The infusion of ex vivo, interleukin-15 and -21-activated donor NK cells after haploidentical HCT in high-risk AML and MDS patients-a randomized trial.

Clinical effect of donor-derived natural killer cell infusion (DNKI) after HLA-haploidentical hematopoietic cell transplantation (HCT) was evaluated in high-risk myeloid malignancy in phase 2, randomized trial. Seventy-six evaluable patients (aged 21-70 years) were randomized to receive DNKI (N = 40) or not (N = 36) after haploidentical HCT. For the HCT conditioning, busulfan, fludarabine, and anti-thymocyte globulin were administered. DNKI was given twice 13 and 20 days after HCT. Four patients in the DNKI group failed to receive DNKI. In the remaining 36 patients, median DNKI doses were 1.0 × 108/kg and 1.4 × 108/kg on days 13 and 20, respectively. Intention-to-treat analysis showed a lower disease progression for the DNKI group (30-month cumulative incidence, 35% vs 61%, P = 0.040; subdistribution hazard ratio, 0.50). Furthermore, at 3 months after HCT, the DNKI patients showed a 1.8- and 2.6-fold higher median absolute blood count of NK and T cells, respectively. scRNA-sequencing analysis in seven study patients showed that there was a marked increase in memory-like NK cells in DNKI patients which, in turn, expanded the CD8+ effector-memory T cells. In high-risk myeloid malignancy, DNKI after haploidentical HCT reduced disease progression. This enhanced graft-vs-leukemia effect may be related to the DNKI-induced, post-HCT expansion of NK and T cells. Clinical trial number: NCT02477787.

Electrical and Optical Properties of Co75Si15B10 Metallic Glass Nanometric Thin Films.

Co-based (Co75Si15B10) thin-film metallic glass (TFMG) with nanometric thicknesses (100~300 nm) was investigated for its structural, electrical, and optical properties. The TFMG structure was examined using scanning electron microscopy and X-ray diffraction, while electrical properties were examined using inductance/capacitance/resistance spectroscopy, cyclic voltammetry, and Hall effect measurements. In addition, optical absorption/reflection/transmittance measurements were performed to examine optical properties. Results revealed that Co-based TFMGs, which have an amorphous structure without surface defects, behave like a dielectric material, with higher resistivity and much lower carrier concentration than pure cobalt (Co) thin films of the same thickness, despite its mobility being modestly larger than its Co counterparts. Meanwhile, the optical investigation of TFMG enabled us to determine the complex relative permittivity (complex relative dielectric constant) ϵr˜ at a visible wavelength (632.8 nm). Moreover, unlike normal metals, TFMGs exhibited a large positive value of the real part of ϵr˜, while exhibiting properties of substantial absorption of light (absorption coefficient α). It was also found that the Co-based TFMG gained optical transparency for thicknesses less than 5 nm. TFMGs demonstrated the nearly thickness-independent properties of the electrical and optical parameters probed, a feature of high-index, dielectric-like material with negligible size effects, which may have applications in micrometer-scaled optoelectronic and magneto-optical devices.

Metabolic engineering of Corynebacterium glutamicum for the production of glutaric acid, a C5 dicarboxylic acid platform chemical.

Corynebacterium glutamicum was metabolically engineered for the production of glutaric acid, a C5 dicarboxylic acid that can be used as platform building block chemical for nylons and plasticizers. C. glutamicum gabT and gabD genes and Pseudomonas putida davT and davD genes encoding 5-aminovalerate transaminase and glutarate semialdehyde dehydrogenase, respectively, were examined in C. glutamicum for the construction of a glutaric acid biosynthesis pathway along with P. putida davB and davA genes encoding lysine 2-monooxygenase and delta-aminovaleramidase, respectively. The glutaric acid biosynthesis pathway constructed in recombinant C. glutamicum was engineered by examining strong synthetic promoters PH30 and PH36, C. glutamicum codon-optimized davTDBA genes, and modification of davB gene with an N-terminal His6-tag to improve the production of glutaric acid. It was found that use of N-terminal His6-tagged DavB was most suitable for the production of glutaric acid from glucose. Fed-batch fermentation using the final engineered C. glutamicum H30_GAHis strain, expressing davTDA genes along with davB fused with His6-tag at N-terminus could produce 24.5 g/L of glutaric acid with low accumulation of l-lysine (1.7 g/L), wherein 5-AVA accumulation was not observed during fermentation.

