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Nonylphenol (NP) residues, as a typical endocrine disrupting chemical (EDC), frequently exist in sewage, surface water, groundwater and even drinking water, which poses a serious threat to human health due to its bioaccumulation. In order to remove NP, a series of MIL-100(Fe)/ZnFe 2 O 4 /flake-like porous carbon nitride (MIL/ZC) was synthesized through in-situ synthesis at room temperature. High performance of ternary MIL/ZC is used to degrade NP under visible light irradiation. The results show that 30MIL/ZC2 (20 wt.% ZnFe 2 O 4) ternary composite had the best photocatalytic activity (99.84%) when the dosage was 30 mg. Further mechanism analysis shows that the excellent photocatalytic activity of 30MIL/ZC2 could be ascribed to the double charge transfer process between flake-like porous carbon nitride (PCN) and other catalysts in the ternary heterojunction, and the separation of photogenerated electron-hole pairs was more effective. In addition, the 30MIL/ZC2 also showed high stability after five cycles of the photodegradation reaction. Furthermore, the active substance (•O 2 −) was considered to be the main active substance in the NP degradation process. Based on the research results, the possible photocatalytic reaction mechanism of 30MIL/ZC2 ternary composite was proposed and discussed in detail. [Display omitted] [ABSTRACT FROM AUTHOR]

The solid-state diversity of active pharmaceutical ingredients can provide theoretical guidance for the production and storage of drugs. In this study, three solid forms of glipizide were obtained through various methods, and the solid-state transformations were extensively investigated. Form I could be prepared using evaporative crystallization, cooling crystallization, anti-solvent crystallization, and solvent-mediated slurry conversion experiments (SSCE). Form II was produced by milling. Form III was obtained by milling and SSCE. The results of solid-state transformations indicated that Form I transformed to II during neat milling at 25 °C. In contrast, solvent inhibited the solid-state transformations of Form I under liquid-assisted milling. Forms II and III remained invariable under neat milling at 25 °C, and solid-state transformation of Form III also did not occur in the liquid-assisted milling. In SSCE, the solvent's nature and its temperature significantly influenced the solid-state conversion of amorphous glipizide. Form II converted to either Form I or III in water above 50 °C, and only transformed into Form I at 25 °C. However, the solid-state transformation did not occur when pure Form I or III was stirred in water. Form II also converted to Form I in the organic solvents SSCE at different temperatures. [ABSTRACT FROM AUTHOR]

Four solid forms of pranlukast (PRS) were obtained during mechanical milling including neat milling (NM) and solvent-drop milling (SDM), which were characterized by various analytical techniques. The effect of milling conditions including 3 milling temperatures and 6 assist solvents on the solid-state transformations of commercial PRS (PRS HH) was systemically investigated. Milling temperature significantly influenced the NM process. A low milling temperature (5°C) led to a complete amorphization of PRS HH, whereas higher milling temperatures (15°C and 30°C) only induced a partial amorphization. The milling at 5°C was proven to be a progressive amorphization process, and the amorphous material showed an increasing stability with prolonged milling time. Amorphous PRS can stay stable under low temperature and relative humidity conditions and showed significantly higher solubilities and faster dissolution rates in both water and pH 6.8 phosphate buffer solution. A total of 6 solvents were used in the SDM experiments. N,N-dimethylformamide and dimethyl sulfoxide should be avoided in the manufacturing process of PRS because corresponding solvates of PRS can be easily generated by SDM of PRS HH with short milling time and small amount of solvents. [ABSTRACT FROM AUTHOR]

