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Mass individualized prototyping (MIP) is a kind of advanced and high-value-added manufacturing service. In the MIP context, the service providers usually receive massive individualized prototyping orders, and they should keep a stable state in the presence of continuous significant stresses or disruptions to maximize profit. This article proposed a graph convolutional neural network-based deep reinforcement learning (GCNN-DRL) method to achieve the resilient production control of MIP (RPC-MIP). The proposed method combines the excellent feature extraction ability of graph convolutional neural networks with the autonomous decision-making ability of deep reinforcement learning. First, a three-dimensional disjunctive graph is defined to model the RPC-MIP, and two dimensionality-reduction rules are proposed to reduce the dimensionality of the disjunctive graph. By extracting the features of the reduced-dimensional disjunctive graph through a graph isomorphic network, the convergence of the model is improved. Second, a two-stage control decision strategy is proposed in the DRL process to avoid poor solution quality in the large-scale searching space of the RPC-MIP. As a result, the high generalization capability and efficiency of the proposed GCNN-DRL method are obtained, which is verified by experiments. It could withstand system performance in the presence of continuous significant stresses of workpiece replenishment and also make fast rearrangement of dispatching decisions to achieve rapid recovery after disruptions happen in different production scenarios and system scales, thereby improving the system’s resilience.

Some challenges still exist with single-target B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapies due to variable or negative BCMA expression, although they have yielded remarkable efficacy in relapsed or refractory multiple myeloma. We developed anti-BCMA/GPRC5D bispecific CARs to mitigate the limitations and potentiate the functions of CAR T cells.

Platelets are well-known players in several cardiovascular diseases such as atherosclerosis and venous thrombosis. There is increasing evidence demonstrating that reactive oxygen species (ROS) are generated within activated platelets. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a major source of ROS generation in platelets. Ligand binding to platelet receptor glycoprotein (GP) VI stimulates intracellular ROS generation consisting of a spleen tyrosine kinase–independent production involving NOX activation and a following spleen tyrosine kinase–dependent generation. In addition to GPVI, stimulation of platelet thrombin receptors (protease-activated receptors [PARs]) can also trigger NOX-derived ROS production. Our recent study found that mitochondria-derived ROS production can be induced by engagement of thrombin receptors but not by GPVI, indicating that mitochondria are another source of PAR-dependent ROS generation apart from NOX. However, mitochondria are not involved in GPVI-dependent ROS generation. Once generated, the intracellular ROS are also involved in modulating platelet function and thrombus formation; therefore, the site-specific targeting of ROS production or clearance of excess ROS within platelets is a potential intervention and treatment option for thrombotic events. In this review, we will summarize the signaling pathways involving regulation of platelet ROS production and their role in platelet function and thrombosis, with a focus on GPVI- and PAR-dependent platelet responses.

G-protein coupled receptor 15 (GPR15) is expressed on T-cells. We previously reported knockout of GPR15 increased acute graft-versus-host disease (GvHD) in mice. In this study, we identified thrombin receptor activating peptide-6 (TRAP-6, peptide sequence: SFLLRN) as an activator of GPR15. GRP15 and β-arrestin2 were needed for TRAP-6-mediated inhibition of mixed lymphocyte reactions. TRAP-6 decreased acute GvHD in allotransplant models in mice, an effect dependent on GPR15-expression in donor T-cells. RNA-seq and protein analyses indicated TRAP-6 increased binding of β-arrestin2/TAB1 and inhibited phosphorylation of TAK1 and NF-κB-P65. GPR15 is expressed differently on CD4+T-cells and CD8+T-cells. TRAP-6 inhibited phosphorylation of NF-κB-P65 in CD4+T-cells but increased granzyme B expression in CD8+T-cells. TRAP-6 decreased acute GvHD without inhibiting graft-versus-tumor (GvT) efficacy against A20 lymphoma cells. SALLRN, a mutant of TRAP-6, preserved the anti-acute GvHD effect but avoided the adverse effects of TRAP-6. TRAP-6 and SALLRN also decreased allogeneic and xenogeneic reactions induced by human blood mononuclear cells. In conclusion, TRAP-6 activated GPR15 on T-cells and decreased acute GvHD in mice without impairing GvT efficacy.

