A lactate-induced response to hypoxia.

Organisms must be able to respond to low oxygen in a number of homeostatic and pathological contexts. Regulation of hypoxic responses via the hypoxia-inducible factor (HIF) is well established, but evidence indicates that other, HIF-independent mechanisms are also involved. Here, we report a hypoxic response that depends on the accumulation of lactate, a metabolite whose production increases in hypoxic conditions. We find that the NDRG3 protein is degraded in a PHD2/VHL-dependent manner in normoxia but is protected from destruction by binding to lactate that accumulates under hypoxia. The stabilized NDRG3 protein binds c-Raf to mediate hypoxia-induced activation of Raf-ERK pathway, promoting angiogenesis and cell growth. Inhibiting cellular lactate production abolishes the NDRG3-mediated hypoxia responses. Our study, therefore, elucidates the molecular basis for lactate-induced hypoxia signaling, which can be exploited for the development of therapies targeting hypoxia-induced diseases.

The role of morphine- and fentanyl-induced impairment of intestinal epithelial antibacterial activity in dysbiosis and its impact on the microbiota-gut-brain axis.

Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupts the intestinal epithelial layer and causes intestinal dysbiosis. Depleting gut bacteria can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. The mechanism underlying opioid-induced dysbiosis, however, remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine or fentanyl exposure reduces the antimicrobial activity in the ileum, resulting in changes in the composition of bacteria. Fecal samples from morphine-treated mice had increased levels of Akkermansia muciniphila with a shift in the abundance ratio of Firmicutes and Bacteroidetes. Fecal microbial transplant (FMT) from morphine-naïve mice or oral supplementation with butyrate restored (a) the antimicrobial activity, (b) the expression of the antimicrobial peptide, Reg3γ, (c) prevented the increase in intestinal permeability and (d) prevented the development of antinociceptive tolerance in morphine-dependent mice. Improved epithelial barrier function with FMT or butyrate prevented the enrichment of the mucin-degrading A. muciniphila in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which opioids disrupt the microbiota-gut-brain axis.

Rational Design of Lipid Nanoparticles for Enhanced mRNA Vaccine Delivery via Machine Learning.

Since the coronavirus pandemic, mRNA vaccines have revolutionized the field of vaccinology. Lipid nanoparticles (LNPs) are proposed to enhance mRNA delivery efficiency; however, their design is suboptimal. Here, a rational method for designing LNPs is explored, focusing on the ionizable lipid composition and structural optimization using machine learning (ML) techniques. A total of 213 LNPs are analyzed using random forest regression models trained with 314 features to predict the mRNA expression efficiency. The models, which predict mRNA expression levels post-administration of intradermal injection in mice, identify phenol as the dominant substructure affecting mRNA encapsulation and expression. The specific phospholipids used as components of the LNPs, as well as the N/P ratio and mass ratio, are found to affect the efficacy of mRNA delivery. Structural analysis highlights the impact of the carbon chain length on the encapsulation efficiency and LNP stability. This integrated approach offers a framework for designing advanced LNPs and has the potential to unlock the full potential of mRNA therapeutics.

Low-Efficacy Mu Opioid Agonists as Candidate Analgesics: Effects of Novel C-9 Substituted Phenylmorphans on Pain-Depressed Behavior in Mice.

