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RNA modification has emerged as an important epigenetic mechanism that controls abnormal metabolism and growth in acute myeloid leukaemia (AML). However, the roles of RNA N4-acetylcytidine (ac4C) modification in AML remain elusive. Here, we report that ac4C and its catalytic enzyme NAT10 drive leukaemogenesis and sustain self-renewal of leukaemic stem cells/leukaemia-initiating cells through reprogramming serine metabolism. Mechanistically, NAT10 facilitates exogenous serine uptake and de novo biosynthesis through ac4C-mediated translation enhancement of the serine transporter SLC1A4 and the transcription regulators HOXA9 and MENIN that activate transcription of serine synthesis pathway genes. We further characterize fludarabine as an inhibitor of NAT10 and demonstrate that pharmacological inhibition of NAT10 targets serine metabolic vulnerability, triggering substantial anti-leukaemia effects both in vitro and in vivo. Collectively, our study demonstrates the functional importance of ac4C and NAT10 in metabolism control and leukaemogenesis, providing insights into the potential of targeting NAT10 for AML therapy.

Hybrid converter is a promising scheme for current harmonic suppression in high-speed permanent magnet synchronous machine (HSPMSM) drive systems. Considering the limitations of using position sensors, a position sensorless drive for permanent magnet synchronous machine (PMSM) with hybrid converter is proposed, equipped with online inductance identification utilizing current ripple. The main contribution of this method is less computation and high steady-state position estimation accuracy. This method has two salient features. First, the estimated positions updated at different frequencies are achieved by a simple frequency-increasing method. Second, by fully capitalizing on the hybrid frequency control strategy, a current ripple sampling mechanism is implemented without the need for additional sampling. Finally, the effectiveness of the proposed control scheme is validated by simulation and experimental results.

Natural killer/T-cell lymphoma (NKTCL) is a highly heterogeneous disease with a poor prognosis. However, the genomic characteristics and proper treatment strategies for non-upper aerodigestive tract NKTCL (NUAT-NKTCL), a rare subtype of NKTCL, remain largely unexplored. In this study, 1589 patients newly diagnosed with NKTCL at 14 hospitals were assessed, 196 (12.3%) of whom had NUAT-NKTCL with adverse clinical characteristics and an inferior prognosis. By using whole-genome sequencing (WGS) and whole-exome sequencing (WES) data, we found strikingly different mutation profiles between upper aerodigestive tract (UAT)- and NUAT-NKTCL patients, with the latter group exhibiting significantly higher genomic instability. In the NUAT-NKTCL cohort, 128 patients received frontline P-GEMOX chemotherapy, 37 of whom also received anti-PD-1 immunotherapy. The application of anti-PD-1 significantly improved progression-free survival (3-year PFS rate 53.9% versus 17.0%, P= 0.009) and overall survival (3-year OS rate 63.7% versus 29.2%, P = 0.01) in the matched NUAT-NKTCL cohort. WES revealed frequent mutations involving immune regulation and genomic instability in immunochemotherapy responders. Our study showed distinct clinical characteristics and mutational profiles in NUAT-NKTCL compared with UAT patients and suggested adding anti-PD-1 immunotherapy in front-line treatment of NUAT-NKTCL. Further studies are needed to validate the efficacy and related biomarkers for immunochemotherapy proposed in this study.

A core issue of safe human-machine cooperative driving lies in dynamic assessment of the rapidly evolving driving risks. Given that, this paper proposes a shared controller for safe and human-friendly cooperative driving based on predictive risk assessment enabled by Digital Twin technologies. In the digital world, we create a fine-grained digital replica of the driving scene comprising historical motions of vehicles, as well as roadway geometries and topologies. On the basis of that, spatial-temporal interactive features are obtained with a deep learning-based model and subsequently decoded to predict future trajectories of each target vehicle in the neighborhood of the ego-vehicle. In the physical world, the predicted trajectories of neighboring vehicles are integrated into the risk distribution to construct predictive risk fields. A novel shared controller in the framework of multi-objective MPC is designed to minimize the driving risk while matching driver's commands, so that safe cooperative driving is achieved in a smooth and minimal-intervention manner. The results of driver-in-the-loop simulation experiments demonstrate the enabling role of the Digital Twin in improving the assessment of risk in highly dynamic scenes through taking the motion trends of dynamic agents into account. The results also show the superiority of the Digital Twin-based shared controller in terms of implementing cooperation in time while honoring the driver's commands whenever possible.

This article proposes a novel high-speed permanent magnet synchronous machine (HSPMSM) topology. The characteristics of the proposed machine are: 1) The stator winding is divided into two parts and each part is connected by the end ring at one end, which is helpful to solve the existing shortage of overlong end length in traditional HSPMSM. 2) The stator of the machine is designed with closed slot, which can greatly weaken the eddy current loss and the cogging torque of the machine. 3) The machine is driven by two separate three phase converter, which can improve the fault tolerance. In this article, the topology, and the corresponding control system is analyzed firstly. After that the electromagnetic performance, including back electromotive force, cogging torque, torque, etc. are analyzed with finite element analysis (FEA). In addition, the losses, including the stator copper loss, the stator iron loss and the eddy current loss of the permanent magnet and sleeve of the rotor, are calculated by FEA. The mechanical strength and dynamic performance of rotor is also checked. Finally, a prototype was designed and manufactured. The experimental results the validity of the topology.

