To evaluate the efficacy and safety of a combined regimen of bendamustine (B) and rituximab (R) in Japanese patients with relapsed/refractory (r/r) indolent B-cell non-Hodgkin lymphomas (B-NHLs) and ...mantle cell lymphoma (MCL). Patients aged 20–79 years with pathologically confirmed B-NHLs or MCL, which were r/r after 1–2 R-containing regimens, were included in this study. The BR regimen consisted of B (90 mg/m
2
) for two consecutive days and R (375 mg/m
2
) on day 1, 2, or 3. The course was repeated every 4 weeks for up to four cycles. Fifty-three patients were enrolled in this study and analyzed. The diagnosis included follicular lymphoma (FL) (77 %), mucosa-associated lymphoid tissue lymphoma (13 %) and others (10 %). Forty-seven (90 %) patients completed four cycles of treatment as per schedule. Best overall response rate (ORR) and complete response rate (CRR) was 94 and 71 %, respectively (for FL, ORR 95 % and CRR 80 %). The treatment was well tolerated and the primary toxicity was myelosuppression; the incidence of grade 3/4 leukopenia and neutropenia were 42 and 40 %, respectively. There were no grade 5 toxicities. The BR regimen is safe in Japanese patients with r/r indolent B-NHLs and MCL, and is effective for those with r/r indolent B-NHLs. For the evaluation of late toxicity, especially infection, longer follow-up of this cohort is needed.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Magnetorheological (MR) fluids are categorized as smart fluids, which are made of small iron particles suspended in carrier fluids such as silicone oil. The presence of a magnetic field will ...instantaneously increase the viscosity of the MR fluid, also known as the MR effect. The application of the MR fluid as viscous dampers to automobiles and buildings has shown excellent performance in shock absorption. To expand the practical application of the MR fluid, various evaluations of shock-absorption performance under high-loading conditions are needed. Therefore, we decided to investigate its performance in high-speed impact conditions. Impact experiments were conducted in different liquids—tap water, two types of silicone oils with different kinematic viscosities, and an MR fluid—and it was investigated how the properties of each liquid affect the shock-absorption performance. Accordingly, it was found that kinematic viscosity and compressibility affect shock-absorption performance. The kinematic viscosity did not affect the speed attenuation of the projectile. Furthermore, it was found that the compressibility affected the pressure wave generated by the entry of a projectile into the liquid.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The proton-pumping NADH-quinone oxidoreductase from Escherichia coli houses nine iron-sulfur clusters, eight of which are found in its mitochondrial counterpart, complex I. The extra putative ...iron-sulfur cluster binding site with a CXXCXXXCX27C motif in the NuoG subunit has been assigned to ligate a 2Fe-2S (N1c). However, we have shown previously that the Thermus thermophilus N1c fragment containing this motif ligates a 4Fe-4S (Nakamaru-Ogiso, E., Yano, T., Ohnishi, T., and Yagi, T. (2002) J. Biol. Chem. 277, 1680–1688). In the current study, we individually inactivated four sets of the iron-sulfur binding motifs in the E. coli NuoG subunit by replacing all four ligands with Ala. Each mutant subunit, designated ΔN1b, ΔN1c, ΔN4, and ΔN5, was expressed as maltose-binding protein fusion proteins. After in vitro reconstitution, all mutant subunits were characterized by EPR. Although EPR signals from cluster N1b were not detected in any preparations, we detected two 4Fe-4S EPR signals with g values of gx,y,z = 1.89, 1.94, and 2.06, and gx,y,z = 1.91, 1.94, and 2.05 at 6–20 K in wild type, ΔN1b, and ΔN5. The former signal was assigned to cluster N4, and the latter signal was assigned to cluster N1c because of their disappearance in ΔN4 and ΔN1c. Confirming that a 4Fe-4S cluster ligates to the N1c motif, we propose to replace its misleading 2Fe-2S name, N1c, with “cluster N7.” In addition, because these mutations differently affected the assembly of peripheral subunits by in trans complementation analysis with the nuoG knock-out strain, the implicated structural importance of the iron-sulfur binding domains is discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Allogeneic stem cell transplantation (allo-SCT) is the only curative option for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Azacitidine (AZA) has a good toxicity profile compared ...with intensive chemotherapy and can be considered a pre-transplant regimen in elderly patients and in patients with comorbidities. To investigate the impact of pre-transplant AZA on patient outcome after allo-SCT, we conducted a retrospective analysis of AZA pre-treatment followed by allo-SCT in patients with high-risk MDS and AML. Twenty patients who were divided into two groups according to AZA treatment given prior to allo-SCT (AZA
non-AZA group, 10 each). Overall survival, event-free survival and incidence of chronic graft-
-host disease (GVHD) were not significantly different between the two groups. The overall incidence of grade II to IV acute GVHD in the AZA group was significantly lower than that in the non-AZA group (P=0.004). Bridging to transplant with AZA should be considered as an immunomodulator and effective treatment strategy for patients with MDS and AML.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Non-woven fiber mats were fabricated with the electrospinning method using poly(methyl methacrylate)-co-poly(2-(2-bromoisobutyryloxy)ethyl methacrylate) in various solvents. The surface morphology of ...the electrospun fibers depended on the solvent vapor pressure and polymer concentration. Surface-initiated atom transfer radical polymerization (ATRP) with 3-(N-2-methacryloyloxyethyl-N,N-dimethyl) ammonatopropanesulfonate), 2-hydroxyethyl methacrylate or 2-(perfluorooctyl)ethyl acrylate generated surface-grafted polymers, as determined by X-ray photoelectron spectroscopy. Scanning electron microscopic observation revealed that the apparent fiber morphology did not change upon modification. The atomic force microscopic images of the grafted fiber cross-sections indicated that monomers and solvents penetrated slightly into the fibers and polymerization occurred at both internal and external initiation sites. Physicochemical properties, such as contact angle, hydrophobicity and hydrophilicity, and wettability, could be altered by the proper selection of substrates (spin-coated flat films or the variously prepared non-woven fiber mats). We have successfully prepared hydrophilic and hydrophobic fiber surfaces by a combination of the electrospinning protocol and surface-initiated ATRP.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