Low efficacy mu opioid receptor (MOR) agonists may serve as novel candidate analgesics with improved safety relative to high-efficacy opioids. This study used a recently validated assay of pain-depressed behavior in mice to evaluate a novel series of MOR-selective C9-substituted phenylmorphan opioids with graded MOR efficacies. Intraperitoneal injection of dilute lactic acid (IP acid) served as a noxious stimulus to depress locomotor activity by mice in an activity chamber composed of two compartments connected by an obstructed door. Behavioral measures included (1) crosses between compartments (vertical activity over the obstruction) and (2) movement counts quantified as photobeam breaks summed across compartments (horizontal activity). Each drug was tested alone and as a pretreatment to IP acid. A charcoal-meal test and whole-body-plethysmography assessment of breathing in 5% CO2 were also used to assess gastrointestinal (GI) inhibition and respiratory depression, respectively. IP acid produced a concentration-dependent depression in crosses and movement that was optimally alleviated by intermediate- to low-efficacy phenylmorphans with sufficient efficacy to produce analgesia with minimal locomotor disruption. Follow-up studies with two low-efficacy phenylmorphans (JL-2-39 and DC-1-76.1) indicated that both drugs produced naltrexone-reversible antinociception with a rapid onset and a duration of ~1hr. Potency of both drugs increased when behavior was depressed by a lower IP-acid concentration, and neither drug alleviated behavioral depression by a non-pain stimulus (IP lithium chloride). Both drugs produced weaker GI inhibition and respiratory depression than fentanyl and attenuated fentanyl-induced GI inhibition and respiratory depression. Results support further consideration of selective, low-efficacy MOR agonists as candidate analgesics. Significance Statement This study used a novel set of mu opioid receptor (MOR)-selective opioids with graded MOR efficacies to examine the lower boundary of MOR efficacy sufficient to relieve pain-related behavioral depression in mice. Two novel low-efficacy opioids (JL-2-39, DC-1-76.1) produced effective antinociception with improved safety relative to higher- or lower-efficacy opioids, and results support further consideration of these and other low-efficacy opioids as candidate analgesics.

Wafer-scale striped network transistors based on purified semiconducting carbon nanotubes for commercialization.

Highly purified and solution-processed semiconducting carbon nanotubes (s-CNTs) have developed rapidly over the past several decades and are near-commercially available materials that can replace silicon due to its large-area substrate deposition and room-temperature processing compatibility. However, the more s-CNTs are purified, the better their electrical performance, but considerable effort and long centrifugation time are required, which can limit commercialization due to high manufacturing costs. In this work, we therefore fabricated 'striped' CNT network transistor across industry-standard 8 inch wafers. The stripe-structured channel is effective in lowering the manufacturing cost because it can maintain good device performance without requiring high-purity s-CNTs. We evaluated the electrical performances and their uniformity by demonstrating striped CNT network transistors fabricating from various s-CNT solutions (e.g. 99%, 95%, and 90%) in 8 inch wafers. From our results, we concluded that by optimizing the CNT network configurations, CNTs can be sufficiently utilized for commercialization technology even at low semiconducting purity. Our approach can serve as a critical foundation for future low-cost commercial CNT electronics.

Exosomal miR-205-5p Improves Endometrial Receptivity by Upregulating E-Cadherin Expression through ZEB1 Inhibition.

Endometrial receptivity is a complex process that prepares the uterine endometrium for embryo implantation; insufficient endometrial receptivity is one of the causes of implantation failure. Here, we analyzed the microRNA expression profiles of exosomes derived from both receptive (RL95-2) and non-receptive (AN3-CA) endometrial epithelial cell (EEC) lines to identify exosomal miRNAs closely linked to endometrial receptivity. Among the 466 differentially expressed miRNAs, miR-205-5p was the most highly expressed in exosomes secreted from receptive RL95-2 cells. miR-205-5p, enriched at the adhesive junction, was closely related to endometrial receptivity. ZEB1, a transcriptional repressor of E-cadherin associated with endometrial receptivity, was identified as a direct target of miR-205-5p. miR-205-5p expression was significantly lower in the endometrial tissues of infertile women than in that of non-infertile women. In vivo, miR-205-5p expression was upregulated in the post-ovulatory phase, and its inhibitor reduced embryo implantation. Furthermore, administration of genetically modified exosomes overexpressing miR-205-5p mimics upregulated E-cadherin expression by targeting ZEB1 and improved spheroid attachment of non-receptive AN3-CA cells. These results suggest that the miR-205-5p/ZEB1/E-cadherin axis plays an important role in regulating endometrial receptivity. Thus, the use of exosomes harboring miR-205-5p mimics can be considered a potential therapeutic approach for improving embryo implantation.