Causes of death in persons with haematological cancers include the index cancer, a new cancer or a seemingly unrelated cause such as cardio-vascular disease. These causes are complex and sometimes confounded. We analyzed trends in cause of death in 683,333 persons with an index haematological cancer diagnosed in 1975–2016 reported in the Surveillance, Epidemiology and End Results dataset. Non-cancer deaths were described using standardized mortality ratios. The index cancer was the predominant cause of death amongst persons with plasma cell myeloma, acute lymphoblastic leukaemia and acute myeloid leukaemia. Non-cancer death was the major cause of death in persons with chronic lymphocytic leukaemia, Hodgkin lymphoma and chronic myeloid leukaemia, mostly from cardio-vascular diseases. The greatest relative decrease in index-cancer deaths was amongst persons with Hodgkin lymphoma, chronic myeloid leukaemia and chronic lymphocytic leukaemia, where the proportion of non-cancer deaths increased substantially. Changing distribution of causes of death across haematological cancers reflects substantial progress in some cancers and suggests strategies to improve the survival of persons with haematological cancers in the future.

As one of the walkability attributes, attractiveness seems to play an essential role in improving urban vitality and is highly correlated with urban redevelopment. This paper aims to examine whether and to what extent the improvement of the level of attractiveness can encourage urban vitality. Four squares from the “Open Squares” project in Milan are selected as cases. This project transformed several neighborhood squares into attractive nodes by a series of similar low-cost interventions to encourage urban vitality. The methodology is subdivided into four steps. First of all, the spatial features of the squares were measured before and after the transformation. Then, several relevant walkability attributes of the surroundings, where the squares locate, were measured incorporating GIS (Geographic information system) and semantic segmentation of street view data. Thirdly, urban vitality levels before and after the transformation were evaluated based on the analysis of posts, photos, and textual contents of the squares posted on social media (e.g., Twitter, Facebook, and Instagram). Finally, with comprehensive comparisons between the results of walkability assessment and social media data in different periods, the potentiality of attractiveness in improving urban vitality was evaluated.

Accurate survival prediction of persons with plasma cell myeloma (PCM) is challenging. We interrogated clinical and laboratory co-variates and RNA matrices of 1040 subjects with PCM from public datasets in the Gene Expression Omnibus database in training (N= 1) and validation (N= 2) datasets. Genes regulating plasma cell metabolism correlated with survival were identified and seven used to build a metabolic risk score using Lasso Cox regression analyses. The score had robust predictive performance with 5-year survival area under the curve (AUCs): 0.71 (95% confidence interval, 0.65, 0.76), 0.88 (0.67, 1.00) and 0.64 (0.57, 0.70). Subjects in the high‐risk training cohort (score > median) had worse 5-year survival compared with those in the low‐risk cohort (62% [55, 68%] vs. 85% [80, 90%]; p< 0.001). This was also so for the validation cohorts. A nomogram combining metabolic risk score with Revised International Staging System (R-ISS) score increased survival prediction from an AUC = 0.63 [0.58, 0.69] to an AUC = 0.73 [0.66, 0.78]; p= 0.015. Modelling predictions were confirmed in in vitro tests with PCM cell lines. Our metabolic risk score increases survival prediction accuracy in PCM.

With the number of connected devices increasing rapidly, the access latency issue increases drastically in the edge cloud environment. Massive low time-constrained and data-intensive mobile applications require efficient replication strategies to decrease retrieval time. However, the determination of replicas is not reasonable in many previous works, which incurs high response delay. To this end, a correlation-aware replica prefetching (CRP) strategy based on the file correlation principle is proposed, which can prefetch the files with high access probability. The key is to determine and obtain the implicit high-value files effectively, which has a significant impact on the performance of CRP. To achieve the goal of accelerating the acquisition of implicit high-value files, an access rule management method based on consistent hashing is proposed, and then the storage and query mechanisms for access rules based on adjacency list storage structure are further presented. The theoretical analysis and simulation results corroborate that CRP shortens average response time over 4.8%, improves average hit ratio over 4.2%, reduces transmitting data amount over 8.3%, and maintains replication frequency at a reasonable level when compared to other schemes.

We analyzed reports on safety and efficacy of JAK-inhibitors in patients with coronavirus infectious disease-2019 (COVID-19) published between January 1st and March 6th 2021 using the Newcastle-Ottawa and Jadad scales for quality assessment. We used disease severity as a proxy for time when JAK-inhibitor therapy was started. We identified 6 cohort studies and 5 clinical trials involving 2367 subjects treated with ruxolitinib (N= 3) or baricitinib 45 (N= 8). Use of JAK-inhibitors decreased use of invasive mechanical ventilation (RR = 0.63; [95% Confidence Interval (CI), 0.47, 0.84]; P= 0.002) and had borderline impact on rates of intensive care unit (ICU) admission (RR = 0.24 [0.06, 1.02]; P= 0.05) and acute respiratory distress syndrome (ARDS; RR = 0.50 [0.19, 1.33]; P= 0.16). JAK-inhibitors did not decrease length of hospitalization (mean difference (MD) –0.18 [–4.54, 4.18]; P= 0.94). Relative risks of death for both drugs were 0.42 [0.30, 0.59] (P< 0.001), for ruxolitinib, RR = 0.33 (0.13, 0.88; P= 0.03) and for baricitinib RR = 0.44 (0.31, 0.63; P< 0.001). Timing of JAK-inhibitor treatment during the course of COVID-19 treatment may be important in determining impact on outcome. However, these data are not consistently reported.