Donor-Derived Natural Killer Cell Infusion after Human Leukocyte Antigen-Haploidentical Hematopoietic Cell Transplantation in Patients with Refractory Acute Leukemia.

The optimum method of donor natural killer cell infusion (DNKI) after allogeneic hematopoietic cell transplantation (HCT) remains unclear. Fifty-one patients (age range, 19 years to 67 years) with refractory acute leukemia underwent HLA-haploidentical HCT and underwent DNKI on days 6, 9, 13, and 20 of HCT. Median DNKI doses were .5, .5, 1.0, and 2.0 × 108/kg cells, respectively. During DNKI, 33 of the 45 evaluated patients (73%) developed fever (>38.3°C) along with weight gain (median, 13%; range, 2% to 31%) and/or hyperbilirubinemia (median, 6.2 mg/dL; range, 1.0 mg/dL to 35.1 mg/dL); the toxicity was reversible in 90% of patients. After transplantation, we observed cumulative incidences of neutrophil engraftment (≥500/µL), grade 2 to 4 acute graft-versus-host disease (GVHD), chronic GVHD, and nonrelapse mortality of 84%, 28%, 30%, and 16%, respectively. The leukemia complete remission rate was 57% at 1 month after HCT and 3-year cumulative incidence of leukemia progression was 75%. When analyzed together with our historical cohort of 40 patients with refractory acute leukemia who underwent haploidentical HCT and DNKI on days 14 and 21 only, higher expression of NKp30 (>90%) on donor NK cells was an independent predictor of higher complete remission (hazard ratio, 5.59) and less leukemia progression (hazard ratio, .57). Additional DNKI on days 6 and 9 was not associated with less leukemia progression (75% versus 55%).

Perpendicular Magnetic Anisotropy in Amorphous Ferromagnetic CoSiB/Pd Thin-Film Layered Structures.

Spin transfer torque (STT) induced switching of magnetization has led to intriguing and practical possibilities for magnetic random access memory (MRAM). This form of memory, called STT-MRAM, is a strong candidate for future memory applications. This application usually requires a large perpendicular magnetic anisotropy (PMA), large coercivity, and low saturation magnetization. Therefore, we propose an amorphous ferromagnetic CoSiB alloy and investigate CoSiB/Pd multilayer thin films, which have a large PMA, large coercivity, and low saturation magnetization. In this research, we propose a remarkable layered structure that could be a candidate for future applications and try to address a few factors that might affect the variation of PMA, coercivity, and saturation magnetization in the CoSiB/Pd multilayers. We investigate the magnetic properties of the CoSiB/Pd multilayers with various thicknesses of the CoSiB layer. The coercivity was obtained with a maximum of 228 Oe and a minimum value of 91 Oe in the [CoSiB 7 Å/Pd 14 Å], and [CoSiB 9 Å/Pd 14 Å], multilayers, respectively. The PMA arises from tCoSiB = 3 Å to tCoSiB = 9 Å and disappears after tCoSiB = 9 Å.

Perpendicular Magnetic Anisotropy in CoSiB/Pd/CoSiB Trilayer Thin Films with Varying Pd-Layer Thicknesses.