A series of 0D boron carbon nitride quantum dots (BCNQDs) modified 2D Bi 4 O 5 I 2 (0D/2D Bi 4 O 5 I 2 /BCNQDs) composites were synthesized and applied to photodegradation of tetracyclines (TCs), including tetracycline (TC) and oxytetracycline (OTC). The Bi 4 O 5 I 2 /BCNQDs (1) (1 mL BCNQDs) composite exhibits the highest photocatalytic performance for TCs degradation. The degradation rate constants of TC and OTC by the optimal sample were 4.95 and 2.17 times that of Bi 4 O 5 I 2 , respectively. This can be attributed to the fact that the narrow bandgap Bi 4 O 5 I 2 is the electron acceptor, and the oxygen-containing functional group with the negative charge on BCNQDs can promote the formation of photoexcited holes, which makes the effective separation of photoexcited carriers easier. Furthermore, the active substance (h+ and ·O 2 −) is the major active substance for TCs photodegradation. On this basis, the possible photocatalytic reaction mechanism of Bi 4 O 5 I 2 /BCNQDs (1) composite is proposed. This study provides a new idea for 0D/2D interface engineering of BCNQDs heterojunction. [Display omitted] • The novel 0D/2D Bi 4 O 5 I 2 /BCNQDs photocatalysts were successfully prepared for the first time. • ·O 2 − and h+ are responsible for TCs photodegradation by Bi 4 O 5 I 2 /BCNQDs (1). • The mechanism of TCs photodegradation was well discussed. • The intermediates toxicity of TCs degradation by Bi 4 O 5 I 2 /BCNQDs (1) are evaluated by QSAR method. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor-T (CAR-T) cells have exhibited remarkable efficacy in treating refractory or relapsed multiple myeloma (R/R MM). Although obesity has a favorable value in enhancing the response to immunotherapy, less is known about its predictive value regarding the efficacy and prognosis of CAR-T cell immunotherapy. We conducted a retrospective study of 111 patients with R/R MM who underwent CAR-T cell treatment. Using the body mass index (BMI) classification, the patients were divided into a normal-weight group (73/111) and an overweight group (38/111). We investigated the effect of BMI on CAR-T cell therapy outcomes in patients with R/R MM. The objective remission rates after CAR-T cell infusion were 94.7% and 89.0% in the overweight and normal-weight groups, respectively. The duration of response and overall survival were not significant difference between BMI groups. Compared to normal-weight patients, overweight patients had an improved median progression-free survival. There was no significant difference in cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome between the subgroups. In terms of hematological toxicity, the erythrocyte, hemoglobin, platelet, leukocyte and neutrophil recovery was accelerated in the overweight group. Fewer patients in the overweight group displayed moderate percent CD4 and CD4/CD8 ratios compared to the normal-weight group. Furthermore, the percent CD4 ratios were positively correlated with the levels of cytokines [interleukin-2 (IL-2) (day 14), interferon gamma (IFN-γ) (day 7) and tumor necrosis factor alpha (TNF-α) (days 14 and 21)] after cells infusion. On the other hand, BMI was positively associated with the levels of IFN-γ (day 7) and TNF-α (days 14 and 21) after CAR-T cells infusion. Overall, this study highlights the potential beneficial effect of a higher BMI on CAR-T cell therapy outcomes. [ABSTRACT FROM AUTHOR]

The growth of personalized demands requires socialized resources to timely self-organize themselves with crowd intelligence for co-creating open architecture products. This social manufacturing paradigm drives an increased demand for makers to track the authenticity and quality of products. A new decentralized blockchain-driven model, named Makerchain, is presented to handle the cyber-credit of social manufacturing among various makers. An anti-counterfeiting method composed of chemical signature is proposed to represent unique features of personalized products. Twinning unique signature data to blockchain and other functional databases is realized and anticipated to make manufacturing service transactions among makers more trustworthy. Based on an automated execution mechanism of smart contracts among makers, a decentralized manufacturing network can be enabled for automating transactions among makers, as well as third-party verification of product lifecycle through a trail of historic events. A Makerchain Decentralized Application (DApp) is presented to demonstrate the proposed approach through which clustered makers can self-organizing themselves around personalized demands. [ABSTRACT FROM AUTHOR]

Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) multiple myeloma (MM). We present a retrospective study performed on 113 patients with R/R MM who received single anti-BCMA CAR T-cell, combined with anti-CD19 CAR T-cell or anti-CD138 CAR T-cell therapy. Eight patients were given G-CSF after successful management of CRS, and no CRS re-occurred thereafter. Of the remaining 105 patients that were finally analyzed, 72 (68.6%) received G-CSF (G-CSF group), and 33 (31.4%) did not (non G-CSF group). We mainly analyzed the incidence and severity of CRS or NEs in two groups of patients, as well as the associations of G-CSF timing, cumulative dose and cumulative time with CRS, NEs and efficacy of CAR T-cell therapy. Both groups of patients had similar duration of grade 3–4 neutropenia, and the incidence and severity of CRS or NEs.There were also no differences in the incidence and severity of CRS or NEs between patients with the timing of G-CSF administration ≤3 days and those >3 days after CAR T-cell infusion. The incidence of CRS was greater in patients receiving cumulative doses of G-CSF >1500 μg or cumulative time of G-CSF administration >5 days. Among patients with CRS, there was no difference in the severity of CRS between patients who used G-CSF and those who did not. The duration of CRS in anti-BCMA and anti-CD19 CAR T-cell–treated patients was prolonged after G-CSF administration. There were no significant differences in the overall response rate at 1 and 3 months between the G-CSF group and the non–G-CSF group. Our results showed that low-dose or short-time use of G-CSF was not associated with the incidence or severity of CRS or NEs, and G-CSF administration did not influence the antitumor activity of CAR T-cell therapy. [ABSTRACT FROM AUTHOR]