Detection and observation of reactive intermediates is an essential step in investigation of reaction pathways. However, most reactive intermediates are unstable and present at low concentrations; their short lifetimes make them difficult to detect and characterize. Supramolecular containers offer opportunities for the stabilization and characterization of those labile species, through isolation from the media and protection inside the cavity of the host. In this review, we summarize the examples of labile reaction intermediates that are stabilized and characterized with the help of supramolecular containers. The container compounds include carcerands, deep cavitands and amide naphthotubes. We focus on unstable guest species – cyclobutadiene, benzocyclopropenone, o-benzyne, 1,2,4,6-cycloheptatetraene, anti-Bredt's olefin, fluorophenoxycarbene, O-acylisoamide, and hemiaminal – that act as intermediates in certain organic reactions

Natural killer/T-cell lymphoma (NKTL) is a sub-type of Epstein–Barr virus (EBV)-related non-Hodgkin lymphomas common in Asia and Latin America but rare elsewhere. Its pathogenesis is complex and incompletely understood. Lymphoma cells are transformed from NK- or T-cells, sometimes both. EBV-infection and subsequent genetic alterations in infected cells are central to NKTL development. Hemophagocytic syndrome is a common complication. Accurate staging is important to predict outcomes but there is controversy which system is best. More than two-thirds of NKTL lympohmas are localized at diagnosis, are frequently treated with radiation therapy only and have 5-year survival of about 70 percent. Persons with advanced NKTLs receive radiation therapy synchronously or metachronously with diverse multi-drug chemotherapy typically including l-asparginase with 5-year survival of about 40 percent. Some persons with widespread NKTL receive chemotherapy only. There are few data on safety and efficacy of high-dose therapy and a haematopoietic cell autotransplant. Immune therapies, histone deacetylase (HDAC)-inhibitors and other drugs are in early clinical trials. There are few randomized controlled clinical trials in NKTLs and no therapy strategy is clearly best; more effective therapy(ies) are needed. Some consensus recommendations are not convincingly evidence-based. Mechanisms of multi-drug resistance are considered. We discuss these issues including recent advances in our understanding of and therapy of NKTLs.

We performed a meta-analysis to determine safety and efficacy of tocilizumab in persons with coronavirus disease-2019 (COVID-19). We searched PubMed, Web of Science and Medline using Boolean operators for studies with the terms coronavirus OR COVID-19 OR 2019-nCoV OR SARS-CoV-2 AND tocilizumab. Review Manager 5.4 was used to analyze data and the modified Newcastle–Ottawa and Jadad scales for quality assessment. We identified 32 studies in 11,487 subjects including three randomized trials and 29 cohort studies with a comparator cohort, including historical controls (N= 5), a matched cohort (N= 12), or concurrent controls (N= 12). Overall, tocilizumab decreased risk of death (Relative Risk [RR] = 0.74; 95% confidence interval [CI], 0.59, 0.93; P= 0.008; I2= 80%) but not of surrogate endpoints including ICU admission (RR = 1.40 [0.64,3.06]; P= 0.4; I2= 88%), invasive mechanical ventilation (RR = 0.83 [0.57,1.22]; P= 0.34; I2= 65%) or secondary infections (RR = 1.30 [0.97,1.74]; P= 0.08; I2= 65%) and increased interval of hospitalization of subjects discharged alive(mean difference [MD] = 2 days [<1, 4 days]; P= 0.006; I2= 0). RRs of death in studies with historical controls (RR = 0.28 [0.16,0.49; P< 0.001]; I2= 62%) or a matched cohort (RR = 0.68 [0.53, 0.87]; P= 0.002; I2= 42%) were decreased. In contrast, RRs of death in studies with a concurrent control (RR = 1.10 [0.77, 1.56]; P= 0.60; I2= 85%) or randomized (RR = 1.18 [0.57,2.44]; P= 0.66; I2= 0) were not decreased. A reduced risk of death was not confirmed in our analyses which questions safety and efficacy of tocilizumab in persons with COVID-19.

