Although it is known that human leukocyte antigen (HLA)-DPB1 disparity has a strong impact on outcomes in unrelated hematopoietic transplantation with induction of acute graft-versus-host disease ...(GVHD) and a graft-versus-leukemia (GVL) effect, its role in unrelated umbilical cord blood transplantation (UR-CBT) has yet to be fully clarified. Our current study is being conducted to elucidate the impact of HLA-DPB1 mismatch, along with the effect of other HLA loci mismatches at the allele level. HLA six loci alleles were retrospectively typed in 1157 Japanese donors and patients with leukemia or myelodysplastic syndrome who underwent transplantation with a single unit of cord blood. HLA-DPB1 mismatch was associated with a significant reduction in leukemia relapse (hazard ratio 0.61, P<0.001), whereas the other HLA loci allele-level mismatches did not. No significant effect of HLA-DPB1 mismatch was observed in the risk of acute GVHD, engraftment or mortality. This HLA-DPB1 GVL effect without induction of severe acute GVHD or deterioration of survival rate has not been reported in unrelated bone marrow or peripheral blood stem cell transplantations, suggesting apparent advantages of UR-CBT. Accordingly, selection of an HLA-DPB1 mismatch cord blood might be the preferable choice for single-unit UR-CBT.
We present a novel method for simulating liquid with asynchronous time steps on Eulerian grids. Previous approaches focus on Smoothed Particle Hydrodynamics (SPH), Material Point Method (MPM) or ...tetrahedral Finite Element Method (FEM) but the method for simulating liquid purely on Eulerian grids have not yet been investigated. We address several challenges specifically arising from the Eulerian asynchronous time integrator such as regional pressure solve, asynchronous advection, interpolation, regional volume preservation, and dedicated segregation of the simulation domain according to the liquid velocity. We demonstrate our method on top of staggered grids combined with the level set method and the semi‐Lagrangian scheme. We run several examples and show that our method considerably outperforms the global adaptive time step method with respect to the computational runtime on scenes where a large variance of velocity is present.
The kinetically controlled area-specific activities, jk, for the oxygen reduction reaction (ORR) were evaluated at well-defined Pt-skin/Pt100−xCox(111) single crystal electrodes as a function of Co ...content by use of the rotating disk electrode method. The Pt-skin layer formed by annealing under a pure H2 atmosphere was clarified to consist of atomically flat terraces with the same atomic arrangement as the underlying crystal. At 25 atom%-Co, the jk value reached a maximum as high as 3.0mAcm−2 at 0.9V vs. RHE, which is ca. 25 times larger than that on pure Pt(111). Such an enhanced ORR activity of Pt-skin/Pt–Co(111) electrodes cannot be explained on the basis of decreased OH poisoning, because the surface oxidation charge densities measured at 0.9V in N2-purged solution were nearly constant.
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•Pt-skin/Pt–Co(111) single crystals exhibited extremely high ORR activity, jk.•Pt-skin had atomically flat terraces with the same atomic arrangement as the bulk.•Maximum jk at Pt-skin/Pt0.75Co0.25 was 25 times higher than that at pure Pt(111).•The enhanced ORR activity cannot be explained by decreased OH poisoning.•An alternate ORR model must be developed to explain all of the present results.
Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for lymphoma. The choice ...between high-dose therapy with autologous HCT and allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed lymphoma. We retrospectively analyzed incidence and risk factors for the development of t-AML/MDS in lymphoma patients treated with autologous or allogeneic HCT. A total of 13 810 lymphoma patients who received autologous (n=9963) or allogeneic (n=3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, lymphoma patients receiving autologous HCT (1.38% at 3 years after autologous HCT) had a significant risk for developing t-AML/MDS compared to allogeneic HCT (0.37% at 3 years after allogeneic HCT, P<0.001). Significant risk factors for the development of t-AML/MDS after autologous and allogeneic HCT were high-stage risk at HCT (P=0.04) or secondary malignancies (P<0.001) and receiving cord blood stem cell (P=0.03) or involved field radiotherapy (P=0.002), respectively. Strategies that carefully select lymphoma patients for autologous HCT, by excluding lymphoma patients with high-stage risk at HCT, may allow the identification of individual lymphoma patients at particular high risk for t-AML/MDS.
In unrelated hematopoietic SCT (HSCT), HLA allele mismatch has been shown to have a significant role. To clarify the importance of HLA allele mismatch in the GVH direction in related HSCT, we ...retrospectively evaluated 2377 patients who received stem cells from an HLA serologically matched related donor in the GVH direction using the database of the Japan Society for Hematopoietic Cell Transplantation. The cumulative incidences of grade II-IV and grade III-IV acute GVHD in patients with an HLA allele-mismatched donor (n=133, 5.6%) were significantly higher than those in patients with an HLA allele-matched donor. Multivariate analyses showed that the presence of HLA allele mismatch was associated with increased risks of grade II-IV and grade III-IV acute GVHD. In particular, HLA-B mismatch and multiple allele mismatches were associated with an increased risk of acute GVHD. The presence of HLA allele mismatch was associated with an inferior OS owing to an increased risk of non-relapse mortality (NRM). In conclusion, the presence of HLA allele mismatch in the GVH direction in related HSCT was associated with increased risks of GVHD and NRM, which led to an inferior OS. HLA allele typing is recommended in related HSCT.