High‐dose chemotherapy and autologous stem cell transplantation (ASCT) are too toxic for elderly patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL). Therefore, effective and ...tolerable regimens for elderly patients are urgently needed. The present phase II study assessed the efficacy and safety of dose‐adjusted therapy with gemcitabine, dexamethasone, cisplatin, and rituximab (GDP‐R) in this population. ASCT‐ineligible elderly patients with relapsed or refractory DLBCL received dose‐adjusted GDP‐R in each 28‐day cycle for up to six cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints were complete response (CR) rate, progression‐free survival (PFS), and safety. Thirty‐three patients were enrolled and received dose‐adjusted GDP‐R. The median age was 75 years (range: 68‐87 years). The ORR was 82.8% (90% confidence interval CI, 67.1‐93.0%), with a CR rate of 58.6% (90% CI, 41.7‐74.1%). At a median follow‐up of 20.9 months, the 2‐year PFS rate was 46.8% (90% CI, 30.7‐61.5%) and the 2‐year overall survival rate was 63.2% (90% CI, 45.8‐76.3%). The most frequently observed grade 4 adverse events were neutropenia (63.6%), thrombocytopenia (57.6%), and lymphocytopenia (39.4%). Dose‐adjusted GDP‐R is a promising salvage regimen for ASCT‐ineligible elderly patients with relapsed DLBCL after rituximab‐containing chemotherapy and warrants further investigation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Previously, we investigated ubisemiquinone (SQ) EPR spectra associated with NADH-ubiquinone oxidoreductase (complex I) in the tightly coupled bovine heart submitochondrial particles (SMP). Based upon ...their widely differing spin relaxation rate, we distinguished SQ spectra arising from three distinct SQ species, namely SQNf (fast), SQNs (slow), and SQNx (very slow). The SQNf signal was observed only in the presence of the proton electrochemical gradient (ΔμH+), while SQNs and SQNx species did not require the presence of ΔμH+. We have now succeeded in characterizing the redox and EPR properties of SQ species in the isolated bovine heart complex I. The potentiometric redox titration of the gz,y,x=2.00 semiquinone signal gave the redox midpoint potential (Em) at pH 7.8 for the first electron transfer step Em1(Q/SQ) of −45 mV and the second step Em2(SQ/QH2) of −63 mV. It can also be expressed as Em(Q/QH2) of −54 mV for the overall two electron transfer with a stability constant (Kstab) of the SQ form as 2.0. These characteristics revealed the existence of a thermodynamically stable intermediate redox state, which allows this protein-associated quinone to function as a converter between n=1 and n=2 electron transfer steps. The EPR spectrum of the SQ species in complex I exhibits a Gaussian-type spectrum with the peak-to-peak line width of ∼6.1 G at the sample temperature of 173 K. This indicates that the SQ species is in an anionic Q− state in the physiological pH range. The spin relaxation rate of the SQ species in isolated complex I is much slower than the SQ counterparts in the complex I in situ in SMP. We tentatively assigned slow relaxing anionic SQ species as SQNs, based on the monophasic power saturation profile and several fold increase of its spin relaxation rate in the presence of reduced cluster N2. The current study also suggests that the very slowly relaxing SQNx species may not be an intrinsic complex I component. The functional role of SQNs is further discussed in connection with the SQNf species defined in SMP in situ.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mature T cell lymphoma has been noted for poor prognosis when compared with B cell lymphoma, even in the pre-rituximab era. To confirm this difference, a retrospective cohort study was conducted. One ...hundred-and nineteen patients with mature T cell lymphoma and 568 patients with diffuse large B cell lymphoma (DLBCL) who did not receive rituximab as first induction were studied. Overall survival (OS) was worse for patients with international prognostic index (IPI) scores indicating low-risk mature T cell lymphoma than for those with DLBCL (3-year OS 87 % vs. 58 %,
P
= 0.001), but not in other risk groups. Prognosis of mature T cell lymphoma was significantly poorer in the IPI low-risk group, as compared with DLBCL.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of mature CD5-positive, CD10-negative, CD20 weakly positive, and CD23-positive B-cells within blood, bone ...marrow, lymph nodes, and spleen. In proliferation centers, the survival and growth of CLL cells requires a permissive microenvironment comprising T-cells, macrophages, and stromal cells. FISH analysis has revealed that almost 80% of CLL cases carry chromosomal abnormalities including the most frequent del (13q14) and the strongest poor prognostic factor del (17p), both related to TP53 mutations. Current treatment approaches are not curative for CLL, except allogeneic hematopoietic stem cell transplantation, which is rarely offered to the majority of patients aged 70 years and older. Currently, there is no evidence that the initiation of therapy for asymptomatic early-stage disease improves the overall survival, even for patients with high-risk disease. The identification that the B-cell receptor (BCR) signaling pathway is aberrantly and constitutively activated in CLL has recently led to the development of BCR signaling inhibitors, ibrutinib and idelalisib. In addition, a novel BCL-2 antagonist, venetoclax, appears promising when used alone or in combination with anti-CD20 antibodies. The advent of novel small-molecule inhibitors has revolutionized the treatment approaches for patients with CLL.
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