Blended coal combustion technology was extensively used in coal-fired power plants in China. In order to investigate the in-situreaction between trace elements and minerals in fly ash during blended coal combustion, a bituminous (HLH), anthracite (ZW) and the blended coal of these two parent coals were combusted in a drop tube furnace at 1150°C. The ash gathered at high temperature segment (HTA) and low temperature segment (LTA) of the furnace were analyzed, respectively. The results indicated that the retention rates of arsenic in HTA were lower than that in LTA, which suggested that arsenic would be re-absorbed by ash during cooling down of flue gas. For HTA the retention rates of arsenic in ash of ZW, Z3H1, Z1H1, Z1H3, HLH were 60.31%, 26.85%, 13.29%, 20.23% and 36.11%, respectively. The arsenic was more difficult to be captured by HTA of blended coal than that of parent coal. As for selenium, the retention rates in HTA of five coal samples were 24.68%, 23.60%, 20.58%, 15.19% and 38.13%, which had the same retention law as arsenic. The results of X-ray diffraction (XRD) demonstrated that the mineral morphology was changed obviously during blended coal combustion. Unlike parent coal, mullite appeared in HTA of blended coal, and peak of mullite was enhanced with proportion of ZW increased in blended coal. It was consistent with the trend of retention of As and Se in HTA. It illustrated that change of mineral species and in-situreaction between minerals and trace elements significantly affected emission of arsenic and selenium during blended coal combustion.

Large-scale sequencing studies of hematologic malignancies have revealed notable epistasis among high-frequency mutations. One of the most striking examples of epistasis occurs for mutations in RNA splicing factors. These lesions are among the most common alterations in myeloid neoplasms and generally occur in a mutually exclusive manner, a finding attributed to their synthetic lethal interactions and/or convergent effects. Curiously, however, patients with multiple-concomitant splicing factor mutations have been observed, challenging our understanding of one of the most common examples of epistasis in hematologic malignancies. In this study, we performed bulk and single-cell analyses of patients with myeloid malignancy who were harboring ≥2 splicing factor mutations, to understand the frequency and basis for the coexistence of these mutations. Although mutations in splicing factors were strongly mutually exclusive across 4231 patients (q < .001), 0.85% harbored 2 concomitant bona fide splicing factor mutations, ∼50% of which were present in the same individual cells. However, the distribution of mutations in patients with double mutations deviated from that in those with single mutations, with selection against the most common alleles, SF3B1K700E and SRSF2P95H/L/R, and selection for less common alleles, such as SF3B1 non-K700E mutations, rare amino acid substitutions at SRSF2P95, and combined U2AF1S34/Q157 mutations. SF3B1 and SRSF2 alleles enriched in those with double-mutations had reduced effects on RNA splicing and/or binding compared with the most common alleles. Moreover, dual U2AF1 mutations occurred in cis with preservation of the wild-type allele. These data highlight allele-specific differences as critical in regulating the molecular effects of splicing factor mutations as well as their cooccurrences/exclusivities with one another.

We performed a meta-analysis to determine safety and efficacy of corticosteroids in SARS-CoV-2, SARS-CoV, and MERS-CoV infections. We searched PubMed, Web of Science, Medline, WanFang Chinese database, and ZhiWang Chinese database using Boolean operators and search terms covering SARS-CoV-2, SARS-CoV, OR MERS-CoV AND corticosteroids to find appropriate studies. Review Manager 5.3 was used to analyze results of meta-analysis. Observational studies were analyzed for quality using the modified Newcastle–Ottawa scale and randomized clinical trials, using the Jadad scale. Subjects were divided into those with severe-only and other (severe and not severe) cohorts based on published criteria. Efficacy endpoints studied included mortality, hospitalization duration, rates of intensive care unit (ICU) admission, use of mechanical ventilation, and a composite endpoint (death, ICU admission, or mechanical ventilation). We included 11 reports including 10 cohort studies and 1 randomized clinical trial involving 5249 subjects (2003–2020). Two discussed the association of corticosteroids and virus clearing and 10 explored how corticosteroids impacted mortality, hospitalization duration, use of mechanical ventilation, and a composite endpoint. Corticosteroid use was associated with delayed virus clearing with a mean difference (MD) = 3.78 days (95% confidence Interval [CI] = 1.16, 6.41 days; I2= 0%). There was no significant reduction in deaths with relative Risk Ratio (RR) = 1.07 (90% CI = 0.81; 1.42; I2= 80%). Hospitalization duration was prolonged and use of mechanical ventilation increased. In conclusion, corticosteroid use in subjects with SARS-CoV-2, SARS-CoV, and MERS-CoV infections delayed virus clearing and did not convincingly improve survival, reduce hospitalization duration or ICU admission rate and/or use of mechanical ventilation. There were several adverse effects. Because of a preponderance of observational studies in the dataset and selection and publication biases our conclusions, especially regarding SARS-CoV-2, need confirmation in a randomized clinical trial. In the interim we suggest caution using corticosteroids in persons with COVID-19.

To explore the therapeutic effect of the fire needling with the three-edged needle and the cupping on popliteal cyst.

