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Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer originating from rare populations of leukemia stem cells (LSCs). AML relapse after conventional chemotherapy is caused by a remaining population of drug-resistant LSCs. Selective targeting of the chemoresistant population is a promising strategy for preventing and treating AML relapse. Polycomb repressive complex 2 (PRC2) trimethylates histone H3 at lysine 27 to maintain the stemness of LSCs. Here, we show that quiescent LSCs expressed the highest levels of enhancer of zeste (EZH) 1 and EZH2, the PRC2 catalytic subunits, in the AML hierarchy, and that dual inactivation of EZH1/2 eradicated quiescent LSCs to cure AML. Genetic deletion of Ezh1/2 in a mouse AML model induced cell cycle progression of quiescent LSCs and differentiation to LSCs, eventually eradicating AML LSCs. Quiescent LSCs showed PRC2-mediated suppression of Cyclin D, and Cyclin D-overexpressing AML was more sensitive to chemotherapy. We have developed a novel EZH1/2 dual inhibitor with potent inhibitory activity against both EZH1/2. In AML mouse models and patient-derived xenograft models, the inhibitor reduced the number of LSCs, impaired leukemia progression, and prolonged survival. Taken together, these results show that dual inhibition of EZH1/2 is an effective strategy for eliminating AML LSCs.

SummaryRoot amputation, immunosuppressive therapy, mandibular tooth extraction, pre-existing inflammation, and longer duration of treatment with bone-modifying agents were significantly associated with an increased risk of medication-related osteonecrosis of the jaw. Hopeless teeth should be extracted without drug holiday before the development of inflammation in cancer patients receiving high-dose bone-modifying agents.IntroductionNo studies have comprehensively analyzed the influence of pre-existing inflammation, surgical procedure–related factors such as primary wound closure, demographic factors, and drug holiday on the incidence of medication-related osteonecrosis of the jaw (MRONJ). The purpose of this study was to retrospectively investigate the relationships between these various factors and the development of MRONJ after tooth extraction in cancer patients receiving high-dose bone-modifying agents (BMAs) such as bisphosphonates or denosumab.MethodsRisk factors for MRONJ after tooth extraction were evaluated with univariate and multivariate analyses. The following parameters were investigated in all patients: demographics, type and duration of BMA use, whether BMA use was discontinued before tooth extraction (drug holiday), the duration of such discontinuation, the presence of pre-existing inflammation, and whether additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed.ResultsWe found that root amputation (OR = 22.62), immunosuppressive therapy (OR = 16.61), extraction of mandibular teeth (OR = 12.14), extraction of teeth with pre-existing inflammation, and longer duration (≥ 8 months) of high-dose BMA (OR = 7.85) were all significantly associated with MRONJ.ConclusionsTooth extraction should not necessarily be postponed in cancer patients receiving high-dose BMA. The effectiveness of a short-term drug holiday was not confirmed, as drug holidays had no significant impact on MRONJ incidence. Tooth extraction may be acceptable during high-dose BMA therapy until 8 months after initiation.

Background How glial cells and cytokines are associated with the progression of delayed neuronal death induced by transient global ischemia is still unclear. To further clarify this point, we studied morphological changes in glial cells (microglial cells and astrocytes), and cytokine protein levels, during the progression of neuronal cell loss in CA1 (Cornu Ammonis 1) of the hippocampus after transient global ischemia. Methods Morphological changes in glial cells were studied immuno-histochemically. Nine cytokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-γ and TNF-α) were simultaneously measured by a multiplexed bead-based immunoassay from 6 h to day21 after transient four vessel occlusion (4VO) in rats. Results During the process of neuronal loss, we observed four distinct phases: (1) lag phase day0-2 (no NeuN+ cell loss observed), (2) exponential phase day2-7 (NeuN+ cells reduced in number exponentially), (3) deceleration phase day7-14 (reduction rate of NeuN+ cells became low), (4) stationary phase day14 onward (NeuN+ cell loss progressed no longer). In the lag phase, activated glial cells were observed in the entire hippocampus but later were gradually restricted to CA1. Cytokine protein levels in the lag and exponential phases were lower than in the deceleration and stationary phases. IL-1α, IL-1β, IL-4, IL-6 and IFN-γ in 4VO were significantly higher in all four phases than in sham. Compared with sham level, GM-CSF was significantly high in the deceleration phase. TNF-α was significantly high in both the deceleration and stationary phases. Conclusion Ischemic stress in 4VO activated glial cells in areas beyond CA1 in the lag phase. Pyramidal neurons were injured in CA1 from the end of the lag phase and then neuronal cells reduced in CA1 in the exponential phase. After neuronal death began, the influence of dead cells on glial cells and cytokine expression gradually became stronger than the influence by ischemic stress. Therefore, from the deceleration phase, changes in glial cells and cytokine production were likely caused by dead cells. Cytokine interaction in the microenvironment may determine the functions of IL-1α, IL-1β, IL-4, IL-6 and IFN-γ in all four phases. The function of GM-CSF and TNF-α in the deceleration phase may be neurotrophic.

