriftsartikel (refereegranskat)abstract
- The mean time in target range for each centre, cTTR, has previously been shown to correlate to the rate of complications in poorly managed warfarin treatment. However less is known about the correlation when warfarin treatment is well managed.
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| 3050. |
- Sandhow, Lakshmi, et al.
(författare)
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Skin mesenchymal niches maintain and protect AML-initiating stem cells
- 2023
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Ingår i: Journal of Experimental Medicine. - 0022-1007 .- 1540-9538. ; 220:10
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Tidskriftsartikel (refereegranskat)abstract
- Leukemia cutis or leukemic cell infiltration in skin is one of the common extramedullary manifestations of acute myeloid leukemia (AML) and signifies a poorer prognosis. However, its pathogenesis and maintenance remain understudied. Here, we report massive AML cell infiltration in the skin in a transplantation-induced MLL-AF9 AML mouse model. These AML cells could regenerate AML after transplantation. Prospective niche characterization revealed that skin harbored mesenchymal progenitor cells (MPCs) with a similar phenotype as BM mesenchymal stem cells. These skin MPCs protected AML-initiating stem cells (LSCs) from chemotherapy in vitro partially via mitochondrial transfer. Furthermore, Lama4 deletion in skin MPCs promoted AML LSC proliferation and chemoresistance. Importantly, more chemoresistant AML LSCs appeared to be retained in Lama4−/− mouse skin after cytarabine treatment. Our study reveals the characteristics and previously unrecognized roles of skin mesenchymal niches in maintaining and protecting AML LSCs during chemotherapy, meriting future exploration of their impact on AML relapse.
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