In Industry 5.0 vision, machines are empowered with the interaction capability to autonomously make local decisions and coordinate with each other as well as humans. However, how to form a group consensus on the rapid self-organizing of the manufacturing process is critical for achieving manufacturing resilience under disturbances and disruptions. Based on our formerly developed system ManuChain (Leng et al., 2020), this article proposes a blockchained smart contract system (BSCS), named ManuChain II, as the digital twin of a decentralized autonomous manufacturing system for achieving resilience in Industry 5.0. A blockchain-secured multiagent system architecture together with a product data model is established to form the BSCS. The BSCS could prevent tampering with data and enhance the transparency of the product manufacturing process. In BSCS, two types of blockchained smart contracts (SCs) are established with a bi-level interplay computing architecture. The lower-level contracts perform the predefined and learned patterns of task coordination for achieving resilience under internal disruptions. The upper-level contracts are incorporated with communication-efficient decentralized deep-learning algorithms for the learning, updating, transferring, and sharing of coordination patterns used in the autonomous decision in lower-level SCs, thereby achieving the continuous improvement of the system’s decentralized autonomous intelligence. Via incorporating the decentralized deep learning algorithms into blockchained SCs, this study reveals a new way to realize the self-organizing intelligence of the manufacturing system for enhancing resilience toward Industry 5.0.

De novo CD5+diffuse large B-cell lymphoma (DLBCL) has poor survival in the era of immunochemotherapy. Accurate gene-based typing and prognostic stratification can enhance the development of effective individualized treatments. Therefore, we conducted a multicenter retrospective study to evaluate the clinicopathologic characteristics, genomic profiles, and prognostic parameters of 61 patients with CD5+DLBCL and 60 patients with CD5−DLBCL, with the goal of facilitating accurate prognostic stratification and potential individualized treatment strategies. Compared with patients with CD5−DLBCL, older age, advanced stage, higher incidence of central nervous system involvement, and MYC/BCL-2 and p53 overexpression were more prevalent in CD5+DLBCL. Most patients with CD5+DLBCL had lymph nodes with non–germinal center B-cell–like or activated B-cell–like subtype according to immunohistochemistry or Lymph2Cx assay. Next-generation sequencing showed that the proportion of MCD subtype (based on the co-occurrence of MYD88and CD79Bmutations) in the CD5+DLBCL cohort was higher than that in the CD5−DLBCL cohort (54.2% vs. 13.0%, P=0.005). Compared with the CD5−cohort, CD5+DLBCL patients showed poor 5-year overall survival (70.9% vs. 39.0%, P<0.001). Kaplan-Meier survival analysis indicated that cell of origin, MYC/BCL-2, p53, and BCL-6 expression did not have a prognostic impact on patients with CD5+DLBCL. Multivariate analysis showed that age above 76 years, advanced stage, higher incidence of central nervous system involvement, and hypoalbuminemia were independent factors for poor prognosis in CD5+DLBCL patients. In summary, CD5+DLBCL displays poor prognosis, distinctive clinicopathologic characteristics and predominant genetic features of activated B-cell–like and MCD subtypes with worse survival outcome.

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a protein tyrosine phosphatase that negatively regulates T-cell signaling. However, whether it is expressed and functions in platelets remains unknown. Here we investigated the expression and role of PTPN22 in platelet function. We reported PTPN22 expression in both human and mouse platelets. Using PTPN22−/− mice, we showed that PTPN22 deficiency significantly shortened tail-bleeding time and accelerated arterial thrombus formation without affecting venous thrombosis and the coagulation factors VIII and IX. Consistently, PTPN22-deficient platelets exhibited enhanced platelet aggregation, granule secretion, calcium mobilization, lamellipodia formation, spreading, and clot retraction. Quantitative phosphoproteomic analysis revealed the significant difference of phosphodiesterase 5A (PDE5A) phosphorylation in PTPN22-deficient platelets compared with wild-type platelets after collagen-related peptide stimulation, which was confirmed by increased PDE5A phosphorylation (Ser92) in collagen-related peptide–treated PTPN22-deficient platelets, concomitant with reduced level and vasodilator-stimulated phosphoprotein phosphorylation (Ser157/239). In addition, PTPN22 interacted with phosphorylated PDE5A (Ser92) and dephosphorylated it in activated platelets. Moreover, purified PTPN22 but not the mutant form (C227S) possesses intrinsic serine phosphatase activity. Furthermore, inhibition of PTPN22 enhanced human platelet aggregation, spreading, clot retraction, and increased PDE5A phosphorylation (Ser92). In conclusion, our study shows a novel role of PTPN22 in platelet function and arterial thrombosis, identifying new potential targets for future prevention of thrombotic or cardiovascular diseases.