The present status of kinetic modeling of particle dynamics in hydrogen negative ion (H−) source plasmas and their comparisons with experiments are reviewed and discussed with some new results. The main focus is placed on the following topics, which are important for the research and development of H− sources for intense and high-quality H− ion beams: (i) effects of non-equilibrium features of electron energy distribution function on volume and surface H− production, (ii) the origin of the spatial non-uniformity in giant multi-cusp arc-discharge H− sources, (iii) capacitive to inductive (E to H) mode transition in radio frequency-inductively coupled plasma H− sources and (iv) extraction physics of H− ions and beam optics, especially the present understanding of the meniscus formation in strongly electronegative plasmas (so-called ion-ion plasmas) and its effect on beam optics. For these topics, mainly Japanese modeling activities, and their domestic and international collaborations with experimental studies, are introduced with some examples showing how models have been improved and to what extent the modeling studies can presently contribute to improving the source performance. Close collaboration between experimental and modeling activities is indispensable for the validation/improvement of the modeling and its contribution to the source design/development.

Aims/hypothesis The physiological increase in muscle protein anabolism induced by insulin is blunted in healthy, glucose-tolerant older adults. We hypothesised that the age-related defect in muscle protein anabolism is a true insulin resistance state and can be overridden by supraphysiological hyperinsulinaemia. Methods We used dye dilution, stable isotopic and immunoblotting techniques to measure leg blood flow, muscle protein synthesis, protein kinase B/mammalian target of rapamycin (Akt/mTOR) signalling, and amino acid kinetics in 14 healthy, glucose-tolerant older volunteers at baseline, and during an insulin infusion at postprandial (PD, 0.15 mU min⁻¹ 100 ml⁻¹) or supraphysiologically high (HD, 0.30 mU min⁻¹ 100 ml⁻¹) doses. Results Leg blood flow, muscle protein synthesis, and Akt/mTOR signalling were not different at baseline. During hyperinsulinaemia, leg blood flow (p < 0.01) and muscle protein synthesis increased in the HD group only (PD [%/h]: from 0.063 ± 0.006 to 0.060 ± 0.005; HD [%/h]: from 0.061 ± 0.007 to 0.098 ± 0.007; p < 0.01). Muscle Akt phosphorylation increased in both groups, but the increase tended to be greater in the HD group (p = 0.07). The level of p70 ribosomal S6 kinase 1 (S6K1) phosphorylation increased in the HD group only (p < 0.05). Net amino acid balance across the leg improved in both groups, but a net anabolic effect was observed only in the HD group (p < 0.05). Conclusions/interpretation We conclude that supraphysiological hyperinsulinaemia is necessary to stimulate muscle protein synthesis and anabolic signalling in healthy older individuals, suggesting the existence of a true age-related insulin resistance of muscle protein metabolism.

Purpose This study aimed to compare perioperative outcomes of robotic and laparoscopic transabdominal peritoneal repair (TAPP) for unilateral inguinal hernia. Methods This single institutional retrospective cohort study used de-identified data of patients who underwent robotic TAPP (R-TAPP) or laparoscopic TAPP (L-TAPP) for unilateral inguinal hernia between January 1, 2016 and October 31, 2021. Two cohorts were propensity matched, and data were analyzed. The learning curve was evaluated in the R-TAPP group. Results Among 938 patients analyzed, 704 were included. After propensity-score matching, 80 patients were included in each group. The difference in operative time between R-TAPP and L-TAPP groups was 10 min (99.5 and 89.5 min, p  = 0.087); however, console/laparoscopic time was similar (67 and 66 min, p  = 0.71). The dissection time for medial-type hernia in the R-TAPP group was marginally shorter than that in the L-TAPP group (17 and 27 min, p  = 0.056); however, there was no difference for lateral-type hernia (38.5 and 40 min p  = 0.37). Perioperative variables, including estimated blood loss, postoperative hospital stay, and postoperative pain, had no significant difference, and chronic pain, which needed medication or intervention, was not observed in each group. The number of cases needed to achieve plateau performance was 7–10 in the R-TAPP group. Conclusion This study suggests that R-TAPP was safely introduced, and its perioperative outcomes were not inferior to those of L-TAPP. A shorter dissection time for medial-type hernia might be due to the robot’s advantages, and a fast-learning curve could help with the early standardization of the procedure.

The recovery of a 1.5 million yr long ice core from Antarctica represents a keystone of our understanding of Quaternary climate, the progression of glaciation over this time period and the role of greenhouse gas cycles in this progression. Here we tackle the question of where such ice may still be found in the Antarctic ice sheet. We can show that such old ice is most likely to exist in the plateau area of the East Antarctic ice sheet (EAIS) without stratigraphic disturbance and should be able to be recovered after careful pre-site selection studies. Based on a simple ice and heat flow model and glaciological observations, we conclude that positions in the vicinity of major domes and saddle position on the East Antarctic Plateau will most likely have such old ice in store and represent the best study areas for dedicated reconnaissance studies in the near future. In contrast to previous ice core drill site selections, however, we strongly suggest significantly reduced ice thickness to avoid bottom melting. For example for the geothermal heat flux and accumulation conditions at Dome C, an ice thickness lower than but close to about 2500 m would be required to find 1.5 Myr old ice (i.e., more than 700 m less than at the current EPICA Dome C drill site). Within this constraint, the resolution of an Oldest-Ice record and the distance of such old ice to the bedrock should be maximized to avoid ice flow disturbances, for example, by finding locations with minimum geothermal heat flux. As the geothermal heat flux is largely unknown for the EAIS, this parameter has to be carefully determined beforehand. In addition, detailed bedrock topography and ice flow history has to be reconstructed for candidates of an Oldest-Ice ice coring site. Finally, we argue strongly for rapid access drilling before any full, deep ice coring activity commences to bring datable samples to the surface and to allow an age check of the oldest ice.

