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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]

Regulating electron density at active sites holds profound importance in the advancement of highly efficient photocatalysts for hydrogen peroxide (H 2 O 2) production. In this study, a novel and stable multiphasic BiFeO 3 /MoSe 2 -1 T/2 H (BFO/MSe) catalyst with selenium (Se) sites, was successfully synthesized. This catalyst exhibited distinctive multiphasic structures and an abundance of active sites, showcasing unexpectedly high activity and stability within photocatalytic systems. Notably, the optimized 4BFO/MSe demonstrated an outstanding catalytic rate for H 2 O 2 production (1640 μmol•g−1•h−1). The spontaneously generated internal electric field facilitated charge transport, which enhanced the photocatalytic property. Moreover, the characteristics of multiphasic structures further facilitated efficient charge transfer and conduction, providing active sites. Furthermore, the electron-deficient Se sites (Seδ+) within the BFO/MSe catalysts accelerated the redox cycling of transition metals, thereby accelerating the production of reactive oxygen species. By employing multiphasic engineering and Se sites, the potential applications of catalysts in H 2 O 2 production can be effectively broadened. [Display omitted] • The multiphasic BFO/MSe catalyst with selenium (Se) sites was synthesized. • 4BFO/MSe exhibited excellent photocatalytic activation for H 2 O 2 production. • The internal electric field in BFO/MSe boosted charge separation confirmed. • The incorporation of Se sites augmented the adsorption of O 2 on active sites. [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]

Preparing active pharmaceutical ingredients (APIs) by designing methods with the concept of "green production" is challenging. In this study, an efficient mechanochemical salinization method was developed to prepare trelagliptin succinate (TRE-S), the first once-weekly oral treatment drug for type II diabetes. Trelagliptin (TRE), trelagliptin ethanol solvate (TRE-Et), trelagliptin methanol solvate (TRE-Me), and TRE-S were prepared and characterized via different analytical techniques. Various trelagliptin solid forms were assessed to verify the efficacy of forming TRE-S by the milling method. Intriguingly, TRE-S could be obtained by milling trelagliptin solvates and succinic acid (SA) with a mole ratio of 1 : 1. However, only amorphous solid forms were obtained by milling the mixture of TRE and SA. Liquid-assisted grinding of TRE and SA with ethanol or methanol could also prepare TRE-S. We have attempted to unearth the reaction mechanism for the formation of TRE-S via the ball-milling method. This work illustrates that similar intermolecular interactions in crystals and any factor inducing proton transfer have a vital role in the formation of API salts by mechanochemistry. [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]

Engraftment of hematopoietic stem cells (HSCs) is a pre-requisite for the success of hematopoietic stem cell transplantation (HSCT). Fetal blood cell (FBC)-derived endothelial progenitor cells (EPCs) are known to facilitate HSC reconstitution in the early phase. However, longer term effects on HSCs remain unclear. The purpose of this study was to evaluate the effect of EPCs on the quality of transplanted hematopoietic stem cells in mouse HSCT model. BALB/c mice were randomly divided into four groups, namely, control, total body irradiation only, HSCT, and HSCT + EPCs (with infusion of 5 × 105 EPCs). Mice was sacrificed on days 7, 14, 21, and 28 post-HSCT for the analysis of the bone marrow pathology by H&E staining, measurement of c-kit+sca-1+, c-kit+, apoptosis, and necrosis by flow cytometry as well as colony formation assay. Secondary transplantation involved the injection of transplanted BALB/c-derived HSCs into new TBI-treated BALB/c mice. Compared with HSCT, EPCs infusion promoted the differentiation and reduced apoptosis of transplanted HSCs, possibly through promotion of vascular repair of the bone marrow microenvironment via differentiation into the bone marrow endothelial cells. Significantly, EPCs' effect on HSCs was maintained for a long period as demonstrated using a secondary transplantation approach. These data revealed EPCs improved the quality and quantity of transplanted HSCs and maintained their effects over the longer term, suggesting a novel approach to improve HSCT efficiency and outcomes. [ABSTRACT FROM AUTHOR]

In this study, the amorphization of glipizide was systematically investigated through high-energy ball milling at different temperatures. The results of solid-state amorphization through milling indicated that glipizide underwent direct crystal-to-glass transformation at 15 and 25 °C and crystal-to-glass-to-crystal conversion at 35 °C; hence, milling time and temperature had significant effects on the amorphization of glipizide, which should be effectively controlled to obtain totally amorphous glipizide. Solid forms of glipizide were detailedly characterized through analyses of X-ray powder diffraction, morphology, thermal curves, vibrational spectra, and solid-state nuclear magnetic resonance. The physical stability of solid forms was investigated under different levels of relative humidity (RH) at 25 °C. Forms I and III are kinetically stable and do not form any new solid-state forms at various RH levels. By contrast, Form II is kinetically unstable, undergoing direct glass-to-crystal transformation when RH levels higher than 32.8%. Therefore, stability investigation indicated that Form II should be stored under relatively dry conditions to prevent rapid crystallization. High temperatures can also induce the solid-state transformation of Form II; the conversion rate increased with increasing temperature. [ABSTRACT FROM AUTHOR]

A new polymorph of glipizide was obtained through environmentally friendly approaches without using any organic solvent. This polymorph exhibits enhanced apparent solubility, dissolution rates, stability, and powder liquidity compared with the reported solid forms. [ABSTRACT FROM AUTHOR]

Two phase-pure solid forms of tauroursodeoxycholic acid (TUDCA) were prepared and characterized by thermal analysis, vibrational spectroscopy, X-ray diffraction, solid-state nuclear magnetic resonance, and morphological analysis. All solid forms can be produced from solvents and also can be obtained by mechanically and non-mechanically activated polymorph conversion. Near-infrared (NIR) spectroscopy, in combination with chemometrical techniques, was used for the quantitative monitoring of the polymorph conversion of TUDCA in milling process and at different storage temperatures. The NIR spectra in the range of 7139–5488 cm −1 were considered for multivariate analysis. Results demonstrated that the NIR multivariate chemometric model can predict the percentage of crystal and amorphous TUDCA with the correlation coeffcient of 0.9998, root mean square error of calibration of 0.740%, root mean square error of prediction of 0.698%, and root mean square error of cross-validation of 1.49%. In the milling process of crystal TUDCA (Form I), a direct transformation from crystal to glass was observed in 4 h. Moreover, the impact of different storage temperatures on the stability of amorphous TUDCA was investigated, and the rate of polymorph transformation was found to be accelerated with increasing temperature. [ABSTRACT FROM AUTHOR]