The Guts of the Opioid Crisis.

Bidirectional interactions of the gut epithelium with commensal bacteria are critical for maintaining homeostasis within the gut. Chronic opioid exposure perturbs gut homeostasis through a multitude of neuro-immune-epithelial mechanisms, resulting in the development of analgesic tolerance, a major underpinning of the current opioid crisis. Differences in molecular mechanisms of opioid tolerance between the enteric and central pain pathways pose a significant challenge for managing chronic pain without untoward gastrointestinal effects.

Cost-effective method for fabricating carbon nanotube network transistors by reusing a 99% semiconducting carbon nanotube solution.

Carbon nanotubes (CNTs) are one-dimensional materials that have been proposed to replace silicon semiconductors and have been actively studied due to their high carrier mobility, high current density, and high mechanical flexibility. Specifically, highly purified, pre-separated, and solution-processed semiconducting CNTs are suitable for mass production. These CNTs have advantages, such as room-temperature processing compatibility, while enabling a fast and straightforward manufacturing process. In this paper, CNT network transistors were fabricated on a total of five 8 inch wafers by reusing a highly purified and pre-separated 99% semiconductor-enriched CNT solution. The results confirmed that the density of semiconducting CNTs deposited on the five selected wafers was notably uniform, even though the CNT solution was reused up to four times after the initial CNT deposition. Moreover, there was no significant degradation in the key CNT network transistor metrics. Therefore, we believe that our findings regarding this CNT reuse method may provide additional guidance in the field of wafer-scale CNT electronics and may contribute strongly to the development of practical device applications at an ultralow cost.

Regulation of hypoxia responses by flavin adenine dinucleotide-dependent modulation of HIF-1α protein stability.

Oxygen deprivation induces a range of cellular adaptive responses that enable to drive cancer progression. Here, we report that lysine-specific demethylase 1 (LSD1) upregulates hypoxia responses by demethylating RACK1 protein, a component of hypoxia-inducible factor (HIF) ubiquitination machinery, and consequently suppressing the oxygen-independent degradation of HIF-1α. This ability of LSD1 is attenuated during prolonged hypoxia, with a decrease in the cellular level of flavin adenine dinucleotide (FAD), a metabolic cofactor of LSD1, causing HIF-1α downregulation in later stages of hypoxia. Exogenously provided FAD restores HIF-1α stability, indicating a rate-limiting role for FAD in LSD1-mediated HIF-1α regulation. Transcriptomic analyses of patient tissues show that the HIF-1 signature is highly correlated with the expression of LSD1 target genes as well as the enzymes of FAD biosynthetic pathway in triple-negative breast cancers, reflecting the significance of FAD-dependent LSD1 activity in cancer progression. Together, our findings provide a new insight into HIF-mediated hypoxia response regulation by coupling the FAD dependence of LSD1 activity to the regulation of HIF-1α stability.

Directly drawn top-gate semiconducting carbon nanotube thin-film transistors and complementary inverters.

As the emerging demand for electronic devices that are simple, cost effective and capable of rapid fabrication has increased, novel fabrication techniques for designing and manufacturing such devices have attracted remarkable research interest. One method for prototyping these electronic devices is to draw them using a handwriting tool that is commonly available. In this work, we demonstrate a transistor and complementary logic inverter that are directly drawn using a brush and that are based on solution-based materials such as semiconducting carbon nanotubes (CNTs), silver ink and paste, and cross-linked poly(4-vinylphenol) (cPVP). The directly drawn CNT thin-film transistor (TFT) has p-type behavior due to the adsorption of oxygen and moisture, a high current on/off ratio (approximately 103), and a low operating voltage. By employing a solution-based chemical doping treatment with an amine-rich polymer, polyethyleneimine (PEI), that has strong electron-donating ability, the drawn p-type CNT-TFT is successfully converted to an n-type CNT-TFT. Therefore, we fabricate a drawn complementary logic inverter consisting of the p-type CNT-TFT and PEI-treated n-type CNT-TFT and evaluate its electrical performance.