The interaction between carthamin and human serum albumin (HSA) was investigated by multiple spectroscopic analyses, surface plasmon resonance (SPR), isothermal titration microcalorimetry (ITC), and molecular docking studies. Fluorescence lifetime measurements implied that carthamin quenched the intrinsic fluorescence of HSA with the formation of a new complex via static mode. Binding affinities regarding this interaction were obtained from SPR analysis. Results demonstrated that carthamin could form a 1:1 complex with HSA at the binding affinity of K D = 8.726 × 10 −5 M and that a high temperature was unfavourable for the interaction. ITC analyses and molecular docking results illustrated that HSA shaped a proper cavity (site I) to embed the whole carthamin molecule and that the complex was formed depending on intermolecular forces, including hydrophobic interaction, hydrogen bonding, and electrostatic force. Moreover, circular dichroism and 3D fluorescence demonstrated that carthamin slightly disturbed the microenvironment of amino residues and affected the secondary structure of HSA. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy is a new and effective method in relapsed or refractory (R/R) multiple myeloma (MM). This study was aimed to explore the risk factors of infection events. We retrospectively analyzed 68 patients with R/R MM who received CAR T-cell therapy at the Affiliated Hospital of Xuzhou Medical University from June 2017 to June 2021.35 patients received anti-CD19 combined with anti-BCMA CAR T-cell therapy and 33 patients received anti-BCMA CAR T-cell therapy alone. Infection events in patients who received ≥4 prior lines of treatment or with grade 3–5 cytokines released syndrome (CRS) mainly occurred within 4 months after CAR T-cell infusion(CTI). The duration of infection-free survival was positively correlated with progression-free survival of patients with R/R MM (R2 = 0.962, p < 0.001) and the first infection event was closely accompanied by the disease relapse or progression. Treatment lines (p = 0.05), duration of ANC<500 cells/mm3 after CTI (p = 0.036), CRS grade (p = 0.007) and treatment response (p < 0.001) were the independent risk factors associated with infection for a multivariable model. The infection incidence was higher in patients with dual CAR T-cell therapy than with mono CAR T-cell therapy18 months after CTI although no statistic differences were observed within 18 months. Infections after CTI were closely associated with more lines of prior treatment, longer duration of ANC<500 cells/mm3, higher grade CRS and poor treatment response. Infections tended to occur in the early stage after CTI in patients with more lines of prior treatment and higher grade CRS. [ABSTRACT FROM AUTHOR]

In this study, a variety of boron nitride (BN) modified BiVO 4 (BN–BiVO 4) composites with visible-light response were prepared and used to degrade tetracyclines (TCs), including tetracycline (TC) and oxytetracycline (OTC). When treating the TCs solution under visible light irradiation, 4BN-BiVO 4 displayed high photocatalytic performance (87.1% for TC and 86.2% for OTC), which were 3.6 and 2.3 times than that of BiVO 4 , respectively. Photoluminescence spectroscopy (PL) and transient photocurrent proved that the combination of BN and BiVO 4 effectively promotes the efficient separation of photogenerated electrons and holes in the material, resulting in enhanced photocatalytic activity. Further, radical trapping experiments in combination with electron spin resonance (ESR) revealed that ·OH radicals and holes were the predominant reactive species. Ultimately, the possible photocatalytic mechanism for TCs degradation was proposed on the basis of the experiments and characterization analysis. This study offers a new promising approach for the design of photocatalysts with visible-light response for efficient TCs elimination. [Display omitted] • The novel BN-BiVO 4 photocatalysts were successfully prepared for the first time. • ·OH and h+ are responsible for TCs photodegradation by 4BN-BiVO 4. • The mechanism of TCs photodegradation was well discussed. • The separation of photogenerated carriers lead to high efficiency. [ABSTRACT FROM AUTHOR]