B cell maturation antigen (BCMA)-targeted immunotherapy has shown unprecedented results in the treatment of relapsed or refractory (R/R) multiple myeloma (MM). However, disease progression remains an issue attributed to variable BCMA expression, BCMA downregulation, and heterogeneity of tumor antigens in MM. Therefore, additional treatment options with novel therapeutic targets are warranted. G protein-coupled receptor, class C group 5 member D (GPRC5D), an orphan receptor expressed on malignant plasma cells with limited expression in normal tissue, has emerged as a promising therapeutic target for R/R MM. GPRC5D-targeted chimeric antigen receptor (CAR)-T and CAR-NK cell therapy, as well as bispecific T cell engagers, offer remarkable anti-tumor activities. We summarized some latest reports on GPRC5D-targeted treatments for R/R MM from the 2022 ASH Annual Meeting (ASH 2022). [ABSTRACT FROM AUTHOR]

A surface molecular imprinting technique was used to prepare a novel molecularly imprinted polymer using urea as the template molecule, chitosan as the functional matrix, epichlorohydrin as the cross-linker, and formaldehyde as the amino-protecting agent. Infrared analysis of the polymer confirmed that urea was successfully imprinted on cross-linked chitosan. On the basis of a single-factor test, Box–Behnken central composite experimental design and response surface methodology were used to optimize the preparation conditions. The optimum preparation conditions included 0.05 mL of acetic acid, 0.79 g of urea, a pre-polymerization time of 2.41 h, 1.63 mL of epichlorohydrin, and 0.6 g of chitosan. The predicted maximum adsorption capacity of urea (9.53 mg/g) was consistent with the experimental value (9.61 ± 0.16 mg/g), which confirmed the accuracy of the response surface method to optimize the preparation conditions of molecularly imprinted polymer. The recycling rate of the molecularly imprinted polymers was up to 84.6%. The molecularly imprinted polymer was used to adsorb urea from a serum sample. The adsorption efficiency had a maximum value of 54.51%. [ABSTRACT FROM PUBLISHER]

[Display omitted] • The ErCN/BCNQDs photocatalysts were successfully prepared for the first time. • ErCN/BCNQDs showed enhanced photocatalytic activity. • The mechanism of TC photodegradation was well discussed. A series of Er-doping g-C 3 N 4 /boron carbon nitride quantum dots (ErCN/BCNQDs) is synthesized for the first time. The prepared ErCN/BCNQDs are used for the degradation of tetracycline (TC) under visible light and results show that the degradation rate of ErCN/BCNQDs photocatalyst can reach 93%. The materials were characterized by XRD, SEM, TEM, EDS, mapping, UV–Vis DRS and PL spectra. The significant photocatalytic ability can be attributed to the doping of Er and the introduction of BCNQDs, which increases the number of effective photogenerated electrons and holes, inhibiting the binding of photogenerated carriers. [ABSTRACT FROM AUTHOR]

A highly efficient, simple and rapid method, injection-ultrasound-assisted emulsification microextraction based on using low-density organic solvents followed by high-performance liquid chromatography-ultraviolet detection, was developed for the determination of trace level pyrethroids in water samples. Various parameters influencing the extraction efficiency, such as type of extractant, extractant volume, ultrasonic time, centrifugation time and salt addition, were studied and optimized by two methods: the single factor experiment and the Box–Behnken design. Under the optimum conditions, great enrichment factors (678–713) and good recoveries (92.48–97.31%) were obtained for the extraction and analysis of artificial water samples. Linearity of the method for three pyrethroids was in the range of 0.11–218 μg L−1 for fenpropathrin, and 0.07–136 μg L−1 for fenvalerate and permethrin, respectively, with correlation coefficients ranging from 0.9994 to 0.9999. The limits of detection for the target analytes were 12.13 to 20.16 ng L−1, and the limits of quantification were 40.43 to 67.19 ng L−1. The recoveries of the three pyrethroids from actual water samples at three spiked levels were in the range of 83.25 to 103.3% with relative standard deviation RSDs less than 7.40%. [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]

Given its nearly ubiquitous expression on plasma cells and limited expression on essential normal tissue, the G protein-coupled receptor class C group 5 member D (GPRC5D) presents a promising opportunity for utilization as an immunotherapy target in multiple myeloma (MM). The therapeutic strategies targeting GPRC5D, such as bispecific antibodies (BsAbs), chimeric antigen receptor (CAR) T cells, and antibody–drug conjugates (ADCs), have been prominently emphasized in relapsed/refractory MM (R/R MM) in recent years. Further clinical trials are necessary to confirm the long-term efficacy of GPRC5D-targeting immunotherapies alone, explore their potentials co-targeting with other specific antigens, or investigate their combinations with existing treatments to overcome MM resistance. This review provides an overview of current research progress in GPRC5D, encompassing its biological characteristics and translational journey from laboratory to clinical application. [ABSTRACT FROM AUTHOR]