Few studies have described chimeric antigen receptor (CAR) T-cell therapy for patients with B-cell acute lymphoblastic leukemia (B-ALL) with central nervous system leukemia (CNSL) because of concerns regarding poor response and treatment-related neurotoxicity. Our study included 48 patients with relapsed/refractory B-ALL with CNSL to evaluate the efficacy and safety of CD19-specific CAR T cell–based therapy. The infusion resulted in an overall response rate of 87.5% (95% confidence interval [CI], 75.3-94.1) in bone marrow (BM) disease and remission rate of 85.4% (95% CI, 72.8-92.8) in CNSL. With a median follow-up of 11.5 months (range, 1.3-33.3), the median event-free survival was 8.7 months (95% CI, 3.7-18.8), and the median overall survival was 16.0 months (95% CI, 13.5-20.1). The cumulative incidences of relapse in BM and CNS diseases were 31.1% and 11.3%, respectively, at 12 months (P = .040). The treatment was generally well tolerated, with 9 patients (18.8%) experiencing grade ≥3 cytokine release syndrome. Grade 3 to 4 neurotoxic events, which developed in 11 patients (22.9%), were associated with a higher preinfusion disease burden in CNS and were effectively controlled under intensive management. Our results suggest that CD19-specific CAR T cell–based therapy can induce similar high response rates in both BM and CNS diseases. The duration of remission in CNSL was longer than that in BM disease. CD19 CAR T-cell therapy may provide a potential treatment option for previously excluded patients with CNSL, with manageable neurotoxicity. The clinical trials were registered at www.clinicaltrials.gov as #NCT02782351 and www.chictr.org.cn as #ChiCTR-OPN-16008526.

Few studies have described chimeric antigen receptor (CAR) T-cell therapy for patients with B-cell acute lymphoblastic leukemia (B-ALL) with central nervous system leukemia (CNSL) because of concerns regarding poor response and treatment-related neurotoxicity. Our study included 48 patients with relapsed/refractory B-ALL with CNSL to evaluate the efficacy and safety of CD19-specific CAR T cell–based therapy. The infusion resulted in an overall response rate of 87.5% (95% confidence interval [CI], 75.3-94.1) in bone marrow (BM) disease and remission rate of 85.4% (95% CI, 72.8-92.8) in CNSL. With a median follow-up of 11.5 months (range, 1.3-33.3), the median event-free survival was 8.7 months (95% CI, 3.7-18.8), and the median overall survival was 16.0 months (95% CI, 13.5-20.1). The cumulative incidences of relapse in BM and CNS diseases were 31.1% and 11.3%, respectively, at 12 months (P= .040). The treatment was generally well tolerated, with 9 patients (18.8%) experiencing grade ≥3 cytokine release syndrome. Grade 3 to 4 neurotoxic events, which developed in 11 patients (22.9%), were associated with a higher preinfusion disease burden in CNS and were effectively controlled under intensive management. Our results suggest that CD19-specific CAR T cell–based therapy can induce similar high response rates in both BM and CNS diseases. The duration of remission in CNSL was longer than that in BM disease. CD19 CAR T-cell therapy may provide a potential treatment option for previously excluded patients with CNSL, with manageable neurotoxicity. The clinical trials were registered at www.clinicaltrials.govas #NCT02782351 and www.chictr.org.cnas #ChiCTR-OPN-16008526.