A novel MICA allele, MICA*070, was defined by sequencing. The new allele differs from the MICA*008:04 sequence in exon 2, encoding a C instead of G corresponding to cDNA nucleotide position 183. This ...nucleotide substitution is predicted to encode serine instead of arginine at residue 38 of the α1 domain of the MICA molecule.
Abstract A novel MICA allele, MICA∗ 070, was defined by sequencing. The new allele differs from the MICA∗ 008:04 sequence in exon 2, encoding a C instead of G corresponding to cDNA nucleotide ...position 183. This nucleotide substitution is predicted to encode serine instead of arginine at residue 38 of the α1 domain of the MICA molecule.
Apoptotic and necrotic blebs elicited by H(2)O(2) were compared in terms of dynamics, structure and underlying biochemistry in HeLa cells and Clone 9 cells. Apoptotic blebs appeared in a few minutes ...and required micromolar peroxide concentrations. Necrotic blebs appeared much later, prior to cell permeabilization, and required millimolar peroxide concentrations. Strikingly, necrotic blebs grew at a constant rate, which was unaffected throughout successive cycles of budding and detachment. At 1 microm diameter, the necks of necrotic and apoptotic blebs were almost identical. ATP depletion was discarded as a major factor for both types of bleb. Inhibition of ROCK-I, MLCK and p38MAPK strongly decreased apoptotic blebbing but had no effect on necrotic blebbing. Taken together, these data suggest the existence of a novel structure of fixed dimensions at the neck of both types of plasma membrane blebs in epithelial cells. However, necrotic blebs can be distinguished from apoptotic blebs in their susceptibility to actomyosin kinase inhibition.
Background and purpose:
The α
1L
‐adrenoceptor has pharmacological properties that distinguish it from three classical α
1
‐adrenoceptors (α
1A
, α
1B
and α
1D
). The purpose of this was to identify ...α
1L
‐adrenoceptors in mice and to examine their relationship to classical α
1
‐adrenoceptors.
Experimental approach:
Radioligand binding and functional bioassay experiments were performed on the cerebral cortex, vas deferens and prostate of wild‐type (WT) and α
1A
‐, α
1B
‐ and α
1D
‐adrenoceptor gene knockout (AKO, BKO and DKO) mice.
Key results:
The radioligand
3
H‐silodosin bound to intact segments of the cerebral cortex, vas deferens and prostate of WT, BKO and DKO but not of AKO mice. The binding sites were composed of two components with high and low affinities for prazosin or RS‐17053, indicating the pharmacological profiles of α
1A
‐adrenoceptors and α
1L
‐adrenoceptors. In membrane preparations of WT mouse cortex, however,
3
H‐silodosin bound to a single population of prazosin high‐affinity sites, suggesting the presence of α
1A
‐adrenoceptors alone. In contrast,
3
H‐prazosin bound to two components having α
1A
‐adrenoceptor and α
1B
‐adrenoceptor profiles in intact segments of WT and DKO mouse cortices, but AKO mice lacked α
1A
‐adrenoceptor profiles and BKO mice lacked α
1B
‐adrenoceptor profiles. Noradrenaline produced contractions through α
1L
‐adrenoceptors with low affinity for prazosin in the vas deferens and prostate of WT, BKO and DKO mice. However, the contractions were abolished or markedly attenuated in AKO mice.
Conclusions and implications:
α
1L
‐Adrenoceptors were identified as binding and functional entities in WT, BKO and DKO mice but not in AKO mice, suggesting that the α
1L
‐adrenoceptor is one phenotype derived from the α
1A
‐adrenoceptor gene.
British Journal of Pharmacology
(2008)
155
, 1224–1234; doi:
10.1038/bjp.2008.360
; published online 22 September 2008
Background and purpose:
In addition to α
1A
, α
1B
and α
1D
‐adrenoceptors (ARs), putative α
1L
‐ARs with a low affinity for prazosin have been proposed. The purpose of the present study was to ...identify the α
1A
‐AR and clarify its pharmacological profile using a radioligand binding assay.
Experimental approach:
Binding experiments with
3
H‐silodosin and
3
H‐prazosin were performed in intact tissue segments and crude membrane preparations of rat cerebral cortex. Intact tissue binding assays were also conducted in rat tail artery.
Key results:
3
H‐silodosin at subnanomolar concentrations specifically bound to intact tissue segments and membrane preparations of rat cerebral cortex at the same density (approximately 150 fmol mg
−1
total tissue protein). The binding sites in intact segments consisted of α
1A
and α
1L
‐ARs that had different affinities for prazosin, while the binding sites in membranes showed an α
1A
‐AR‐like profile having single high affinity for prazosin.
3
H‐prazosin also bound at subnanomolar concentrations to α
1A
and α
1B
‐ARs but not α
1L
‐ARs in cerebral cortex; the binding densities being approximately 200 and 290 fmol mg
−1
protein in the segments and the membranes, respectively. In the segments of tail artery,
3
H‐silodosin only recognized α
1A
‐ARs, whereas
3
H‐prazosin bound to α
1A
and α
1B
‐ARs.
Conclusions and implications:
The present study clearly reveals the presence of α
1L
‐ARs as a pharmacologically distinct entity from α
1A
and α
1B
‐ARs in intact tissue segments of rat cerebral cortex but not tail artery. However, the α
1L
‐ARs disappeared after tissue homogenization, suggesting their decomposition and/or their pharmacological profile changes to that of α
1A
‐ARs.
British Journal of Pharmacology
(2008)
153
, 1485–1494; doi:
10.1038/sj.bjp.0707679
; published online 28 January 2008
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