Background: Tocilizumab is commonly used for the management of chimeric antigen receptor (CAR) T‐cell therapy–associated cytokine release syndrome (CRS). However, it remains unknown whether tocilizumab or its dosage affects the efficacy and safety of CAR T‐cell therapy. The objective of this multicenter retrospective study was to explore the impact of tocilizumab on CAR T‐cell therapy. Methods: In total, 93 patients with B‐cell acute lymphoblastic leukemia (B‐ALL) receiving humanized anti‐CD19 CAR T cells were recruited from May 2016 to November 2022. Forty‐five patients received tocilizumab (tocilizumab group), whereas 48 patients did not (nontocilizumab group). Thirteen patients received >1 dose of tocilizumab. The primary end point was the effect of tocilizumab on the efficacy and safety of CAR T cells. Additionally, proliferation, killing, and cytokine assays of CAR T cells were performed in vitro in the presence of tocilizumab. Results: The median age of the patients was 33 years, with 47 males and 46 females. Patients in the tocilizumab group showed similar complete response (CR) rate, overall survival (OS), and event‐free survival (EFS) compared with the nontocilizumab group. Compared with patients who received ≤1 dose of tocilizumab, receiving >1 dose of tocilizumab did not affect their CR rate, OS, or EFS. In the tocilizumab group, all patients experienced CRS and 26.7% experienced immune effector cell–associated neurotoxicity syndrome (ICANS). In the nontocilizumab group, 64.6% of patients experienced CRS and 8.3% experienced ICANS. Up to 75% of ICANS and 87.5% of grade ≥3 ICANS occurred in the tocilizumab group. In vitro, tocilizumab did not impair the proliferation and killing effects of CAR T cells. Conclusions: Tocilizumab does not affect the efficacy of CAR T cells but may increase the likelihood of ICANS. Tocilizumab does not affect the efficacy of anti‐CD19 chimeric antigen receptor (CAR) T cells and the survival outcome of patients with B‐cell acute lymphoblastic leukemia. Tocilizumab may increase the likelihood of immune effector cell–associated neurotoxicity syndrome after CAR T‐cell therapy. [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]

NLRP6 plays a crucial role in maintaining intestinal homeostasis by regulating the interaction between the intestinal mucosa and the microbiota. However, the impact of NLRP6 deficiency on intestinal damage following hematopoietic stem cell transplantation (HSCT) remains poorly understood. In this study, we established a syngeneic HSCT mouse model using C57BL/6 mice as donors and NLRP6-/- or C57BL/6 mice as recipients. Our findings revealed that NLRP6 deficiency had minimal influence on peripheral blood cell counts and splenic immune cell proportions in transplanted mice. However, it exacerbated pathological changes in the small intestine on day 14 post-transplantation, accompanied by increased proportions of macrophages, dendritic cells, and neutrophils. Furthermore, the NLRP6 deficiency resulted in elevated expression of MPO and CD11b, while reducing the levels mature caspase-1 and mature IL-1β in the intestine. Moreover, the NLRP6 deficiency disturbed the expression of apoptosis-related molecules and decreased the tight junction protein occludin. Notably, recipient mice with NLRP6 deficiency exhibited lower mRNA expression levels of antimicrobial genes, such as Reg3γ and Pla2g2a. The short-term increase in inflammatory cell infiltration caused by NLRP6 deficiency was associated with intestinal damage, increased apoptosis, reduced expression of antimicrobial peptides, and impaired intestinal repair. Taken together, our findings demonstrate that the loss of NLRP6 exacerbates post-transplantation intestinal damage in recipient mice. [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) B-cell acute lymphoblastic leukemia (B-ALL). We present a retrospective study of 67 patients with R/R B-ALL who received anti-CD19 CAR T-cell therapy, 41 (61.2%) patients received G-CSF (G-CSF group), while 26 (38.8%) did not (non-G-CSF group). Patients had similar duration of grade 3–4 neutropenia between the two groups. The incidences of CRS and NEs were higher in G-CSF group, while no differences in severity were found. Further stratified analysis showed that the incidence and severity of CRS were not associated with G-CSF administration in patients with low bone marrow (BM) tumor burden. None of the patients with low BM tumor burden developed NEs. However, there was a significant increase in the incidence of CRS after G-CSF administration in patients with high BM tumor burden. The duration of CRS in patients who used G-CSF was longer. There were no significant differences in response rates at 1 and 3 months after CAR T-cell infusion, as well as overall survival (OS) between the two groups. In conclusion, our results showed that G-CSF administration was not associated with the incidence or severity of CRS in patients with low BM tumor burden, but the incidence of CRS was higher after G-CSF administration in patients with high BM tumor burden. The duration of CRS was prolonged in G-CSF group. G-CSF administration was not associated with the efficacy of CAR T-cell therapy. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effect of C-reactive protein (CRP) on the prognosis of adult patients with Immune thrombocytopenia purpura (ITP). A retrospective study of 628 adult ITP patients, as well as 100 healthy and 100 infected patients, attending the Affiliated Hospital of Xuzhou Medical University from January 2017 to June 2022 was performed. The ITP patients were grouped according to their CRP levels, and the differences in clinical characteristics of each group and the influencing factors of efficacy in newly diagnosed ITP patients were analyzed. CRP levels were significantly higher in the ITP and infected groups compared with healthy controls (P < 0.001), and platelet counts were significantly lower in the ITP group (P < 0.001). Between the CRP normal and elevated group, their age, white blood cell count, neutrophil count, lymphocyte count, red blood cell count, hemoglobin, platelet count, complement C3 and C4, PAIgG, bleeding score, proportion of severe ITP, and proportion of refractory ITP were significantly different (P < 0.05). Patients of severe ITP (P < 0.001), refractory ITP (P = 0.002), and with active bleeding (P < 0.001) had significantly higher CRP levels. Patients with no response after treatment had significantly higher CRP levels than those who achieved CR or R (P < 0.001). Platelet counts (r = − 0.261, P < 0.001) in newly diagnosed ITP patients and treatment outcomes (r = − 0.221, P < 0.001) were negatively correlated with CRP levels, and bleeding score was positively correlated with CRP levels (r = 0.207, P < 0.001). Treatment outcome was positively correlated with decrease in CRP levels (r = 0.313, P = 0.027). A multifactorial regression analysis of the influencing factors of treatment outcomes on newly diagnosed patients found that CRP was an independent risk factor of the prognosis (P = 0.011). In conclusion, CRP can help assess the severity and predict the prognosis of ITP patients. [ABSTRACT FROM AUTHOR]