Photovoltaic (PV) array equipped on an unmanned surface vehicle (USV) suffers from rapid-changing partial-shading conditions since USV maneuvers frequently alter shadows on deck, thereby facing a challenge in time-varying maximum power point tracking (MPPT). In this paper, a fuzzy neural directed adaptive particle optimization (FN-APSO) solution is innovatively provided to dynamically determine the global maximum power point (GMPP) in a fast-accurate manner. To facilitate the accuracy, an adaptive PSO (APSO) algorithm is created by assigning region-wise update laws which sufficiently avoid unnecessary search behaviors and ensure global convergence, simultaneously. To further enhance the rapidity, using history data, a fuzzy neural network is devised to judge the evolution direction of GMPP, and enables the APSO to incrementally execute, thereby establishing the entire FN-APSO scheme. Simulation results clearly show remarkable MPPT performance in terms of both speed and accuracy under rapid-changing partial-shading conditions.

Systematic and dynamic humoral immune reconstitution is little-known for patients with relapsed/refractory (R/R) multiple myeloma (MM) who received anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy. We investigated the kinetics of B-cell, normal plasma cell, and immunoglobulin recovery in 40 patients who achieved ongoing response after anti-BCMA CAR T-cell therapy. All patients developed B-cell aplasia and the median duration of B-cell aplasia was 70 days (range, 23-270). The B-cell count reached its nadir on median day 7 and returned to baseline level on median day 97. BCMA+cells in bone marrow turned undetectable on median day 28 (13-159) in 94.87% (37 of 39) of patients. Normal plasma cells in bone marrow were first redetected on median day 212. All patients developed a significant decrease in serum IgG, IgA, and IgM on median day 60. At year 1, recovery of serum IgG, IgM, and IgA was observed in 53.33% (8 of 15; non-IgG MM), 73.08% (19 of 26; non-IgM MM), and 23.81% (5 of 21;non-IgA MM) of the patients, respectively. Median time to IgG, IgM, and IgA recovery were days 386, 254, and not reached during follow-up, respectively. Virus-specific IgG levels decreased with loss of protection. Twenty-three of 40 (57.5%) patients had a total of 44 infection events. There were no infection-related deaths. These results reveal a 7-month aplasia of bone marrow normal plasma cells and longer period of hypogammaglobulinemia, suggesting a profound and lasting humoral immune deficiency after anti-BCMA CAR T-cell therapy, especially for IgA.

Systematic and dynamic humoral immune reconstitution is little-known for patients with relapsed/refractory (R/R) multiple myeloma (MM) who received anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy. We investigated the kinetics of B-cell, normal plasma cell, and immunoglobulin recovery in 40 patients who achieved ongoing response after anti-BCMA CAR T-cell therapy. All patients developed B-cell aplasia and the median duration of B-cell aplasia was 70 days (range, 23-270). The B-cell count reached its nadir on median day 7 and returned to baseline level on median day 97. BCMA+ cells in bone marrow turned undetectable on median day 28 (13-159) in 94.87% (37 of 39) of patients. Normal plasma cells in bone marrow were first redetected on median day 212. All patients developed a significant decrease in serum IgG, IgA, and IgM on median day 60. At year 1, recovery of serum IgG, IgM, and IgA was observed in 53.33% (8 of 15; non-IgG MM), 73.08% (19 of 26; non-IgM MM), and 23.81% (5 of 21;non-IgA MM) of the patients, respectively. Median time to IgG, IgM, and IgA recovery were days 386, 254, and not reached during follow-up, respectively. Virus-specific IgG levels decreased with loss of protection. Twenty-three of 40 (57.5%) patients had a total of 44 infection events. There were no infection-related deaths. These results reveal a 7-month aplasia of bone marrow normal plasma cells and longer period of hypogammaglobulinemia, suggesting a profound and lasting humoral immune deficiency after anti-BCMA CAR T-cell therapy, especially for IgA.