How-things-work visualizations use a variety of visual techniques to depict the operation of complex mechanical assemblies. We present an automated approach for generating such visualizations. Starting with a 3D CAD model of an assembly, we first infer the motions of the individual parts and the interactions across the parts based on their geometry and a few user-specified constraints. We then use this information to generate visualizations that incorporate motion arrows, frame sequences, and animation to convey the causal chain of motions and mechanical interactions across parts. We demonstrate our system on a wide variety of assemblies. [ABSTRACT FROM AUTHOR]

Byline: Se-Hwa Wu, Liang-Yang Lin, Mu-Yen Hsu This paper is an empirical study exploring the effects of intellectual capital and Dynamic Capabilities (DC) on Innovative Performance (IP) of organisations. Data were collected from a survey of 100 Taiwan companies related to the electronic and Information Technology (IT) industries. Hypotheses were tested using hierarchical regression analysis. Results show that Structural Capital (SC) and Relationship Capital (RC) fully mediate the effects of Human Capital (HC) on IP. Moreover, DC have a direct effect on IP. Dynamic capabilities, on the other hand, enhance the positive effect of RC on IP. The implication of the study is that managers should build and cultivate the firm's dynamic capabilities, because of its significant main and moderating effects.

Cofiring of biomass and coal significantly reduces carbon emissions and alleviates ash-related problems of biomass. This study investigates the effect of the biomass/coal blending ratio on ash fusion characteristics through the ash fusion test, X-ray fluorescence, and X-ray diffractometry. Meanwhile, kinetic analysis of the ash fusion process was conducted to provide a new method and reading benchmark for obtaining precise and repeatable initial deformation temperature (IDT). Results showed that the IDT decreased with the increase of the biomass blending ratio because of the decrease of alumina content and the increase of potassium content. When the biomass blending ratio increased, the content of orthoclase and diopside at the low melting point increased, while the content of andalusite, quartz, and anhydrite at the high melting point decreased, resulting in the decline of IDT. Kinetic analysis indicated that with increasing biomass blending ratio, the activation energy of ash fusion reaction decreased, which is the essential reason for the decrease of IDT. Coal ash had an activation energy of 1144.67 kJ·mol–1, while it decreased to 145.89 kJ·mol–1with an increased biomass blending ratio to 100%. Compared with the larger error (up to 60 °C) caused by visual reading on the morphological change of the triangle ash cone, kinetics calculation gave precise prediction with less error between 2 and 7 °C. As an optimal recommendation, the average shrinkage rate of height at 41% could be used as a reading benchmark for the determination of IDT in further study.

The investigated alloys are newly developed Tribaloy alloys with enhanced crack and oxidation resistance over the traditional Tribaloy alloys. The cyclic oxidation performance and effects of complex oxides on the hardness of cobalt-based Tribaloy alloys T-401 (hypoeutectic) and T-900 (hypereutectic) were assessed. The results showed that T-900 alloy has a lower oxidation rate as compared to T-401 alloy at 800 and 1000 °C, which attributed to the formation of dense continuous Cr2O3layer with an upper thinner continuous layer of CoCr2O4and NiCr2O4oxides. At 1000 °C, T-401 alloy exhibited poor oxidation resistance due to severe spallation after 3 cycles (45 h). After oxidation, T-900 alloy exhibits 98% and 18% lower mass gain than T-401 alloy at 1000 and 800 °C, respectively. For T-900 alloy, relationship between mass gain and thickness of oxide layer revealed that mass will increase 0.162 mg/cm2for every 1-µm increase in the oxides thickness. Internal SiO2oxide was observed at 800 and 1000 °C for both alloys. However, the extent of internal Si oxides increased with increasing oxidation temperature from 800 to 1000 °C. Consequently, internal oxidation of Si led to the formation of Laves phase-depleted region near oxide/alloy interface in T-900 alloy at 1000 °C. Thus, hardness of T-900 alloy decreased from 618 to 392 HV beneath the oxide/alloy interface at 1000 °C, whereas hardness of T-900 and T-401 alloys after cyclic oxidation test at 800 °C increased from 618 to 855 and 519 to 685 HV, respectively.

Aflatoxin B1(AFB1), the most toxic and harmful mycotoxin, has a high likelihood of occurring in animal feed and human food, which seriously affects agriculture and food safety and endangers animal and human health. Recently, natural plant products have attracted widespread attention due to their low toxicity, high biocompatibility, and simple composition, indicating significant potential for resisting AFB1. The mechanisms by which these phytochemicals resist toxins mainly involve antioxidative, anti-inflammatory, and antiapoptotic pathways. Moreover, these substances also inhibit the genotoxicity of AFB1by directly influencing its metabolism in vivo, which contributes to its elimination. Here, we review various phytochemicals that resist AFB1and their anti-AFB1mechanisms in different animals, as well as the common characteristics of phytochemicals with anti-AFB1function. Additionally, the shortcomings of current research and future research directions will be discussed. Overall, this comprehensive summary contributes to the better application of phytochemicals in agriculture and food safety.