To explore the prognostic value of red blood cell distribution width (RDW) in newly diagnosed aplastic anemia (AA) patients treated with cyclosporine A (CsA) plus androgen or CsA alone. We retrospectively analyzed the clinical outcome of 220 patients with AA. According to the baseline level of RDW before treatment, the patients were divided into the high-RDW group (RDW ≥ 15%) and the normal-RDW group (RDW < 15%). The median RDW of non-severe AA (NSAA) and severe AA (SAA) patients was 15.65% and 15.35%, respectively; this were significantly higher than that of very severe AA (VSAA) patients (13.35%). With median follow-up being 46 months, AA patients in the high-RDW group showed better 5-year OS and PFS than the normal-RDW group (93%: 75.3%; 74.3%: 61%). There was a higher ORR in the high-RDW group than the normal-RDW group (68.7%: 52.3%). The ORR of NSAA patients in the high-RDW group was better than that in the normal RDW group (75.8%: 60%). The 5-year OS of SAA/VSAA patients in the high-RDW group was significantly higher than the normal-RDW group (81.8%: 50.8%). This is the first documentation on the prognostic value of RDW in AA patients receiving CsA treatment with long-term follow-up, which had shown that high RDW at diagnosis was a better prognostic factor. [ABSTRACT FROM AUTHOR]

Clinical outcome of patients with chronic myeloid leukemia (CML) has improved dramatically since the introduction of tyrosine kinase inhibitors such as imatinib mesylate (IM). However, approximately 20-30% of patients experience IM resistance. SH-4-54, which targets the SH2 domains of both proteins STAT3 and STAT5, has been reported to exhibit anticancer activity in solid tumors. However, the roles of SH-4-54 in CML remain unclear. The aim was to explore whether SH-4-54 could overcome IM resistance and identify novel targets for CML. Cell viability was measured by CCK-8 assays after treatment of K562 and K562R cells with different concentrations of SH-4-54. Annexin V-FITC and PI were applied to assess the effects of SH-4-54 on cell apoptosis. Effects of SH-4-54 on the expression of proteins downstream of BCR::ABL1 were assessed by western blotting (WB). Effects of SH-4-54 on gene expression profile of CML cells were analyzed by Next generation sequence (NGS). SH-4-54 inhibited the growth of CML cell lines with increasing concentration. SH-4-54 cytotoxic effects correlated with a significant induction of apoptosis. The results of WB analysis showed the downstream proteins of BCR::ABL1, such as STAT3 and STAT5, decreased after SH-4-54 treatment; moreover, the phosphorylation of both proteins were inhibited in dose-dependent manner. Using NGS, we obtained Mrna expression profiles in SH-4-54 treated K562 and K562R cells and identified differentially expressed mRNAs. Among these, STAT3 and STAT5 were markedly downregulated. SH-4-54 may overcome IM resistance and represent a promising novel approach to improve the outcome of CML. [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]

Summary: Chimeric antigen receptor T (CAR‐T) cell therapy is highly effective in inducing complete remission in haematological malignancies. Severe cytokine release syndrome (CRS) is the most significant and life‐threatening adverse effect of this therapy. This multi‐centre study was conducted at six hospitals in China. The training cohort included 87 patients with multiple myeloma (MM), an external validation cohort of 59 patients with MM and another external validation cohort of 68 patients with acute lymphoblastic leukaemia (ALL) or non‐Hodgkin lymphoma (NHL). The levels of 45 cytokines on days 1–2 after CAR‐T cell infusion and clinical characteristics of patients were used to develop the nomogram. A nomogram was developed, including CX3CL1, GZMB, IL4, IL6 and PDGFAA. Based on the training cohort, the nomogram had a bias‐corrected AUC of 0.876 (95% CI = 0.871–0.882) for predicting severe CRS. The AUC was stable in both external validation cohorts (MM, AUC = 0.907, 95% CI = 0.899–0.916; ALL/NHL, AUC = 0.908, 95% CI = 0.903–0.913). The calibration plots (apparent and bias‐corrected) overlapped with the ideal line in all cohorts. We developed a nomogram that can predict which patients are likely to develop severe CRS before they become critically ill, improving our understanding of CRS biology, and may guide future cytokine‐directed therapies. [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]

Background. Cluster of differentiation 86 (CD86), also known as B7-2, is a molecule expressed on antigen-presenting cells that provides the costimulatory signals required for T cell activation and survival. CD86 binds to two ligands on the surface of T cells: the antigen CD28 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). By binding to CD28, CD86—together with CD80—promotes the participation of T cells in the antigen presentation process. However, the interrelationships among CD86, immunotherapy, and immune infiltration in acute myeloid leukemia (AML) are unclear. Methods. The immunological effects of CD86 in various cancers (including on chemokines, immunostimulators, MHC, and receptors) were evaluated through a pan-cancer analysis using TCGA and GEO databases. The relationship between CD86 expression and mononucleotide variation, gene copy number variation, methylation, immune checkpoint blockers (ICBs), and T-cell inflammation score in AML was subsequently examined. ESTIMATE and limma packages were used to identify genes at the intersection of CD86 with StromalScore and ImmuneScore. Subsequently, GO/KEGG and PPI network analyses were performed. The immune risk score (IRS) model was constructed, and the validation set was used for verification. The predictive value was compared with the TIDE score. Results. CD86 was overexpressed in many cancers, and its overexpression was associated with a poor prognosis. CD86 expression was positively correlated with the expression of CTLA4, PDCD1LG2, IDO1, HAVCR2, and other genes and negatively correlated with CD86 methylation. The expression of CD86 in AML cell lines was detected by QRT-PCR and Western blot, and the results showed that CD86 was overexpressed in AML cell lines. Immune infiltration assays showed that CD86 expression was positively correlated with CD8 T cell, Dendritic cell, macrophage, NK cell, and Th1_cell and also with immune examination site, immune regulation, immunotherapy response, and TIICs. ssGSEA showed that CD86 was enriched in immune-related pathways, and CD86 expression was correlated with mutations in the genes RB1, ERBB2, and FANCC, which are associated with responses to radiotherapy and chemotherapy. The IRS score performed better than the TIDE website score. Conclusion. CD86 appears to participate in immune invasion in AML and is an important player in the tumor microenvironment in this malignancy. At the same time, the IRS score developed by us has a good effect and may provide some support for the diagnosis of AML. Thus, CD86 may serve as a potential target for AML immunotherapy. [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]