Intracranial hemorrhage (ICH) is a rare but fatal central nervous system complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, factors that are predictive of early mortality in patients who develop ICH after undergoing allo-HSCT have not been systemically investigated. From January 2008 to June 2020, a total of 70 allo-HSCT patients with an ICH diagnosis formed the derivation cohort. Forty-one allo-HSCT patients with an ICH diagnosis were collected from 12 other medical centers during the same period, and they comprised the external validation cohort. These 2 cohorts were used to develop and validate a grading scale that enables the prediction of 30-day mortality from ICH in all-HSCT patients. Four predictors (lactate dehydrogenase level, albumin level, white blood cell count, and disease status) were retained in the multivariable logistic regression model, and a simplified grading scale (termed the LAWS score) was developed. The LAWS score was adequately calibrated (Hosmer-Lemeshow test, P > .05) in both cohorts. It had good discrimination power in both the derivation cohort (C-statistic, 0.859; 95% confidence interval, 0.776-0.945) and the external validation cohort (C-statistic, 0.795; 95% confidence interval, 0.645-0.945). The LAWS score is the first scoring system capable of predicting 30-day mortality from ICH in allo-HSCT patients. It showed good performance in identifying allo-HSCT patients at increased risk of early mortality after ICH diagnosis. We anticipate that it would help risk stratify allo-HSCT patients with ICH and facilitate future studies on developing individualized and novel interventions for patients within different LAWS risk groups.

Boosting T cell immune response posttransplant with checkpoint inhibitors increases graft‐versus‐lymphoma (GVL) effects at the cost of increasing acute graft‐versus‐host disease (aGVHD). A combined targeted therapy is needed to decrease checkpoint inhibitors‐induced aGVHD without impairing GVL. We studied whether this competition could be avoided by giving concurrent anti‐PD‐1 antibody and ruxolitinib in allotransplant mouse models in which recipients were challenged with A20 or EL4 lymphoma cells. Given alone the PD‐1 antibody increased GVL but did not improve survival of recipients challenged with A20 cells because of increased deaths from aGVHD. Adding ruxolitinib decreased levels of effector T cells and related cytokines. Tbx21‐T cells had higher PD‐1 levels compared with Tbx21+T cells. Ruxolitinib increased PD‐1 levels on donor T cells by suppressing Tbx21 expression. Ruxolitinib increased apoptosis of T cells which was reversed by the PD‐1 antibody. PD‐1 antibody preserved expression of granzyme B and cytotoxicity of T cells which were decreased by ruxolitinib. The net result of combined therapy was increased GVL, no increase in aGVHD and increased survival. The combined therapy improved survival of recipients challenged by A20 cells which expressed high level of PD‐L1, but not EL4 cells which do not express PD‐L1. Combined therapy with PD‐1 antibody and the Janus‐associated kinase inhibitor, ruxolitinib, decreases proinflammatory profiles without impairing antitumor effect in mice transplanted with allogeneic hematopoietic cells and challenged with A20 lymphoma cell.

•Co-MSC/EPC accelerated injured gut repair, including gut morphology and vasculature.•The combined effects were partially explained by the P38 MAPK/HSP27 pathway.•The microbial community balance of Enterococcusand Akkermansiaplayed a key role.

Chimeric antigen receptor (CAR)-T-cell is a safe and effective therapy of B-cell cancers but it is unknown if this is so in persons with prior hepatitis B virus (HBV) infection. We studied 70 subjects with advanced B-cell cancers receiving CAR-T-cell therapy, 12 of whom had chronic HBV-infection (HBsAg positive) and 29 with resolved HBV-infection (HBsAg negative and anti-HBc positive). Safety and efficacy were compared with 29 subjects without HBV-infection. HBV was reactivated in 2 subjects with chronic HBV-infection and 1 with resolved HBV-infection. There was no HBV-related hepatitis flare. Responses to CAR-T-cell therapy in the three cohorts were not significantly different. There was no significant difference in the incidence or severity of cytokine release syndrome (CRS) and neurologic toxicity between the cohorts. Our data suggest that chronic and resolved HBV-infection do not affect the safety and efficacy of CAR-T-cell therapy.