Triclocarban (TCC), an emerging contaminant in water environments, its effects on freshwater biofilms remain insufficiently understood. This study investigates the effects of TCC exposure (at concentrations of 10 μg L−1 and 10 mg L−1) on mature freshwater biofilms. TCC was found to inhibit biofilm activity as evidenced by changes in surface morphology and the ratio of live/dead cells. Moreover, both concentrations of TCC were observed to modify the structure of the biofilm community. Metabolomics analysis revealed an overlap in the toxicity mechanisms and detoxification strategies triggered by various concentrations of TCC in biofilms. However, the higher toxicity induced by 10 mg L−1 TCC resulted from the downregulation of proline betaine, disrupting the homeostasis of cellular osmotic pressure regulation in biofilms. Notably, lipid and lipid-like molecules showed high sensitivity to different concentrations of TCC, indicating their potential as biomarkers for TCC exposure. Annotation of the differential metabolites by KEGG revealed that alterations in amino acid and carbon metabolism constituted the primary response mechanisms of biofilms to TCC. Moreover, the biofilm demonstrated enhanced nucleic acid metabolism, which bolstered resistance against TCC stress and heightened tolerance. Furthermore, elevated TCC concentrations prompted more robust detoxification processes for self-defense. Overall, short-term exposure to TCC induced acute toxicity in biofilms, yet they managed to regulate their community structure and metabolic levels to uphold oxidative homeostasis and activity. This research contributes to a deeper comprehension of TCC risk assessment and policy control in aquatic environments. [Display omitted] • The structure of C-cycling bacteria communities was damaged by triclocarban (TCC). • Rhizobiales were key bacterial communities in biofilm resistance to TCC stress. • Biofilm primarily responded to TCC via changes in amino acid and carbon metabolism. • The unique toxicity of 10 mg L−1 TCC downregulates proline betaine. • Biofilms enhanced nucleic acid metabolism to resist TCC stress. [ABSTRACT FROM AUTHOR]

• A high incidence of coagulation disorders was observed after chimeric antigen receptor (CAR)-T cell therapy infusion. • The changes of coagulation parameters were associated with cytokine release syndrome (CRS). • Disseminated intravascular coagulation was found in patients with severe CRS and indicated a poor prognosis. • Coagulation disorders are manageable in most patients after CAR-T cell infusion. Chimeric antigen receptor (CAR)-T cell therapy, a new immunotherapy for relapsed and refractory (R/R) hematologic malignancies, can be accompanied by adverse events, including coagulation disorders. Here, we performed a comprehensive analysis of coagulation parameters in 100 patients with R/R hematologic malignancies after receiving CAR-T cell therapy to illuminate the profiles of coagulation disorders and to facilitate the management of coagulation disorders. A high incidence of coagulation disorders was observed, including elevated D-dimer (50/100, 50%), increased fibrinogen degradation product (45/100, 45%), decreased fibrinogen (23/100, 23%), prolonged activated partial thromboplastin time (16/100, 16%), and prolonged prothrombin time (10/100, 10%). Coagulation disorders occurred mainly during day 6 to day 20 after CAR-T cell infusion. The changes in coagulation parameters were associated with high tumor burden in acute lymphoblastic leukemia, more lines of prior therapies, lower baseline platelet count, and especially cytokine release syndrome (CRS). Disseminated intravascular coagulation (DIC) was found in 7 patients with grade ≥3 CRS and indicated a poor prognosis. Our study suggests that coagulation disorders are manageable in most patients after CAR-T cell therapy. Coexistence of DIC and severe CRS is closely related to nonrelapsed deaths during the acute toxicity phase, and effective and timely treatment is the key to reduce nonrelapse mortality for patients with DIC and severe CRS. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by immune-mediated platelet destruction, leading to lower platelet count. Thalidomide is considered as a novel immunomodulatory drug for treating several autoimmune diseases. Whether thalidomide can ameliorate ITP remains unclear. This study aims to evaluate the effect of thalidomide on ITP mouse model. ITP mouse model was established through intraperitoneal injection of rat anti-mouse integrin GPIIb/CD41 immunoglobulin. Thalidomide (10, 20 or 50 mg/kg body weight) was intraperitoneally injected into mice followed by antibody injection. Then, peripheral blood and plasma was isolated for analysis of platelet count and the level of IFN-γ and IL-17 in plasma. Meanwhile, spleen was extracted to measure the expression of CD68, a macrophage marker. In addition, macrophage cell line RAW264.7 was cultured and treated with thalidomide followed by analysis of cell viability, apoptosis as well as cell cycle. Thalidomide prevented antiplatelet antibody-mediated platelet destruction in ITP mouse model. Compared with vehicle (phosphate-buffered saline), thalidomide significantly inhibited the secretion of IFN-γ and IL-17 in ITP mouse and reduced the expression of CD68 in spleen. After thalidomide treatment, the cell viability of RAW264.7 cell was significantly reduced and the cell number in S phase was also significantly decreased. In addition, the expression of cyclin E2 was significantly reduced. In conclusion, thalidomide prevents antiplatelet antibody-mediated platelet destruction in ITP mouse possibly through reducing the number of macrophages, suggesting that it might be a novel approach for treating ITP. • Thalidomide prevented antibody-mediated platelet destruction in ITP mice. • Thalidomide reduced level of IFN-γ, IL-17 and CD68 in ITP mice. • Thalidomide reduced RAW264.7 cell viability and cell numbers in S phase. • Thalidomide decreased cyclin E2 expression. [ABSTRACT FROM AUTHOR]