Pillar[5]arene-functionalized rhodium nanoparticles (Rh@CPA NPs) are first synthesized via a facile one-pot chemical reduction method. Rh@CPA NPs with good reusability and biocompatibility show excellent catalytic activities in reducing toxic nitrophenols and azo dyes, and also exhibit superior photothermal ablation capability towards Staphylococcus aureus under 808 nm laser irradiation. This work suggests that the supramolecular capping strategy could be used to construct novel hybrid materials for various applications. [ABSTRACT FROM AUTHOR]

trans -N-Caffeoyltyramine (TNC), which was isolated from the Cortex Lycii in our laboratory, is a phenolic amide compound with multiple pharmacological activities. The interaction between TNC and human serum albumin (HSA) was studied by Nuclear magnetic resonance (NMR) relaxation experiment, fluorescence spectroscopy, and docking simulation. NMR methodology is based on the analysis of selective and non-selective spin-lattice relaxation rate enhancements of TNC protons in the presence of the HSA. Result indicated that the interaction occurred between HSA and TNC, and changed the proton magnetic environment of TNC. Fluorescence spectroscopy confirmed that TNC displayed a strong capability to quench the fluorescence of HSA, and the acting forces for binding were hydrogen bonds and van der Waals forces. Furthermore, the circular dichroism, synchronous, and three-dimensional fluorescence spectra, which were employed to determine the conformation of protein, revealed that binding of TNC with HSA could induce conformational changes in HSA. In addition, the molecular modeling results exhibited that TNC mainly bonded to site I in sub-domain IIA of HSA. [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]

The object of the present study was to investigate the feasibility of applying ultraviolet-visible and shortwave near-infrared diffuse reflectance spectroscopy (UV–vis–SWNIR DRS) coupled with chemometrics in qualitative and simultaneous quantitative analysis of drug polymorphs, using cimetidine as a model drug. Three polymorphic forms (A, B and D) and a mixed crystal (M1) of cimetidine, obtained by preparation under different crystallization conditions, were characterized by microscopy, X-ray powder diffraction (XRPD) and infrared spectroscopy (IR). The discriminant models of four forms (A, B, D and M1) were established by discriminant partial least squares (PLS-DA) using different pretreated spectra. The R and RMSEP of samples in the prediction set by discriminant model with original spectra were 0.9959 and 0.1004. Among the quantitative models of binary mixtures (A and D) established by partial least squares (PLS) and least squares-support vector machine (LS-SVM) with different pretreated spectra, the LS-SVM models based on original and MSC spectra had better prediction effect with a R of 1.0000 and a RMSEP of 0.0134 for form A, and a R of 1.0000 and a RMSEP of 0.0024 for form D. For ternary mixtures, the established PLS quantitative models based on normalized spectra had relatively better prediction effect for forms A, B and D with R of 0.9901, 0.9820 and 0.9794 and RMSEP of 0.0471, 0.0529 and 0.0594, respectively. This research indicated that UV–vis–SWNIR DRS can be used as a simple, rapid, nondestructive qualitative and quantitative method for the analysis of drug polymorphs. [ABSTRACT FROM AUTHOR]

Photocatalysis for H 2 O 2 production suffers from low carrier utilization and slow reaction kinetics. Herein, a photocatalytic system supported by a SrCoO 3 -MoS 2 (SCOS) heterojunction, which possessed a unique S-O electron transport channel, was proposed to facilitate H 2 O 2 production under condition where glycerol served as a sacrificial agent. The SCOS heterojunction achieved a remarkable yield of 15.90 mmol g−1 h−1 H 2 O 2 production, 3.7 times higher than the base component SCO. The construction of the heterojunction enriched the oxygen vacancies on the catalyst surface, facilitated photogenerated charge separation, and promoted the adsorption of O 2 , reducing the oxygen reduction reaction (ORR) energy barrier. Besides, glycerol served as a unique proton donor, efficiently captured holes to enhance H 2 O 2 production, and generated valuable by-products including glyceric acid and dihydroxyacetone. Furthermore, SCOS exhibited excellent stability over repeated cycles with consistent H 2 O 2 yields. This study offers an efficient photocatalytic system and demonstrates glycerol's potential in green oxidation processes. [Display omitted] • SrCoO3-MoS2 (SCOS) heterojunction significantly boosts H2O2 production efficiency. • Unique S-O electron transport channel in SCOS reduced ORR energy barrier. • SCOS achieved 15.90 mmol g−1 h−1 H2O2 production, 3.7 times the component SCO. • Glycerol used as a sacrificial agent transformed into valuable by-products. [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]

Background: Transcription factor c-Myc plays a critical role in various physiological and pathological events. c-Myc gene rearrangement is closely associated with multiple myeloma (MM) progression and drug resistance. Thereby, targeting c-Myc is expected to be a useful therapeutic strategy for hematological disease, especially in MM. Methods: Molecular docking-based virtual screening and dual-luciferase reporter gene assay were used to identify novel c-Myc inhibitors. Cell viability and flow cytometry were performed for evaluating myeloma cytotoxicity. Western blot, immunofluorescence, immunoprecipitation, GST pull down and Electrophoretic Mobility Shift Assay were performed for protein expression and interaction between c-Myc and Max. c-Myc downstream targets were measured by Q-PCR and Chromatin immunoprecipitation methods. Animal experiments were used to detect myeloma xenograft and infiltration in vivo. Results: We successfully identified a novel c-Myc inhibitor D347-2761, which hindered the formation of c-Myc/Max heterodimer and disturbed c-Myc protein stability simultaneously. Compound D347-2761 dose-and time-dependently inhibited myeloma cell proliferation and induced apoptosis. Dual knockout Bak/Bax partially restored D347-2761-mediated cell death. Additionally, compound D347-2761 could, in combination with bortezomib (BTZ), enhance MM cell DNA damage and overcome BTZ drug resistance. Our in vivo studies also showed that compound D347-2761 repressed myeloma growth and distal infiltration by downregulating c-Myc expression. Mechanistically, novel dual-targeting c-Myc inhibitor D347-2761 promoted c-Myc protein degradation via stimulating c-Myc Thr58 phosphorylation levels, which ultimately led to transcriptional repression of CDK4 promoter activity. Conclusions: We identified a novel dual-targeting c-Myc small molecular inhibitor D347-2761. And this study may provide a solid foundation for developing a novel therapeutic agent targeting c-Myc. CCo5k36iLrbCHdtx-yHunT Video Abstract [ABSTRACT FROM AUTHOR]