Wafer-scale carbon nanotube network transistors.

Highly purified, preseparated semiconducting carbon nanotubes (CNTs) hold great potential for high-performance CNT network transistors due to their high electrical conductivity, high mechanical strength, and room-temperature processing compatibility. In this paper, we report our recent progress on CNT network transistors integrated on an 8-inch wafer. We observe that the key device performance parameters of CNT network transistors at various locations on an 8-inch wafer are highly uniform and that the device yield is impressive. Therefore, this work validates a promising path toward mass production and will make a significant contribution to the future field of wafer-scale CNT electronics.

Connexin-purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation.

Morphine is one of the most widely used drugs for the treatment of pain. However, side effects, including persistent constipation and antinociceptive tolerance, limit its clinical efficacy. Prolonged morphine treatment results in a "leaky" gut, predisposing to colonic inflammation that is facilitated by microbial dysbiosis and associated bacterial translocation. In this study, we examined the role of enteric glia in mediating this secondary inflammatory response to prolonged treatment with morphine. We found that purinergic P2X receptor activity was significantly enhanced in enteric glia that were isolated from mice with long-term morphine treatment (in vivo) but not upon direct exposure of glia to morphine (in vitro). LPS, a major bacterial product, also increased ATP-induced currents, as well as expression of P2X4, P2X7, IL6, IL-1ß mRNA in enteric glia. LPS increased connexin43 (Cx43) expression and enhanced ATP release from enteric glia cells. LPS-induced P2X currents and proinflammatory cytokine mRNA expression were blocked by the Cx43 blockers Gap26 and carbenoxolone. Likewise, colonic inflammation related to prolonged exposure to morphine was significantly attenuated by carbenoxolone (25 mg/kg). Carbenoxolone also prevented gut wall disruption and significantly reduced morphine-induced constipation. These findings imply that enteric glia activation is a significant modulator of morphine-related inflammation and constipation.-Bhave, S., Gade, A., Kang, M., Hauser, K. F., Dewey, W. L., Akbarali, H. I. Connexin-purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation.

Vertically Integrated Nanowire-Based Unified Memory.

A vertically integrated nanowire-based device for multifunctional unified memory that combine dynamic random access memory (DRAM) and flash memory in a single transistor is demonstrated for the first time. The device utilizes a gate-all-around (GAA) structure that completely surrounds the nanowire; the structure is built on a bulk silicon wafer. A vertically integrated unified memory (VIUM) device composed of five-story channels was fabricated via the one-route all-dry etching process (ORADEP) with reliable reproducibility, stiction-free stability, and high uniformity. In each DRAM and flash memory operation, the five-story VIUM showed a remarkably enhanced sensing current drivability compared with one-story unified memory (UM) characteristics. In addition to each independent memory mode, the switching endurance of the VIUM was evaluated in the unified mode, which alternatively activates two memory modes, resulting in an even higher sensing memory window than that of the UM. In addition to our previous work on a logic transistor joining high performance with good scalability, this work describes a novel memory hierarchy design with high functionality for system-on-chip (SoC) architectures, demonstrating the practicality and versatility of the vertically integrated nanowire configuration for use in various applications.

A Vertically Integrated Junctionless Nanowire Transistor.

A vertically integrated junctionless field-effect transistor (VJ-FET), which is composed of vertically stacked multiple silicon nanowires (SiNWs) with a gate-all-around (GAA) structure, is demonstrated on a bulk silicon wafer for the first time. The proposed VJ-FET mitigates the issues of variability and fabrication complexity that are encountered in the vertically integrated multi-NW FET (VM-FET) based on an identical structure in which the VM-FET, as recently reported, harnesses a source and drain (S/D) junction for its operation and is thus based on the inversion mode. Variability is alleviated by bulk conduction in a junctionless FET (JL-FET), where current flows through the core of the SiNW, whereas it is not mitigated by surface conduction in an inversion mode FET (IM-FET), where current flows via the surface of the SiNW. The fabrication complexity is reduced by the inherent JL structure of the JL-FET because S/D formation is not required. In contrast, it is very difficult to dope the S/D when it is positioned at each floor of a tall SiNW with greater uniformity and with less damage to the crystalline structure of the SiNW in a VM-FET. Moreover, when the proposed VJ-FET is used as nonvolatile flash memory, the endurance and retention characteristics are improved due to the above-mentioned bulk conduction.