Coordinating order acceptance decisions with production scheduling to maximize revenue is challenging for Mass Individualized Prototyping (MIP) service providers. This paper presents a dual deep reinforcement learning agents-based (DDRLA) integrated order acceptance and scheduling (IOAS) for improving revenue. Firstly, a deep reinforcement learning-based virtual production scheduling (VPS) agent together with 8 state features and 11 action rules is designed. The VPS agent quickly and virtually reschedules a dynamically-arriving accepted order to evaluate the overall impact of accepting this order, including consumed capacity and increased revenue. Then, a deep reinforcement learning-based order acceptance decision (OAD) agent is designed. Based on the information guidance resulting from an interaction with the VPS agent, the OAD agent selectively accepts orders to maximize long-term gains, as well as to improve system resilience in the presence of a high ratio of urgent orders. The experiment results show that the proposed DDRLA method has better performance, compared with other IOAS approaches. [ABSTRACT FROM AUTHOR]

• PAK1 was activated in MPN patients or murine MPN cells with MPLW515L mutant gene. • PAK1 inhibitors reduced the growth of megakaryocytes. • Inhibition of PAK1 alleviated the symptoms of MPN mice by targeting megakaryocytes. Most thrombopoietin receptor (MPL) mutations result in abnormal megakaryocyte expansion in the spleen or bone marrow (BM), leading to progressive fibrosis. It has been reported that p21 (Rac Family Small GTPase 1 [RAC1])-activated kinase 1 (PAK1) participates in the proliferation and differentiation of megakaryoblasts. PAK1 phosphorylation increased in patients with myeloproliferative neoplasms (MPNs) and murine MPN cells with the Mplw515l mutant gene in this study; however, the function of overactivated PAK1 in MPN cells remains unclear. We found that inhibition of PAK1 caused significant changes in the biological behaviors of MPLW515L mutant cells in vitro, including arrested growth or reduced clonality and increased polyploid DNA and cell apoptosis due to upregulated cleaved caspase 3. In vivo, PAK1 inhibitor treatment caused a slow elevation of leukocytosis and hematocrit (HCT) and a reduction in hepatosplenomegaly in 6133/MPLW515L-transplanted mice, along with reduced tumor cell infiltration and prolonged survival. Further, deletion of PAK1 sustained a relatively normal HCT and platelet count at the beginning of the disease but did not completely alleviate the splenomegaly of MPLW515L mutant mice. Notably, PAK1 knockout attenuated the destruction of splenic structure, and reduced the megakaryocyte burden within the BM. These results suggest that inhibition of PAK1 may be a useful method for treating MPLW515L mutant MPN by intervening megakaryocytes. [ABSTRACT FROM AUTHOR]

Abstract Defect of thymus results in poor posttransplant immune recovery and dysfunction of immune tolerance after allogeneic hematopoietic cell transplants (allo-HCT). Improving thymus regeneration represents a potential strategy to accelerate recovery of T-cell immunity. IL-22 was reported to mediate thymus regeneration after injury. In this study, we found donor T-cell is a major source of IL-22 in allotransplant recipient. Through applying IL-22 knock out (IL-22KO) mice in allo-HCT, we found donor T-cell derived IL-22 promotes thymus regeneration in association with increased level of intra-thymic IL-22. IL-22KO T-cell-transplanted recipients show deficient thymus recovery which is reversed by injection of exogenous IL-22. T-cell derived IL-22 promotes proliferation of thymic epithelial cells (TECs) in vitro. In addition, donor T-cell derived IL-22 increases expression level of Aire in the thymus and decreases skin chronic graft-versus-host disease (GVHD). Furthermore, short-term use of exogenous IL-22 posttransplant accelerates recovery of thymus without increasing severity of acute GVHD. Our data indicate that cross-talk between T-cell and TECs is an important mechanism to mediate reconstitution of T-cell immunity after allo-HCT. Highlights • Donor T-cell derived IL-22 promotes thymus regeneration of allotransplant recipient. • Donor T-cell derived IL-22 promotes proliferation of thymic epithelial cells. • Donor T-cell derived IL-22 decreases skin chronic graft-versus-host disease. [ABSTRACT FROM AUTHOR]