We investigate the magnetic properties of CoSiB (1 5-Å-thickness)/Pd (Pd thickness = 8, 11, 14, 17, 20, 24, 27, 29 and 33 Å)/CoSiB (15-Å-thickness) trilayer thin films. The CoSiB-layer thickness was fixed to 15 Å, while the Pd-layer thickness was varied from 8-33 Å. In this paper, we present a new type of thin film containing amorphous Co75Si15B10 and Pd. We investigate the magnetic properties of a fabricated CoSiB/Pd/CoSiB trilayer thin film with perpendicular magnetic anisotropy, and determine the correlation between the magnetic properties and the nonmagnetic Pd-layer thickness. With increasing Pd-layer thickness, both the coercivity and the saturation magnetization decreased. Furthermore, the maximum values of the magnetic anisotropy were calculated as 0.3 x 10(6) erg/cc. In order to examine the difference between the in-plane magnetic anisotropy and perpendicular magnetic anisotropy, magnetic force microscopy images of the CoSiB (15-Å-thickness)/Pd (Pd thickness = 8 and 14 Å)/CoSiB (15-Å-thickness) trilayer thin films were obtained.

Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study.

The doses of donor-derived natural killer (NK) cells that can be given safely after human leukocyte antigen (HLA)-haploidentical hematopoietic cell transplantation (HCT) remain to be defined. Forty-one patients (ages 17 to 75 years) with hematologic malignancy underwent HLA-haploidentical HCT after reduced-intensity conditioning containing busulfan, fludarabine, and antithymocyte globulin. Cell donors (ages 7 to 62 years) underwent growth factor-mobilized leukapheresis for 3 to 4 days. Cells collected on the first 2 to 3 days were used for HCT, whereas those collected on the last day were CD3-depleted and cultured into NK cells using human interleukins-15 and -21. These NK cells were then infused into patients twice at 2 and 3 weeks after HCT at an escalating doses of .2 × 10(8) cells/kg of body weight (3 patients), .5 × 10(8) cells/kg (3 patients), 1.0 × 10(8) cells/kg (8 patients), and ≥ 1.0 × 10(8) cells/kg or available cells (27 patients). At all dose levels, no acute toxicity was observed after NK cell infusion. After HLA-haploidentical HCT and subsequent donor NK cell infusion, when referenced to 31 historical patients who had undergone HLA-haploidentical HCT after the same conditioning regimen but without high-dose NK cell infusion, there was no significant difference in the cumulative incidences of major HCT outcomes, including engraftment (absolute neutrophil count ≥ 500/µL, 85% versus 87%), grade 2 to 4 acute graft-versus-host disease (GVHD, 17% versus 16%), moderate to severe chronic GVHD (15% versus 10%), and transplantation-related mortality (27% versus 19%). There was, however, a significant reduction in leukemia progression (74% to 46%), with post-transplantation NK cell infusion being an independent predictor for less leukemia progression (hazard ratio, .527). Our findings showed that, when given 2 to 3 weeks after HLA-haploidentical HCT, donor-derived NK cells were well tolerated at a median total dose of 2.0 × 10(8) cells/kg. In addition, they may decrease post-transplantation progression of acute leukemia.

Effect of cardiorespiratory fitness on acute inflammation induced increases in arterial stiffness in older adults.

We tested the hypothesis that acute inflammation may cause arterial stiffening in older adults. We further explored if high cardiorespiratory fitness may partially prevent the unfavorable effect of arterial stiffening produced by acute systemic inflammation in older adults. Using a randomized double-blind sham placebo-controlled design, forty healthy older adults were assigned to receive either an influenza vaccine or a sham vaccine. C-reactive protein and interleukin 6 (IL-6) were measured as markers of inflammation. Carotid-femoral pulse wave velocity (PWV) and augmentation index (AIX) as indices of arterial stiffness and wave reflection were assessed at baseline and 24 and 48 h after each vaccination. When compared with sham placebo, the influenza vaccination caused a significant increase in CRP (p < 0.05) and IL-6 (p < 0.05). Carotid-femoral PWV, but not AIX was significantly increased after influenza vaccination (p < 0.05), but not sham vaccination. The high cardiorespiratory fitness group had an attenuated increase in PWV as compared to the low cardiorespiratory fitness group after acute inflammation (p < 0.05). These findings show that acute inflammation may cause significant increases in arterial stiffness in older adults, but these increases were attenuated in the high cardiorespiratory fitness group as compared to the low cardiorespiratory fitness group.