Enhanced Sensitivity of α3ß4 Nicotinic Receptors in Enteric Neurons after Long-Term Morphine: Implication for Opioid-Induced Constipation.

Opioid-induced constipation is a major side effect that persists with long-term opioid use. Previous studies demonstrated that nicotine-induced contractions are enhanced after long-term morphine exposure in guinea pig ileum. In the present study, we examined whether the increased sensitivity to nicotine could be observed in single enteric neurons after long-term morphine exposure, determined the subunits in mouse enteric neurons, and examined the effect of nicotine in reversing opioid-induced constipation. Nicotine (0.03-1 mM) dose-dependently induced inward currents from a holding potential of -60 mV in isolated single enteric neurons from the mouse ileum. The amplitude of the currents, but not the potency to nicotine, was significantly increased in neurons receiving long-term (16-24 h) but not short-term (10 min) exposure to morphine. Quantitative mRNA analysis showed that nicotinic acetylcholine receptor (nAChR) subunit expression in the mouse ileum was α3 ≥ ß2 > ß4 > α5 > α4 > ß3 > α6. Nicotine-induced currents were obtained in neurons from α7, ß2, α5, and α6 knockout mice. The currents were, however, inhibited by mecamylamine (10 µM) and the α3ß4 blocker α-conotoxin AuIB (3 µM), suggesting that nicotine-induced currents were mediated by the α3ß4 subtype of nAChRs on enteric neurons. Conversely, NS3861, a partial agonist at α3ß4 nAChR, enhanced fecal pellet expulsion in a dose-dependent manner in mice that received long-term, but not short-term, morphine treatment. Overall, our findings suggest that the efficacy of nAChR agonists on enteric neurons is enhanced after long-term morphine exposure, and activation of the α3ß4 subtype of nAChR reverses chronic, but not acute, morphine-induced constipation.

Hydroxyapatite (HA)/poly-L-lactic acid (PLLA) dual coating on magnesium alloy under deformation for biomedical applications.

The introduction of a protective coating layer to highly corrosive magnesium (Mg) has been proposed as one of the common approaches for improved corrosion resistance of Mg-based implants as load-bearing biomedical applications. However, only few studies have focused on the mechanical stability of the coated Mg under practical conditions where significant deformation of the load-bearing implants is induced during the surgical operation or under physiological environments. Therefore, in this study, we developed a dual coating system composed of an interlayer hydroxyapatite (HA) and a top layer poly-L-lactic acid (PLLA) to improve the coating stability under deformation of Mg alloy (WE43) substrate. The HA interlayer was directly formed on the Mg alloy surface, followed by dip-coating of PLLA. As the interlayer, HA improved the adhesion of PLLA by modulating nano- and microscale roughness, in addition to its inherently good bonding strength to Mg. The flexible and deformable top coating PLLA layer mitigated crack propagation in the HA layer under deformation. Thus, the dual coating layer provided good protection to the underlying WE43 from corrosion regardless of deformation. The enhanced corrosion behavior of dual-coated WE43 exhibited better mechanical and biological performance compared to the non-coated or single-coated WE43. Therefore, this dual coating layer on Mg is expected to accelerate Mg-based applications in biomedical devices.

Vertically Integrated Multiple Nanowire Field Effect Transistor.