This paper presents an optimized multi-timescale energy management strategy (MTEMS) for a novel all-electric aircraft (AEA) power system unit, which consists of a hybrid energy storage system comprising super-capacitor (SC), battery and fuel cell (FC), as well as a dual three phase permanent magnet synchronous motor (DTP-PMSM) system serving as the propulsion system. During transient states characterized by rapid load changes, the proposed strategy effectively allocates power from the low-frequency, medium-frequency, and high-frequency domains to their respective units, namely FC unit, battery unit, and SC unit. This power allocation is achieved through decentralized droop control implemented in the proposed MTEMS, ensuring a constant and stable bus voltage throughout the operation. In addition, during the steady-state after the change of the load power, a distributed optimization method of the proposed MTEMS can calculate the ratio of power outputs between the battery and FC to maximize the operational efficiency of the fuel cell while ensuring the battery operates in an economically optimal condition. This ultimately guarantees the entire system operates under optimal operating conditions. The achievement of the output power ratio is attainable through the implementation of decentralized droop control. Finally, a 1 kW experimental platform is constructed to validate the effectiveness of the proposed MTEMS and verify the analytical results.

Recurrent mutations in the splicing factor SRSF2are associated with poor clinical outcomes in myelodysplastic syndromes (MDS). Their high frequency suggests these mutations drive oncogenesis, yet the molecular explanation for this process is unclear. SRSF2mutations could directly affect pre-mRNA splicing of a vital gene product; alternatively, a whole network of gene products could be affected. Here we determine how SRSF2mutations globally affect RNA binding and splicing in vivousing HITS-CLIP. Remarkably, the majority of differential binding events do not translate into alternative splicing of exons with SRSF2P95Hbinding sites. Alternative splice alterations appear to be dominated by indirect effects. Importantly, SRSF2P95Htargets are enriched in RNA processing and splicing genes, including several members of the hnRNP and SR families of proteins, suggesting a “splicing-cascade” phenotype wherein mutation of a single splicing factor leads to widespread modifications in multiple RNA processing and splicing proteins. We show that splice alteration of HNRNPA2B1, a splicing factor differentially bound and spliced by SRSF2P95H, impairs hematopoietic differentiation in vivo. Our data suggests a model whereby the recurrent mutations in splicing factors set off a cascade of gene regulatory events that together affect hematopoiesis and drive cancer.

The FLT3-ITD mutation is frequently observed in acute myeloid leukemia (AML) and confer a poor prognosis. FLT3 inhibitors such as Quizartinib could prolong survival. However, very few relapsed patients are cured. Little attention has been paid to the characteristics of the immune microenvironment in FLT3-ITD AML. Within the bone marrow, Flt3/ITD animals demonstrated significantly increased dendritic cells and T cells levels compared to Flt3/WT mice, which suggested that FLT3-ITD can modulate the immune microenvironment in AML. Here, we found that FLT3-ITD cell lines (MV-4-11 and MOLM-13) induced less LDH release compared to FLT3-WT cell lines (HEL and K562) ( Figure a), indicating less macrophage killing. CD47 gene is an integrin related protein, which acts as an “anti phagocytosis” signal, and it interacts with signal-regulatory protein alpha (SIRPalpha) on macrophages, so that tumor cells expressing CD47 can escape being destroyed by macrophages. Further Flow Cytometry results showed that the CD47 Mean fluorescent intensity (MFI) of the FLT3-ITD group was significantly higher than those of the control group ( Figure b). Therefore, we can ask a hypothesis that FLT3-ITD in tumor cells may leads to decreased phagocytic capacity of macrophages and immune tolerance. To test our hypothesis, the FLT3 wildtype (FLT3-OE, FLT3 over expression) or ITD mutant (FLT3-ITD) stable overexpression HEL/K562 cells were constructed by means of lentiviral transfections. In the FLT3-ITD group, the MFI levels of CD47 was higher than FLT3-OE group and FLT3 NC (FLT3 Normal control) group ( Figure c and d). Green-fluorescent (CFSE-stained) Hel and K562 were then added to cultures of macrophages induced by Peripheral Blood Mononuclear Cell stained with the red dye PKH26 (ratio tumor cell:macrophages, 5:1). Flow Cytometry results showed FLT3-ITD decreased the Phagocytic Capacity of Macrophages ( Figure e and f). The TRANSFAC database was used to predict the transcription factor binding sites of the CD47 promoter. We found that HOXB5 may regulate the expression of CD47 at the transcriptional level. Compared with the FLT3-NC and FLT3-OE group, the relative expression level of the CD47 gene in the FLT3-ITD group was significantly upregulated ( Figure g, p < 0.05). To ascertain the mechanism that HOXB5 regulated CD47, we analysed the location CD47 gene on the chromosome, as well as the sequence of promoter and first non-encoding exon of HOXB5 (−2000 ~ 100 bp) by Jaspar online tool (http://jaspar.genereg.net/). Mechanistically, Dual luciferase reporter gene assay and ChIP experiments suggest HOXB5 directly activate CD47( Figure h and i). Compared to the monotherapy group, Combination therapy with CD47 inhibitor and Quizartinib (AC220) significantly promoted the phagocytic ability of M1-like macrophages against MOLM13 cells ( Figure j and k). The mouse model of AML was constructed by injection of 5x106 FLT3-ITD cells via the tail vein. Mouse models further demonstrate that combination therapy with CD47 inhibitor and Quizartinib significantly reduces the tumor burden and improves survival rate. We first revealed that FLT3-ITD can up-regulates CD47 to promote immune escape of macrophages. These evidences indicates that combination therapy with CD47 inhibitor and FLT3-ITD inhibitor can be a promising therapeutic method for impressive treatment of FLT3-ITD AML patients.