Abstract Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disease, characterized by accelerated platelet destruction/clearance or decreased platelet production. ADAM17-mediated platelet receptor GPIbα extracellular domain shedding has been shown to be involved in platelet clearance. Whether GPIbα shedding participates in the pathogenesis of ITP remains poorly understood. This study aims to investigate the role of GPIbα shedding in the development of ITP via incubating normal platelets with ITP plasma to mimic ITP in vivo environment. Plasma was isolated from ITP patients or healthy control and incubated with platelets in vitro followed by measuring GPIbα expression by flow cytometry and western blot, ADAM17 expression by western blot, ROS generation and platelet activation by flow cytometry. Compared with control plasma, ITP plasma-treated platelet displayed significantly reduced GPIbα surface expression, increased ADAM17 expression and ROS generation. However, metalloproteinase inhibitor GM6001 blocked the ITP-plasma-induced decrease in GPIbα surface expression, increase in ADAM17 expression and platelet activation. In addition, inhibitors of NADPH oxidase or mitochondria respiration significantly inhibited ROS generation from ITP plasma-treated platelets. Moreover, ROS inhibition or blocking FcγRIIa attenuated the decrease in GPIbα surface expression, platelet activation and ROS generation (for blocking FcγRIIa) in ITP plasma-treated platelets. In conclusion, ITP plasma induces platelet receptor GPIbα extracellular domain shedding, suggesting that it might participate in the pathogenesis of ITP and targeting it might be a novel approach for treating ITP. Highlights • ITP plasma induced normal platelet GPIbα shedding and ADAM17 upregulation. • ITP plasma triggered normal platelet intracellular ROS generation. • ROS inhibition blocked ITP plasma-induced GPIbα shedding. • Blocking FcγRIIa inhibited ITP plasma-induced GPIbα shedding. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important curative therapy for patients with leukemia. However, relapse remains the leading cause of death after transplantation. In recent years, substantial progress has been made by Chinese physicians in the field of establishment of novel transplant modality, patient selection, minimal residual disease (MRD) monitoring, and immunological therapies, such as modified donor lymphocyte infusion (DLI) and chimeric antigen receptor T (CART) cells, as well as MRD-directed intervention for relapse. Most of these unique systems are distinct from those in the Western world. In this consensus, we reviewed the efficacy of post-HSCT relapse management practice from available Chinese studies on behalf of the HSCT workgroup of the Chinese Society of Hematology, Chinese Medical Association, and compared these studies withthe consensus or guidelines outside China. We summarized the consensus on routine practices of post-HSCT relapse management in China and focused on the recommendations of MRD monitoring, risk stratification directed strategies, and modified DLI system. This consensus will likely contribute to the standardization of post-HSCT relapse management in China and become an inspiration for further international cooperation to refine global practices. [ABSTRACT FROM AUTHOR]