A vertically integrated multiple channel-based field-effect transistor (FET) with the highest number of nanowires reported ever is demonstrated on a bulk silicon substrate without use of wet etching. The driving current is increased by 5-fold due to the inherent vertically stacked five-level nanowires, thus showing good feasibility of three-dimensional integration-based high performance transistor. The developed fabrication process, which is simple and reproducible, is used to create multiple stiction-free and uniformly sized nanowires with the aid of the one-route all-dry etching process (ORADEP). Furthermore, the proposed FET is revamped to create nonvolatile memory with the adoption of a charge trapping layer for enhanced practicality. Thus, this research suggests an ultimate design for the end-of-the-roadmap devices to overcome the limits of scaling.

Effects of HIV-1 Tat on enteric neuropathogenesis.

The gastrointestinal (GI) tract presents a major site of immune modulation by HIV, resulting in significant morbidity. Most GI processes affected during HIV infection are regulated by the enteric nervous system. HIV has been identified in GI histologic specimens in up to 40% of patients, and the presence of viral proteins, including the trans-activator of transcription (Tat), has been reported in the gut indicating that HIV itself may be an indirect gut pathogen. Little is known of how Tat affects the enteric nervous system. Here we investigated the effects of the Tat protein on enteric neuronal excitability, proinflammatory cytokine release, and its overall effect on GI motility. Direct application of Tat (100 nm) increased the number of action potentials and reduced the threshold for action potential initiation in isolated myenteric neurons. This effect persisted in neurons pretreated with Tat for 3 d (19 of 20) and in neurons isolated from Tat(+) (Tat-expressing) transgenic mice. Tat increased sodium channel isoforms Nav1.7 and Nav1.8 levels. This increase was accompanied by an increase in sodium current density and a leftward shift in the sodium channel activation voltage. RANTES, IL-6, and IL-1ß, but not TNF-α, were enhanced by Tat. Intestinal transit and cecal water content were also significantly higher in Tat(+) transgenic mice than Tat(-) littermates (controls). Together, these findings show that Tat has a direct and persistent effect on enteric neuronal excitability, and together with its effect on proinflammatory cytokines, regulates gut motility, thereby contributing to GI dysmotilities reported in HIV patients.

Interaction between hydrogen sulfide-induced sulfhydration and tyrosine nitration in the KATP channel complex.

Hydrogen sulfide (H2S) is an endogenous gaseous mediator affecting many physiological and pathophysiological conditions. Enhanced expression of H2S and reactive nitrogen/oxygen species (RNS/ROS) during inflammation alters cellular excitability via modulation of ion channel function. Sulfhydration of cysteine residues and tyrosine nitration are the posttranslational modifications induced by H2S and RNS, respectively. The objective of this study was to define the interaction between tyrosine nitration and cysteine sulfhydration within the ATP-sensitive K(+) (KATP) channel complex, a significant target in experimental colitis. A modified biotin switch assay was performed to determine sulfhydration of the KATP channel subunits, Kir6.1, sulphonylurea 2B (SUR2B), and nitrotyrosine measured by immunoblot. NaHS (a donor of H2S) significantly enhanced sulfhydration of SUR2B but not Kir6.1 subunit. 3-Morpholinosydnonimine (SIN-1) (a donor of peroxynitrite) induced nitration of Kir6.1 subunit but not SUR2B. Pretreatment with NaHS reduced the nitration of Kir6.1 by SIN-1 in Chinese hamster ovary cells cotransfected with the two subunits, as well as in enteric glia. Two specific mutations within SUR2B, C24S, and C1455S prevented sulfhydration by NaHS, and these mutations prevented NaHS-induced reduction in tyrosine nitration of Kir6.1. NaHS also reversed peroxynitrite-induced inhibition of smooth muscle contraction. These studies suggest that posttranslational modifications of the two subunits of the KATP channel interact to alter channel function. The studies described herein demonstrate a unique mechanism by which sulfhydration of one subunit modifies tyrosine nitration of another subunit within the same channel complex. This interaction provides a mechanistic insight on the protective effects of H2S in inflammation.

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.