•Higher MALT1 level in MM samples correlates with shorter survival of patients with MM.•MALT1 inhibition halts cell growth of MM by inactivation of the B-cell maturation antigen–induced NF-κB pathway and inducing ICD.

1.Hepatocyte-specific Notch1deficiency impairs hepatic thrombopoietin production and reduces circulating platelet number.2.Dll4 on desialylated platelets activates hepatocyte Notch1 signaling and upregulates HES5 expression, leading to JAK2/STAT3 phosphorylation.

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy has been shown to have activity in patients with relapsed or refractory multiple myeloma. Reports have suggested that a small subgroup of less differentiated myeloma clones express CD19 and anti-CD19 CAR T-cell therapy has shown activity in some of these patients. We aimed to assess the activity and safety of a combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma.

The treatment of multiple myeloma (MM) with bortezomib (BTZ) is promising; however, the emergence of resistance is challenging in the clinical treatment. Thus, a novel targeted treatment or exploring the mechanism underlying BTZ resistance is an urgent requisite. The current data showed that high expression of USP7 in myeloma was a predictor of short overall survival and poor outcome. USP7 knockout significantly suppressed the colony formation, inhibited the proliferation of BTZ‐resistant MM cells even in the presence of growth factors, and overcame BTZ resistance. The knockout markedly inhibited the tumor growth and prolonged the survival of mice bearing BTZ‐resistant MM cells. Mechanistically, USP7 knockout remarkably increased the sensitivity to BTZ by stabilizing ΙκΒα and blocking the NF‐κB pathway. Not surprisingly, when IκBα was knocked down by siRNA transfection, the MM cells restored the BTZ resistance. Importantly, usage of USP7 inhibitors also suppressed the activation of NF‐κB and combination with BTZ triggered the synergistic antitumor activity in BTZ‐resistant MM cells. Taken together, this study provides the rationale for clinical protocols evaluating USP7 inhibition, alone and in combination with BTZ, to overcome BTZ resistance and improve the patient outcome in MM. our study provides the rationale for clinical protocols evaluating USP7 inhibition, alone and combination with bortezomib, to overcome bortezomib resistance.

Since the important role of inflammation in myeloproliferative neoplasms (MPN) progression, inflammasome is an important regulator of inflammation involved in the development of tumor. Here, we aimed to investigate the function of NLRP6 in bone marrow (BM) microenvironment in MPN in the hope of getting better treatment for MPN.

Background:Autologous CD-19 directed chimeric antigen receptor (CAR) T-cell therapy has become the standard of care of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) who have received two or more prior lines of therapy. In June 2021, Axi-cel was approved by the China National Medical Products Administration (NMPA) for the treatment of these patients as the first commercial CAR-T product in China. To better understand the efficacy and safety of commercial Axi-cel in Chinese R/R NHL patients in a real-world setting, we conducted this multi-center, non-interventional study (ChiCTR2100047990). The accrual goal is 200 patients, and the primary endpoint is mOS. Here we made the pre-specific interim analysis and the reported the clinical outcomes.

Notch signaling is highly conserved and regulates cell-fate decisions in several developmental processes and cell functions. However, a role for Notch in hepatic thrombopoietin (TPO) production has not been described. We noted that mice with a deficiency in hepatic Notch1 had thrombocytopenia, and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control mice and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO mRNA levels, concomitant with lower numbers of circulating platelets and impaired megakaryocyte differentiation and maturation. Addition of exogenous TPO rescued megakaryocyte maturation and circulating platelet numbers. Additionally, JAK2/STAT3 phosphorylation was significantly inhibited in Notch1-deficient hepatocytes. RNA-seq analysis showed significantly reduced JAK-STAT signaling. JAK2/STAT3 phosphorylation and TPO production was also impaired in purified cultured Notch1-deficient hepatocytes after treatment with desialylated platelets. Interestingly, Notch1 deficiency downregulated the expression of HES5 but not HES1. Moreover, desialylated platelets promoted the binding of HES5 to JAK2/STAT3, leading to JAK2/STAT3 phosphorylation and pathway activation. Furthermore, blockage of Dll4 on desialylated platelets inhibited hepatocyte Notch1 activation and HES5 expression, JAK2/STAT3 phosphorylation and subsequent TPO production. In conclusion, our study identifies a novel regulatory role of Notch1 in hepatic TPO production, indicating that it might be a target for modulating TPO level.