Highlights • NLRP3 knockout mice were used as recipients in an allo-HCT model. • NLRP3 knockout reduced hepatic graft-versus-host-disease after allo-HCT. • NLRP3 knockout reduces IL-1β, TNF-α, adenosine triphosphate, and NLRP1a levels, which could protect the liver. Abstract NLRP3 is associated with multiple risks in graft-versus-host disease, though unifying principles for these findings remain largely unknown. To explore the effects and mechanisms of the absence of NLRP3 function on hepatic graft-versus-host-disease, we established an allogeneic hematopoietic cell transplantation mice model by infusing bone marrow mononuclear cells and spleno-T cells of the BALB/c mouse into either NLRP3 knockout (NLRP3−/−) or wild-type C57BL/6 mice. Elevated inflammatory cell infiltration, liver fibrosis, and secretions of alanine aminotransferase (ALT) and aspartate transaminase (AST), together with weight loss, were observed in C57BL/6 recipients after transplantation. However, moderate injury pathology was detected in the liver of NLRP3−/− recipients at day 14, which gradually improved over time. Likewise, proinflammatory cytokine IL-1β, a downstream effecter of NLRP3 inflammasome activation, showed significantly lower expression (P <.05) in the liver of NLRP3−/− recipients relative to C57BL/6 recipients at day 7 and day 21. Moreover, compared with C57BL/6 recipients, the expression of both TNF-α and IL-1β were decreased 3-fold and 4.7-fold, respectively, at day 21 in NLRP3−/− recipients. Interestingly, NLRP1a was expressed at a significantly reduced level in the liver of NLRP3−/− recipients (P <.001). Furthermore, systemic inflammation was analyzed by measuring the concentration of IL-1β and adenosine triphosphate (ATP) in serum. The concentration of IL-1β achieved a maximum at day 14, then decreased at day 21 and day 28 in NLRP3−/− recipients. In contrast, the concentration of IL-1β in C57BL/6 recipients gradually increased from day 7 to day 28. ATP levels reduced from day 7 to day 28 in NLRP3−/− recipients, but were extremely high in C57BL/6 recipients from day 14 to day 28 (P <.01). The decreased levels of P2X7R were connected to less ATP in NLRP3−/− recipients at day 21 and day 28. In conclusion, NLRP3 knockout in recipients could significantly relieve liver injury after transplantation and block the NLRP3 inflammasome pathway, thus providing a promising strategy for the treatment of graft-versus-host disease prophylaxis. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an extremely serious plasma cell malignancy. Despite the recent introduction of chemotherapies such as bortezomib and lenalidomide, it remains an incurable disease due to the high rate of relapse and the development of drug resistance. Epigenetic regulation is closely related to MM progression, but the epigenetic modification mechanism of MM cell apoptosis has remained unclear. As a novel histone deacetylase inhibitor (HDACi), Scriptaid's possible roles in MM progression have not been explored. Herein, we found that Scriptaid decreased several human MM cell viabilities in a dose-dependent manner. Scriptaid was also able to dose dependently and significantly induce MM cell cycle arrest at the G 2 /M phase. Moreover, Scriptaid facilitates p21 transcriptional activities by mediating H3Ac gene-activated modification, eventually leading to MM cell apoptosis. Overall, our results show that Scriptaid is an inducer of MM cell death, suggesting the possibility for Scriptaid-mediated therapeutics to cure refractory/relapsed MM. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is an autoimmune disease, which is characterized by abnormal of T immunity. A disintegrin and metalloproteinase (ADAM) 10, a member of proteinase family, has been demonstrated to regulate T cell proliferation and effector function. Considering the closely association of dysregulation of T cell function with ITP, whether ADAM10 involves in the pathogenesis of ITP remains unclear. In this study, 54 active ITP patients, 18 ITP in remission and 24 age and gender matched healthy control were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated from patients and control for isolation of RNA and plasma which were used to measure mRNA level of ADAM10 and tissue inhibitor of metalloproteinase 3 (TIMP3) by quantitative real-time PCR and soluble level of FasL and lymphocyte activation gene-3 (LAG-3) in plasma by ELISA. Meanwhile, T cell activation was measured by flow cytometry. Our results showed significantly higher expression of ADAM10 and lower expression of TIMP3 in active ITP patients compared with control, which were all restored into normal level in remission patients. Consistent with the expression profile of ADAM10, increased soluble plasma level of FasL and LAG-3 were observed in active ITP patients and reduced to normal level in patients in remission. Furthermore, increased T cell activation as demonstrated by higher expression of HLA-DR and CD69 were found in active ITP patients. In conclusion, elevated expression of ADAM10 was associated with the pathogenesis and development of ITP and therapeutically targeting it might be a novel approach for the treatment of ITP. [ABSTRACT FROM AUTHOR]

BCR/ABL tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis for in dividuals with chronic myeloid leukemia (CML). However, many patients treated with TKIs suffer from TKI-related complications. In particular, vascular events such as peripheral artery occlusive disease have become aserious clinical problem for patients who receive the TKI, nilotinib. At present, the molecular mechanisms by which TKIs cause vascular endothelial cell insults remain unknown.This study explored the effects of the TKIs, imatinib, nilotinib and dasatinib, on vascular endothelial cells in vitro , and found that only nilotinib induced expression of interleukin-1β ( IL-1β ) by vascular endothelial cells. Nilotinib-induced IL-1β expression stimulated the adhesion of monocytes to vascular endothelial cells in association with an increase in levels of adhesion molecules. MicroRNA database searching identified miR-3121-3p binding sites in the 3′-UTR of the IL-1β gene. Exposure of endothelial cells to nilotinib caused downregulation of miR-3121-3p in these cells. Importantly, forced-expression of miR-3121-3p counteracted nilotinib-induced expression of IL-1β . Importantly, serum levels if IL-1β were significantly elevated in CML patients receiving nilotinib (n = 14) compared to those receiving other TKIs (n = 16) (3.76 ± 1.22 pg/ml vs 0.27 ± 0.77 pg/ml, p < 0.05). Taken together, our data suggest that nilotinib decreases levels of miR-3121-3p resulting in an increase in expression of IL-1β and adhesion molecules in vascular endothelial cells. The miR-3121-3p/ IL-1β axis could be a potential target to prevent vascular events in CML patients with high risk of vascular events. [ABSTRACT FROM AUTHOR]