The use of lead-free ceramic film materials with positive temperature coefficient of resistivity (PTCR) is widespread in temperature heaters and sensors in micro-electromechanical systems. In this research, the out of plane transport properties of the BiFeO3 (BFO) films have been studied. Surprisingly, PTCR was found in the BFO ceramic films due to the strongly correlated interaction between the multiferroic material BFO and the superconductor YBCO perovskite oxides. To our knowledge, this is the first report on the PTCR effect of BFO films. The BFO/YBCO interface and the bulk conductivity of BFO are important for the PTCR effect, as they make it possible to compare the transport properties of Au/BFO/YBCO- and YBCO/BFO/YBCO-type structures. PTCR was observed in Au/BFO/YBCO at a bias voltage of more than 2 V, but not in the YBCO/BFO/YBCO, even with a 40 V bias voltage. PTCR was found after BFO breakdown of a YBCO/BFO/YBCO capacitor. This indicated that the conductivity of BFO is critical for PTCR. The dependence of PTCR on the superconducting transition temperature illustrates that a cooper-pair can be injected into BFO. Our work presents a method by which to produce a lead-free ceramic film material with PTCR. [ABSTRACT FROM AUTHOR]

The NF-κB signaling pathway is an important downstream pathway of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL) cells. However, the molecular mechanisms underlying the cascade activation of Notch1 in T-ALL cells are poorly understood. Here, we evaluated the role of CARMA1 in Notch1-induced NF-κB activation in T-ALL cells. CARMA1 was highly and specifically expressed in T-ALL cells and correlated with the prognosis of T-ALL patients. Interestingly, CARMA1 knockdown only inhibited the growth and proliferation of SIL-TAL1 fusion gene-negative T-ALL cells. In addition, CARMA1 knockdown arrested T-ALL cells at the G1 phase. Furthermore, CARMA1 knockdown significantly inhibited the proliferation of T-ALL cells in vivo and prolonged the survival of mice. Mechanistically, CARMA1 deficiency abolished Notch1-induced NF-κB transcriptional activation and significantly reduced expression levels of the NF-κB target genes c-Myc, Bcl-2, and CCR7. Taken together, these results of our study identify CARMA1 as one of the crucial mediators of Notch1-induced transformation of T-All cells, suggesting that CARMA1 is a promising therapeutic target for T-ALL due to its specific expression in lymphocytes. Key messages: CARMA1 contributes to cell survival only in SIL-TAL1 negative T-ALL cells. CARMA1 is a crucial mediator of Notch1-induced activation of NF-κB pathway. CARMA1 is a promising therapeutic target for T-ALL. [ABSTRACT FROM AUTHOR]

Introduction: Somatic mutations in the calreticulin (CALR) gene occur in most myeloproliferative neoplasm (MPN) patients who lack Janus kinase 2 or thrombopoietin receptor (MPL) mutations, but the molecular pathogenesis of MPN with mutated CALR is unclear, which limited the further treatment for CALR gene mutant patients. Objectives: Previous studies showed that CALR mutations not only activated serine/threonine protein kinase (AKT) in primary mouse bone marrow cells but also mitogen-activated protein kinases (MAPKs) in MARIMO cells harboring a heterozygous 61-bp deletion in CALR exon 9, which were responsible for mutant CALR cell survival, respectively. Hence, we aimed to initially explore the mechanism of AKT activation and observe the synergistic inhibitory effect of combining AKT (MK-2206) and MAPK kinase (AZD 6244) inhibitors in MARIMO cells. Methods: We detected the expression of phosphorylated AKT in MARIMO cells treated with inhibitors for 24 or 48 h by western blotting and analyzed cell proliferation, cell cycle, and apoptosis by flow cytometry. We further examined the synergistic inhibitory effect of combining MK-2206 and AZD 6244 in MARIMO cells using the median effect principle of Chou and Talalay. Results: We found that the AKT was activated in MARIMO cells, and blocking its activity significantly inhibited MARIMO cell growth with downregulation of cyclin D and E, and accelerated cell apoptosis by decreasing Bcl-2 but increasing Bax and cleaved caspase-3 levels in a dose-dependent manner. Further analysis showed that AKT activation was dependent on mammalian target of rapamycin but not on the JAK signaling pathway in MARIMO cells, displaying that inhibition of JAK activity by ruxolitinib (RUX) did not decrease the AKT phosphorylation. Furthermore, the combination of MK-2206 and AZD 6244 produced a significantly synergistic inhibitory effect on MARIMO cells. Conclusions: AKT activation is a feature of MARIMO cells and co-targeting of AKT and MAPKs signaling pathways synergistically inhibits MARIMO cell growth. [ABSTRACT FROM AUTHOR]