Background

The mutational spectrum and prognostic stratification of intermediate-risk acute myeloid leukemia (IR-AML), which accounts for a substantial number of AML, are unclear. In order to explore the prognostic significance of the mutational spectrum in IR-AML, 106 IR-AML patients were collected from The Cancer Genome Atlas database. Sixty-two patients underwent chemotherapy-only, forty-four proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Fifty-five patients had more than five recurrent genetic mutations. NPM1had the highest mutation frequency, followed by DNMT3A, FLT3, RUNX1, IDH2, IDH1, and TET2. In all patients, allo-HSCT was an independent favorable factor for EFS and OS (P= 0.036, P= 0.001, respectively); age ≥60 years, FLT3-ITDand mutations in DNMT3Aand RUNX1were independent risk factors for survival (all P< 0.05). In the chemotherapy-only group, multivariate analysis showed that age ≥60 years was an independent risk factor for EFS and OS (P= 0.008, P= 0.017, respectively). In the allo-HSCT group, multivariate analysis indicated that MLL-PTDwas an independent risk fact for EFS (P= 0.037), FLT3-ITDand RUNX1mutations independently contributed to poor OS (P= 0.035, P= 0.014, respectively). In conclusion, older age was an important risk factor for IR-AML patients undergoing chemotherapy-only; FLT3-ITD, MLL-PTD and RUNX1mutations were significant risk factors for IR-AML patients who received allo-HSCT.

Deregulation of key regulators of histone modification is important in the initiation and progression of human leukemia. Acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) participates in histone acetylation and its role in acute myeloid leukemia remains unclear. Here we observed significant upregulation of ANP32A in primary AML cells, which was essential for AML cell proliferation, survival, and colony formation. Integrative analysis of the genome-wide histone H3 acetylation and gene expression demonstrated that ANP32A deficiency reduced histone H3 acetylation, in accordance with changes in gene expression. Notably, significant histone H3 acetylation enrichment was associated with mRNA changes in lipid-related genes, including APOC1, PCSK9, P2RX1, and LPPR3. Indeed, over-expression of APOC1 partially compensated the proliferation-defect phenotype in ANP32A deficient AML cells while APOC1 knockdown alone mimicked the effect of ANP32A deficiency. Collectively, our data indicate that ANP32A is a novel regulator of histone H3 acetylation and promotes leukemogenesis.

•Thymosin β4 (Tβ4) exerts a cytoprotective effect and has anti-inflammatory and antioxidant roles in hepatic sinusoidal endothelial cell (HSEC) damage induced by irradiation.•Tβ4 exerts a prominent anti-hepatic sinusoidal obstruction syndrome (HSOS) effect in a murine HSOS model.•The mechanism of HSEC injury, liver fibrosis, and subsequent HSOS may be related to the depletion of Tβ4 in HSECs and hepatic stellate cells.•The pro-proliferation, pro-angiogenic, and anti-apoptotic effects of Tβ4 in HSECs are related to activation of the AKT pathway.

Chimeric antigen receptor (CAR) T cell therapy lacks persistent efficacy with “on-target, off-tumor” toxicities for treating solid tumors. Thus, an antibody-guided switchable CAR vector, the chimeric Fc receptor CD64 (CFR64), composed of a CD64 extracellular domain, is designed. T cells expressing CFR64 exert more robust cytotoxicity against cancer cells than CFR T cells with high-affinity CD16 variant (CD16v) or CD32A as their extracellular domains. CFR64 T cells also exhibit better long-term cytotoxicity and resistance to T cell exhaustion compared with conventional CAR T cells. With trastuzumab, the immunological synapse (IS) established by CFR64 is more stable with lower intensity induction of downstream signaling than anti-HER2 CAR T cells. Moreover, CFR64 T cells exhibit fused mitochondria in response to stimulation, while CARH2 T cells contain predominantly punctate mitochondria. These results show that CFR64 T cells may serve as a controllable engineered T cell therapy with prolonged persistence and long-term antitumor activity.