Fabric (distribution of crystallographic orientations) along the full NEEM ice core, Greenland was measured in the field by an automatic ice texture analyzer every 10 m, from 33 m down to 2461 m depth. The fabric evolves from a slightly anisotropic fabric at the top, toward a strong single maximum at about 2300 m, which is typical of a deformation pattern mostly driven by uniaxial compression and simple shearing. A sharp increase in the fabric strengthening rate is observed at the Holocene to Wisconsin (HW) climatic transition. From a simple model we estimate that this depth is located at a transition from a state dominated by vertical compression to a state dominated by vertical shear. Comparisons are made to two others ice cores drilled along the same ridge; the GRIP ice core, drilled at the summit of the ice sheet, and the NGRIP ice core, drilled 325 km to the NNW of the summit along the ridge, and 365 km upstream from NEEM. This comparison tends to demonstrate that the ice viscosity change with the HW climatic transition must be associated with the shear-dominated state to induce the abrupt fabric strengthening observed at NEEM. This comparison therefore reflects the increasing role of shear deformation on the coring site when moving NW along the ridge from GRIP to NGRIP and NEEM. The difference in fabric profiles between NEEM and NGRIP also evidences a stronger lateral extension associated with a sharper ridge at NGRIP. Further along the core, centimeter scale abrupt texture (fabric and microstructure) variations are observed in the bottom part of the core. Their positions are in good agreement with the observed folding layers in Dahl-Jensen et al. (2013).

The biodiversity loss in Southeast Asia indicates an urgent need for long-term monitoring, which is lacking. Much attention is being directed toward bird diversity monitoring using remote sensing, based on relation to forest structure. However, few studies have utilized space-borne active microwave remote sensing, which has considerable advantages in terms of repetitive observations over tropical areas. Here, we evaluate threatened bird occurrence from L-band satellite data explaining forest structure in Sumatra, Indonesia. First, we identified L-band parameters with strong correlations with the forest layer structure, defined as forest floor, understory, and canopy layers. Then, we analyzed the correlation between threatened bird occurrence and L-band parameters identified as explaining forest structure. The results reveal that several parameters can represent the layers of forest floor, understory, and canopy. Subsequent statistical analysis elucidated that forest-dependent and threatened bird species exhibit significant positive correlations with the selected L-band parameters explaining forest floor and understory. Our results highlight the potential of applying microwave satellite remote sensing to evaluate bird diversity through forest structure estimation, although a more comprehensive study is needed to strengthen our findings.

Two deep ice cores, Dome Fuji (DF) and EPICA Dome C (EDC), drilled at remote dome summits in Antarctica, were volcanically synchronized to improve our understanding of their chronologies. Within the past 216 kyr, 1401 volcanic tie points have been identified. DFO2006 is the chronology for the DF core that strictly follows O2 / N2 age constraints with interpolation using an ice flow model. AICC2012 is the chronology for five cores, including the EDC core, and is characterized by glaciological approaches combining ice flow modelling with various age markers. A precise comparison between the two chronologies was performed. The age differences between them are within 2 kyr, except at Marine Isotope Stage (MIS) 5. DFO2006 gives ages older than AICC2012, with peak values of 4.5 and 3.1 kyr at MIS 5d and MIS 5b, respectively. Accordingly, the ratios of duration (AICC2012 / DFO2006) range between 1.4 at MIS 5e and 0.7 at MIS 5a. When making a comparison with accurately dated speleothem records, the age of DFO2006 agrees well at MIS 5d, while the age of AICC2012 agrees well at MIS 5b, supporting their accuracy at these stages. In addition, we found that glaciological approaches tend to give chronologies with younger ages and with longer durations than age markers suggest at MIS 5d–6. Therefore, we hypothesize that the causes of the DFO2006–AICC2012 age differences at MIS 5 are (i) overestimation in surface mass balance at around MIS 5d–6 in the glaciological approach and (ii) an error in one of the O2 / N2 age constraints by ~ 3 kyr at MIS 5b. Overall, we improved our knowledge of the timing and duration of climatic stages at MIS 5. This new understanding will be incorporated into the production of the next common age scale. Additionally, we found that the deuterium signals of ice, δDice, at DF tends to lead the one at EDC, with the DF lead being more pronounced during cold periods. The lead of DF is by +710 years (maximum) at MIS 5d, −230 years (minimum) at MIS 7a and +60 to +126 years on average.