Background: Immune thrombocytopenia (ITP) is an autoimmune disease characterized as a low platelet count resulting from immune-mediated platelet destruction. Dimethyl fumarate (DMF) is widely applied for the treatment of several autoimmune diseases with immunosuppressive effect. However, whether it ameliorates ITP is unclear. This study aims to evaluate whether DMF has a preventive effect on ITP in mice. Methods: DMF (30, 60 or 90 mg/kg body weight) was intraperitoneally injected into mice followed by injection of rat anti-mouse integrin GPIIb/CD41antibody to induce ITP. Peripheral blood was isolated to measure platelet count and spleen mononuclear cells were extracted to measure Th1 and Treg cells along with detecting the levels of IFN-γ, and TGFβ-1 in plasma and CD68 expression in spleen by immuohistochemical staining. Additionally, macrophage cell line RAW264.7 was cultured and treated with DMF followed by analysis of cell apoptosis and cycle, and the expression of FcγRI, FcγRIIb and FcγRIV mRNA. Results: DMF significantly inhibited antiplatelet antibody-induced platelet destruction, decreased Th1 cells and the expression of T-bet and IFN-γ, upregulated Treg cells and the expression of Foxp3 and TGF-β1 as well as reduced CD68 expression in the spleen of ITP mouse. DMF-treated RAW264.7 cells showed S-phase arrest, increased apoptosis and downregulated expression of FcγRI and FcγRIV. Meanwhile, in vitro treatment of DMF also decreased the expression of cyclin D1 and E2, reduced Bcl-2 level and increased Bax expression and caspase-3 activation. Conclusions: In conclusion, DMF prevents antibody-mediated platelet destruction in ITP mice possibly through promoting apoptosis, indicating that it might be used as a new approach for the treatment of ITP. [ABSTRACT FROM AUTHOR]

• CRS is the most prevalent complication of CAR-T therapy. • Therapeutic plasma exchange can be a valuable and safe treatment for severe CRS caused by CAR-T cell infusion. • The temperature and inflammatory markers exhibited a significant reduction following therapeutic plasma exchange treatment. The chimeric antigen receptor T (CAR-T) cell therapy significantly enhances the prognosis of various hematologic malignancies; however, the systemic expansion of CAR-T cells also gives rise to severe cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Despite the successful application of corticosteroids and tocilizumab in alleviating severe CRS in most patients, there are still individuals who experience life-threatening CRS without responding to the aforementioned therapies. In our retrospective cohort, we conducted an analysis of clinical and laboratory parameters, including inflammatory cytokines, in 17 patients from three centers who underwent therapeutic plasma exchange (TPE) for refractory CRS with or without ICANS following CAR-T products treatment. Our findings demonstrate a significant improvement in both clinical symptoms and laboratory parameters subsequent to TPE treatment. The rapid decrease in temperature and levels of inflammatory indexes indicates the remarkable scavenging efficacy of TPE against cytokine storm following CAR-T therapy. In conclusion, TPE may serve as a valuable and safe adjunct to corticosteroids and tocilizumab in the management of severe CRS resulting from CAR-T cell infusion. We eagerly await further prospective studies to validate this finding. [ABSTRACT FROM AUTHOR]

• 1.Clod-Lip-mediated clearance of macrophages suppressed hematopoietic reconstruction. • 2. Clod-Lip-mediated clearance of macrophages inhibit hematopoietic cell homing. • 3.Clod-Lip-mediated macrophage depletion inhibit the direct supportive effect of macrophages on HSPCs cell expansion. • 4. E-selectin/ICAM-1 may be involved in the direct regulation of HSPCs. Bone marrow macrophages (Mφ) are essential components of the bone marrow niche that regulate the function of hematopoietic stem cells. Poor graft function and inhibition of hematopoietic production can result from abnormal macrophage function; however, the underlying mechanism is unclear. Clodronate liposomes (Clo-Lip) have been used widely to deplete macrophages and study their functions. Our previous results showed that Clod-Lip-mediated clearance of macrophages plays a vital role in regulating hematopoietic reconstruction after allogeneic hematopoietic cell transplantation (HCT). In this study, using an isogenic hematopoietic stem cell transplantation model, we found that Clod-Lip-mediated clearance of macrophages suppressed hematopoietic reconstruction by inhibiting the homing process of hematopoietic cells. We also demonstrated that macrophage depletion inhibited the direct supportive effect of macrophages on hematopoietic stem and progenitor cells and erythroid differentiation but promoted the production of megakaryocytic progenitors ex vivo. We showed that macrophages increase CD49e expression on hematopoietic stem and progenitor cells (HSPCs). However, CD49e inhibitors did not support the proliferative effect of macrophages on hematopoietic cells. In contrast, macrophage E-selectin/ intercellular cell adhesion molecule-1 (ICAM-1) may be involved in directly regulating HSPCs. In conclusion, macrophage depletion with Clo-Lip partially disrupts bone marrow hematopoiesis after HCT by impeding donor cell homing and macrophage-HSPCs interactions. [ABSTRACT FROM AUTHOR]

Background: In the bone marrow microenvironment (BM), endothelial cells are individual cells that form part of the sinusoidal blood vessels called the "bone marrow endothelial-vascular niche." They account for less than 2% of the bone marrow cells. They play essential functions by generating growth and inhibitory factors that promote the hematopoietic stem cells (HSCs) regulation. In response to inflammatory stimuli, the BMECs increase in proliferation to maintain the blood vessels' integrity within the BM. The inflammatory response releases cytokines such as tumor necrosis factor-alpha (TNF-α) that promote vascular endothelial cells' expansion and upregulation of adhesion molecules (ICAM-1 and VCAM-1, respectively) in the BM. However, the evaluation of mouse BMECs in the bone marrow microenvironment is scared by a lack of mouse bone marrow endothelial cell primary culture Methods: Two steps approach for isolation of bone marrow endothelial cells (BMECs) from mice. In brief, the bone marrow cells extracted from the mice long bones were cultured overnight with Dulbecco's modified Eagle's medium (DMEM) supplemented with 20% fetal bovine serum (FBS) and antibiotics to separate between marrow-derived adherent and non-adherent cells. The floating cells were discarded, and the adhered section detached with accutase and BMECs selected using CD31 microbeads. The isolated BMECs were cultured in a dish pre-coated with rat-tail collagen type 1 with endothelial cells medium supplement with growth factors. The cells were verified by confocal microscopy for morphology and tube formation by matrigel assay. We validate the cells' purity by flow cytometry, RT-qPCR, immunofluorescence staining, and immunoblotting by established BMEC markers, PECAM-1, VE-cadherin, vascular endothelial cell growth factor receptor-2 (VEGFR2), CD45, E-selectin, and endothelial selectin adhesion molecule (ESAM). Lastly, we characterize BMEC activation with recombinant TNF-α. Results: Our method clearly defined the cells isolated have the characteristics of BMECs with the expression of CD31, VE-cadherin, E-selectin, VEGFR-2, and ESAM. The cells' response to TNF-α indicates its inflammatory function by increasing proliferation and upregulation of adhesion molecules. Conclusions: This study outline a simple new technique of isolating mouse BMEC primary culture and a suitable method to evaluate the function and dysregulation of BMEC in in vitro studies using mouse models. [ABSTRACT FROM AUTHOR]