Multiple myeloma (MM) is a hematological malignancy which characterized by malignant plasma cells resident in the bone marrow (BM). The BM microenvironment plays critical roles in the invasion, proliferation and migration of myeloma cells. Despite the therapies of MM improved in recent years, this disease is still incurable and requires precise treatment. Resident memory (TRM) cells are a distinct tissue-localized T cell lineage that is crucial for protective immunity in peripheral tissues. Recent studies reveal TRM cells as a vital component of the host immune response to cancer. TRM-like tumor-infiltrating lymphocytes (TILs) can be found in a wide range of human cancers, where they portend improved prognosis. However, the precise role and mechanism of bone marrow TRM cells in MM still remain elusive.

Introduction

Abstract

BACKGROUND

Background: Traditional “3+7” intense chemotherapy (IC) regimen is the standard treatment backbone for fitness patients with newly diagnosed AML. The azacitidine plus venetoclax (AB) regimen has recently been recommended for elderly AML patients or those ineligible for IC treatment. However, neither the “3+7” IC nor “AB” regimen unmet the needs ofadequate safety and effectiveness, especially on aspects of early death and some subtypes of leukemia, such as M5, or with RUNX1, FLT3-ITD, TP53 mutation, or with MCL-1 up-expression. Chidamide, a novel oral histone deacetylase inhibitor, can overcome the upregulating of MCL-1 expression induced by venetoclax, and synergy with azacitidine and venetoclax induces apoptosis of acute myeloid leukemia cells. Azacitidine-Venetoclax -Chidamide (ABC) combination regimen had been successfully used for refractory relapsed AML and newly diagnosed AML-M5 by Prof. Bin Xu and Prof. Shengli Xue, respectively. Whether the ABC regimen can be comparable to the “3+7” IC regimen in newly diagnosed AML induction therapy is still unknown.

Background:Venetoclax, in combination with hypomethylating agents or low-dose cytarabine, is approved for newly diagnosed acute myeloid leukemia (AML) patients who are over 75 years of age or not eligible for intensive chemotherapy, while the efficacy of venetoclax-based regimens in young fit AML patients still needs to be further explored. Although the combination of anthracycline and cytarabine has achieved a remission rate of about 70% in these patients, the low complete response rate in adverse-risk patients, strong adverse reactions, and long duration of myelosuppression limited the clinical benefit. We presumed that venetoclax plus azacitidine in combination with low-intensity regimens CAG (G-CSF priming, low dose cytarabine, and aclarubicin) could have a better composite complete remission with an acceptable safety profile.

*Drs. Yifan Zhai and Xiaojun Huang are co-corresponding authors.

Natural killer (NK) cells are innate lymphocytes that play a key role in the control of infection and malignancy. NK cells are potent killers of target cells and act in an MHC-independent manner, enabling their application as allogenic therapy for cancer. Human iPSCs are pluripotent with the ability to self-renew, thus providing an inexhaustible source for deriving NK cells. With a two-tiered cell bank system, we can manufacture NK cells with more homogeneity between batches. In principle, one single iPSC clone-derived master cell bank and working cell banks can support the life cycle of an affordable, off-the-shelf NK cell product. We developed a robust stepwise protocol for large-scale generation of high-purity NK cells from human iPSCs without the cell isolation procedure. First, human iPSCs formed embryoid bodies and then were differentiated into highly purified (>98.0%) CD34 +CD43 +hematopoietic stem and progenitor cells (HSPCs) using a combination of cytokines and small molecles such as BMP-4, VEGF, BFGF, SCF, FLT-3 and ascorbic acid. During this period, we observed up to an 180-fold cell increase in the number of HSPCs compared with human iPSCs. Second, these HSPCs were differentiated into NK cells with FLT3, SCF, IL-3, IL-7, and IL-15 etc., with cell number increased approximately 9000-fold compared with iPSCs. In the final step, iPSC-derived NK cells were further expanded up to 8000-fold which enable us to produce 1E12 NK cells from less than 1 million iPSCs. After expansion, iNK cells became more homogenous and exhibited a more mature phenotype. More than 99.0% of cells expressed both CD45 and CD56, and more than 70% expressed CD16. The expression of activating and co-stimulatory receptors (NKG2D, NKp46,NKp44, NKp30, CD244 and CD226) of NK cells was also high in these iNK cells. Intrestingly, the cells exhibited robust anti-tumor efficacy against K562 (chronic myelogenous leukemia), RPMI 8226 (multiple myeloma). Furthermore, the cryopreserved iNK cells demonstrated dramatic cytotoxicity to U-87 MG cells (malignant gliomas) in 2D culture and the tumor organoid, indicating that iNK cells derived from our protocol can be used as off-the-shelf therapy for both hematological and solid tumors.