Thrombomodulin (TM) exerts anti-inflammatory functions. We previously found that recombinant human soluble TM alleviated murine graft-versus-host disease (GVHD). Nevertheless, it is unclear how TM mediates its anti-inflammatory functions in GVHD. Here, we identified G-protein coupled receptor 15 (GPR15) expressed on T cells as a receptor/sensor of TM. The fifth region of epidermal growth factor–like domain of TM (TME5) bound GPR15 in vitro. TME5 prolonged survival of mice undergoing acute GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TME5 increased regulatory T cells (Tregs) but decreased Th 1 proportions in targeted organs. TME5 suppressed allo-reaction in vitro in association with an increase in the number of induced Tregs. However, the anti-inflammatory function of TME5 was abolished when GPR15 knockout T cells were used as donor T cells. We further found that TME5 suppressed production of IL-6 in T cells, which probably facilitated differentiation of Tregs. Moreover, TME5 reduced activation of bone marrow–derived dendritic cells (BMDCs) and hampered function of BMDCs in inducing allo-reaction in vivo and in vitro. Our findings suggested that inducing Tregs as well as blocking activation of DCs in vivo by using TME5 is a potential therapeutic option for preventing GVHD in allo-HSCT. [ABSTRACT FROM AUTHOR]

This study aimed to investigate a novel delivery system for salazosulfapyridine (SASP) through encapsulation in 2,6-dimethyl-β-cyclodextrin (DMβCD) and further incorporation in chitosan (CS) to form nanoparticles (NPs). The inclusion complex of SASP and DMβCD was prepared at 1:1 host–guest stoichiometry based on Job’s plot and then characterized through various analytical techniques. Then, the DMβCD/SASP inclusion complex was incorporated in CS to form DMβCD/SASP/CS NPs. The loading efficiency of SASP in the DMβCD/SASP/CS NPs was significantly higher than that of the SASP/CS NPs. A positive zeta potential of +35.4 mV was also observed in the DMβCD/SASP/CS NPs with an average size of 90 nm. SASP exhibited a sustained release after the DMβCD/SASP/CS NPs were formed. The toxicity of the NPs to LO2 cells was lower than that of free SASP. Therefore, the CD inclusion complex-loaded CS NPs can be applied to deliver hydrophobic drugs. [ABSTRACT FROM AUTHOR]

Fatty acid metabolism contributes to energy supply and plays an important role in regulating immunity. Free fatty acids (FFAs) bind to free fatty acid receptors (FFARs) on the cell surface and mediate effects through the intra-cellular FFAR signaling pathways. FFAR4, also known as G-protein coupled receptor 120 (GPR120), has been identified as the primary receptor of omega-3 polyunsaturated fatty acids (ω-3 PUFAs). FFAR4 is a promising target for treating metabolic and inflammatory disorders due to its immune regulatory functions and the discovery of highly selective and efficient agonists. This review summarizes the reported immune regulatory functions of ω-3 PUFAs and FFAR4 in immune cells and immune-related diseases. We also speculate possible involvements of ω-3 PUFAs and FFAR4 in other types of inflammatory disorders. [ABSTRACT FROM AUTHOR]

The supramolecular interaction between salazosulfapyridine (SASP) and hydroxypropyl-β-cyclodextrin (HP-β-CD), as well as the influence of HP-β-CD on SASP’s binding to human serum albumin (HSA), were investigated. Phase-solubility studies indicate that the HP-β-CD/SASP inclusion complex was formed at a 1:1 host–guest stoichiometry with high stability constant. The HP-β-CD/SASP complex, which was characterized by various techniques, exhibited markedly improves aqueous solubility of SASP. The binding of SASP with HSA in the presence and absence of HP-β-CD were investigated. The Stern–Volmer quenching constant and binding constant of SASP with HSA were found to be smaller in the presence of HP-β-CD. The Förster distance between the donor and the acceptor is altered in the presence of HP-β-CD. These results exhibited that the HP-β-CD reduced the quenching and binding of SASP on HSA. Molecular modeling is used to optimize the sites and mode of binding of SASP with HSA. [ABSTRACT FROM AUTHOR]