Introduction: Anti‐CD19 chimeric antigen receptor (CAR) ‐T cells, which recognize and kill both B lymphoblasts and normal B cells, result in B cell aplasia and humoral immunodeficiency. However, there were only a few detailed reports on the profile of immune reconstitution after anti‐CD19 CAR‐T cell therapy. Methods: Thirty nine patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL) receiving anti‐CD19 CAR‐T cell therapy were enrolled. Subjects died, relapsed, received other treatment, or lost to follow‐up within 60 days post‐infusion were excluded. 21 patients were finally selected. Laboratory and clinical data were collected for analysis of immune reconstitution. Results: CD8+ cells were the first to recover with a median time on day 21(7‐87), followed by CD16/CD56+ cells on day 28(14‐87), and finally CD4+ cells with only 5(23.81%) patients recovered within 60 days post‐infusion. CD4/CD8 ratio was inverted, sustaining for at least 1 year. B cell aplasia occurred in all patients and CD19+ cells returned to normal on a median time of day 79(41‐118). All patients developed hypogammaglobulinemia with a median onset time of 2 weeks post‐infusion. IgG recovered in 6 patients with a median time on day 184(89‐346). IgM recovered on days 212, 242, and 346 in 3 patients. IgA recovered most slowly and remained low >1 year postinfusion. A total of 9 infections occurred in 6(28.57%) patients. Conclusions: Our data showed prolonged reconstitution of immune function, especially humoral immunity, in R/R B cell ALL patients receiving anti‐CD19 CAR‐T cell therapy. [ABSTRACT FROM AUTHOR]

Clodronate-liposomes (Clod-Lip) is an effective candidate drug for treating chronic myelomonocytic leukemia, autoimmune hemolytic anemia and immune thrombocytopenic purpura in mice experiments. But its role in hematopoietic recovery after acute myelosuppression is still unknown. We aim to explore the function and underlining mechanisms of Clod-Lip on hematopoietic reconstitution after sublethal dose irradiation in mice. Mice at 8-10 weeks received a total-body sublethal dose γ-irradiation (TBI) and injected with Clod-Lip or PBS-Liposomes (PBS-Lip) every 4 days after TBI. The survival rate of each group was recorded. Flow cytometry was used to analyze changes in hematopoietic stem cells and their progenies in bone marrow. ELISA and RT-qPCR were used for the analysis of hematopoietic regulatory factors. Regarding IL-1β inhibition, 25 mg/kg diacerein or an equal volume of DMSO was intraperitoneally injected into mice every day after TBI. In sublethal dose-irradiated mice, Clod-Lip reduced the survival rate, the total number of bone marrow and hematopoietic stem cells, delayed peripheral blood recovery of red blood cells and platelets. However, it could increase the number of CMP, MEP and myeloid cells, which suggested that Clod-Lip could induce HSC to myeloid differentiation in vivo. We further verified that Clod-Lip may induce myeloid differentiation by bone marrow microenvironmental factor IL-1β. In summary, this study suggested that Clod-Lip may aggravate inhibitor effect of hematopoietic function and promote myeloid differentiation in myelosuppression mice model. [ABSTRACT FROM AUTHOR]

Prevention of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still to be explored. Statins are potent immunomodulatory agents that hold promise as novel and safe agents for aGVHD prophylaxis, yet the controversial effect and regulatory mechanism are incompletely understood. Here, in an MHC mismatched murine model, we found that Fluvastatin-pretreated donor cells could attenuate aGVHD severity by remission tissue pathological injury. Fluvastatin served to restrain effector T cells entry into aGVHD target organs from secondary lymphoid organs (SLOs). The potential mechanism of correcting the effector T cell biased distribution was that Fluvastatin elevated CD62L and CCR7 expression while decreased CXCR3 and CD44 levels, which were correlated with Kruppel-like factor 2 (KLF2) sustention in donor-derived cells. In addition, Fluvastatin was contributed to reducing cytokines IFN-γ, TNF-α, and granzyme-B production in allogeneic effector CD4+ and CD8+ T cells. Furthermore, evidence confirmed that Fluvastatin had a long-lasting effect to sustain KLF2 expression both in vitro and in vivo even under the stimulated circumstance. In conclusion, administration of Fluvastatin to donor mice showed protective effects against recipient aGVHD when compared to untreated mice due to the retention of effector T cells in lymphoid organs accompanying with reduction of nonlymphatic infiltration and related inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by lower platelet count resulting from immune cells-mediated platelet clearance. Tacrolimus is an immunosuppressive agent which selectively inhibits T cell activation. Whether tacrolimus plays a role in ITP remains unclear. This study aimed to investigate the effect of tacrolimus on ITP in mice. An ITP mouse model was established by injection of rat anti-mouse integrin GPIIb/CD41 immunoglobulin and treated with tacrolimus followed by isolation of peripheral blood mononuclear cells and plasma. The mRNA expression of T-bet, GATA3, and Foxp3 was measured by RT-PCR, and level of IFN-γ, IL-12p70, IL-4, IL-13, and TGF-β in plasma was measured by ELISA. Tacrolimus inhibited antiplatelet antibody-mediated platelet clearance in ITP mouse model. Meanwhile, tacrolimus-treated ITP mice displayed a significant decrease in the mRNA expression of T-bet and plasma level of IFN-γ and IL-12p70 compared with ITP mice but without differences when compared with normal mice. Furthermore, the expression of GATA3, Foxp3, and plasma level of IL-4 and TGF-β were upregulated in tacrolimus-treated ITP mice without significant differences to normal mice (except TGF-β). Tacrolimus prevents antiplatelet antibody-mediated thrombocytopenia in ITP mice possibly through regulating T cell differentiations, suggesting it might be a novel approach for preventing ITP. [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]