2-[((3R)-5-oxo-4-phenyltetrahydrofuran-3-yl)methyl]isoindoline-1,3-dione, C19H15NO4, was synthesized for the first time. Its structure was characterized by element analysis, ultraviolet spectrometry, nuclear magnetic resonance, and single X-ray diffraction (SXRD). X-ray powder diffraction (XRPD) data of title compound were collected and calculated. The result of SXRD shows that its crystal system is orthorhombic, space group is Pbca, and unit-cell parameters are a= 8.861 57(7), b= 14.6666(10), c= 24.4247(19) Å, a=ß=?=90°, unit-cell volume V= 3174.4 Å3, and Z= 8. All XRPD measured lines were indexed and consistent with the Pbcaspace group [a= 14.639(7), b= 24.378(3), c= 8.918(1) Å, a= ß= ?= 90°, unit-cell volume V= 3182.7(9) Å3, Z= 8]. No detectable impurities were observed.

X-ray powder diffraction data, unit-cell parameters, and space group for olmesartan medoxomil, C29H30N6O6, are reported [a= 12.3969(7) Å, b= 21.2667(3) Å, c= 10.9603(5) Å, a= ?= 90°, ß= 101.38(9)°, unit-cell volume V= 2832.72 Å3, Z= 4 and space group P21/c]. All measured lines were indexed and are consistent with the P21/cspace group. No detectable impurities were observed.

Emodin (EM), with two pKa values (pKa1 = 8.0 and pKa2 = 10.9), presents low solubility and dissolution rate, which results in low bioavailability. In this report, two EM sodium salts, C15H9O5−·Na+(EM-1Na) and C15H8O52−·2Na+(EM-2Na), were prepared by adding various amounts of sodium hydroxide. Salt forms were characterized by FT-IR, XRPD, 1H NMR, DSC, and SEM, as well as solubility and dissolution rate studies in triple-deionized water, buffer at pH 1.2 and pH 6.8, respectively. The aqueous solubility of EM was notably enhanced by more than 20,000 and 50,000 times, corresponding to EM-1Na and EM-2Na. Meanwhile, the dissolution rate exhibited significant enhancement and the dissolution time was shortened. The results showed the dissolution of EM-1Na and EM-2Na was 25 and 35 times greater than EM in 60 min. The results of β-amyloid (Aβ) self-aggregation inhibition and MIC assay did not show apparent difference from those of EM, indicating that the functional groups were not broken down. Moreover, salt formation significantly enhanced the bioavailability of EM, consistent with the ABTS free radical scavenging test results. The significant decrease in IC50values in the range of 18,394 μg/mL to 29.07 μg/mL indicated a more effective anti-AD action.

A simple method for the determination of trace tetracyclines (TCs) in surface water samples by aluminum hydroxide coprecipitation coupled with high-performance liquid chromatography (HPLC) with UV detection was developed. Tetracyclines (oxytetracycline hydrochloride, tetracycline hydrochloride and chlortetracycline) were coprecipitated by aluminum hydroxide precipitate at pH 6.0. The obtained precipitate by centrifugation was dissolved with 1 mol L−1HCl, and the pH of the solution was adjusted to 4.0 for HPLC analysis. The solution pH value, adsorption time for coprecipitation, centrifugation rate and time were optimized. Under the optimum conditions, calibration curves of the tetracyclines were in the range of 5–50 ng mL−1, with a relative coefficient (R2) of 0.9960 and a limit of detection (LOD) of 0.115 ng L−1for chlortetracycline (CTC), of 0.9990 and 0.0935 ng L−1for oxytetracycline (OTC), and 0.9990 and 0.0817 ng L−1for tetracycline (TC). The proposed method was applied to river water and lake water samples, and the recoveries were in the range of 81.70% to 96.45%, at three spiked concentration levels of 15 ng mL−1, 30 ng mL−1and 40 ng mL−1.