Background:CD47, an immune checkpoint overexpressed by tumor cells, plays a crucial role in evading the antitumor immune response. AK117, an IgG4 monoclonal antibody (mAb) targeting CD47, has emerged as a potential best-in-class therapy with high affinity binding to CD47 and without inducing hemagglutination effects. By blocking CD47, AK117 effectively triggers macrophage-mediated phagocytosis of hematological malignancy cells, and in combination with azacitidine (AZA), it synergistically enhances the activation of “eat me” signals. In this study, we present the Phase 1b data from the AK117-103 study conducted in patients with newly diagnosed higher risk myelodysplastic syndrome (HR-MDS).

We used single-cell ATAC-seq (scATAC-seq) to study how synchronous SRSF2and TET2co-mutations result in skewed myelopoiesis compared with SRSF2mutation only in subjects with myelodysplastic neoplasms (MDNs). We identified 621 differentially expressed genes in comparing of transcriptome sequencing data of bone marrow mononuclear cells ( p< 0.01; |log2FC| > 2; Figure 1 A). Up-regulated genes in the co-mutation cohort involved those expressed in pluripotent haematopoietic stem cells (HSCs), cytokine receptor interactions and cancer-related signaling pathways ( Figure 1 B). We extended our observation by interrogating data from the GSE58831 public dataset where we identified 18 similar pathways in subjects with SRSF2and TET2co-mutations ( Figure 1 C ). We then used scATAC-seq to verify regulatory networks with genes and transcription factors. 49,532 cells had high-quality scATAC-seq profiles and passed stringent quality filtering with a median of 12,858 fragments percell 39% of which mapped to peaks. 16 cell types were annotated according to cell marker genes and aligned with the public single cell RNA-seq gene expression matrix of haematopoietic cell types ( Figure 1 D-E). Next, we compared transcription factor (TF) and cis-elements active during differentiation of HSC to myelopoiesis betweenthe SRSF2and TET2co-mutation and SRSF2mutation-only cohorts. In the SRSF2and TET2co-mutation cohort we found GATA4, RUNX1, SNAI1, RELand JDP2favour myeloid differentiation and in NF-KB related inflammatory responses. Related gene activity correlated with high activity of inflammatory cytokines such as BCL2A1, EGR1, IL-1β, and NLRP3( Figure 1 F). SRSF2and TET2co-mutations result in early clonal dominance at the haematopoietic stem cell stage. 19,836 peaks were accessible in SRSF2and TET2co-mutated samples and annotated for putative functions by GREAT ontology enrichment analysis ( Figure 1 G-H). More accessibility peaks in SRSF2and TET2co-mutation were restricted to cancer-related process (reactive oxygen species biosynthetic process, regulation of phagocytosis, intrinsic apoptotic signaling pathway, mRNA catabolism) and cytokine related pathways (IL-1 mediated signaling pathway) compared with SRSF2mutation-only samples. Next, we focused on the IL-1-mediated signaling pathway, a regulator of HSC function. We isolated umbilical cord blood HSCs (CD34+) monitored their expansion in liquid culture with or without (IL-1A or IL-1B (25 ng/ml). HSCs cultured with IL-1A or IL-1B differentiated and expanded significantly faster than untreated HSCs over 7-day period ( Figure 1 I). To directly address the effects of IL-1 on HSC differentiation we used colony formation assays in methylcellulose ± IL-1. Strikingly, IL-1-treated HSCs produced almost exclusively myeloid-committed granulocyte/macrophage (GM)-type colonies containing abundant macrophages (CFU-GM), a higher proportion of immature multi-lineage granulocyte/ erythrocyte /macrophage/megakaryocyte (CFU-GEMM)-type colonies containing mostly immature myeloblasts and a lower proportion of burst-forming unit-erythroid (BFU-E). IL-1-treated HSCs also had decreased re-placing capacity ( Figure 1 J-K). Next, we constructed a SRSF2P95H single mutation and SRSF2P95H mutation with TET2knockout cell lines. We found that co-mutant cells had significantly increased NLRP3 and IL-1β expression in LPS (1 ug/ml) and ATP (5 mM) treated cultures whereas no change was detected IL-1α expression ( Figure 1 L-M). In conclusion, our data preliminary indicate SRSF2and TET2co-mutated causes increased NLRP3-mediated IL-1β secretion resulting in skewed differentiation of HSCs in persons with MDNs.

Drs. Yifan Zhai and Jie Jin are co-corresponding authors.

Myeloma cells resident in bone marrow (BM), therefore the microenvironment plays critical roles in the invasion, proliferation and migration. Obesity increases the morbidity and drug resistance in patient of multiple myeloma (MM) through changing the bone marrow environment. Extracellular environments such as the BM plasma likely have unique lipidomic metabolite profiles that predicts the prognosis in patients with multiple myeloma. However, the study of multiple omics on metabolic changes in BM of MM patients are still very limited.

Introduction:Orelabrutinib is a second-generation Bruton tyrosine kinase inhibitor (BTKi) with high kinase selectivity. Clinical studies have demonstrated that orelabrutinib achieved a high complete response rate of 26.3% in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), showing promising efficacy and acceptable safety profile. However, the real-world data of Orelabrutinib are not available. This study aimed to evaluate the effectiveness and safety of orelabrutinib-containing regimens for the treatment of patients (pts) with CLL/SLL in a real-world setting.