Reduced doses of emicizumab achieve good efficacy: Results from a national-wide multicentre real-world study in China.

INTRODUCTION: Reduced doses of emicizumab improve the affordability among patients in developing countries. However, the relationship between variant dose selection and efficacy in the real world of China is still unclear. AIM: This study aimed to investigate the efficacy and safety of emicizumab especially in those on reduced dose regimens in a real-world setting. METHODS: We carried out a multicentre study from 28 hospitals between June 2019 and June 2023 in China and retrospectively analysed the characteristics including demographics, diagnosis, treatment, bleeding episodes, and surgical procedures. RESULTS: In total, 127 patients with haemophilia A, including 42 with inhibitors, were followed for a median duration of 16.0 (IQR: 9.0-30.0) months. Median age at emicizumab initiation was 2.0 (IQR: 1.0-4.0) years. Median (IQR) consumption for loading and maintenance was 12.0 (8.0-12.0) and 4.2 (3.0-6.0) mg/kg/4 weeks, respectively. While on emicizumab, 67 (52.8%) patients had no bleeds, whereas 60 (47.2%) patients had any bleeds, including 26 with treated bleeds. Compared to previous treatments, patients on emicizumab had significantly decreased annualized bleeding rate, annualized joint bleeding rate, target joints and intracerebral haemorrhage. Different dosages had similar efficacy except the proportion of patients with treated spontaneous bleeds and target joints. Adverse events were reported in 12 (9.4%) patients. Postoperative excessive bleeding occurred following two of nine procedures. CONCLUSION: This is the largest study describing patients with HA receiving emicizumab prophylaxis on variant dose regimens in China. We confirmed that nonstandard dose is efficacious and can be considered where full-dose emicizumab is ill affordable.

Spatially Confined LiF Nanoparticles in an Aligned Polymer Matrix as the Artificial SEI Layer for Lithium Metal Anodes.

The uncontrollable growth of lithium (Li) dendrites and the instability of the Li/electrolyte interface hinder the development of next-generation rechargeable lithium metal batteries. The combination of inorganic nanoparticles and polymers as the artificial SEI layer shows great potential in regulating lithium-ion flux. Here, we design spatially confined LiF nanoparticles in an aligned polymer matrix as the artificial SEI layer. A high dielectric polymer matrix homogenizes the electric field near the surface of lithium metal. Aligned pores with LiF nanoparticles promote the lithium-ion transport across the artificial SEI layer. The synergistic effect of the highly polar ß-phase PVDF and LiF nanoparticles provides high stability over 900 h for the Li//Li symmetrical cell. Besides, a Li//LFP full battery equipped with this artificial layer shows good performance in the commercial carbonate electrolyte, demonstrating the great potential of this protective film in lithium metal batteries.

Plasmon-enhanced linear and second-order surface nonlinear optical response of silver nanoparticles fabricated using a femtosecond pulse.

We present the plasmon-enhanced linear and second-order surface nonlinear optical response of silver nanoparticles (Ag NPs) fabricated using a femtosecond pulse. Theoretical analysis indicates Ag NPs with a diameter of ∼100 nm have excellent linear response within the visible band, and the electric field intensity enhancement factor reaches ∼105 under excitation of continuous light of 632.8 nm. Meanwhile, the simulation result of second-order surface nonlinear optical response shows that the second harmonic conversion efficiency of the Ag NPs dimer is two orders of magnitude higher than that of a single Ag NP, under excitation of a femtosecond pulse. In experiment, the linear response of Ag NPs is examined using surface-enhanced Raman spectroscopy (SERS) with a Raman enhancement factor of ∼1.7 × 1010, revealing the excellent linear optical response of Ag NPs. Moreover, the spectra of the second harmonic can be measured clearly under conditions of an average pump power of 40 µW, revealing the excellent second-order surface nonlinear optical response of Ag NPs.

Surface-Enhanced Raman Spectroscopy Based on a Silver-Film Semi-Coated Nanosphere Array.

In this paper, we present a convenient and economical method to fabricate a silver (Ag)-film semi-coated polystyrene (PS) nanosphere array substrate for surface-enhanced Raman spectroscopy (SERS). The SERS substrate was fabricated using the modified self-assembled method combined with the vacuum thermal evaporation method. By changing the thickness of the Ag film, the surface morphology of the Ag film coated on the PS nanospheres can be adjusted to obtain the optimized localized surface plasmonic resonance (LSPR) effect. The 3D-finite-difference time-domain simulation results show that the SERS substrate with an Ag film thickness of 10 nm has tens of times the electric field intensity enhancement. The Raman examination results show that the SERS substrate has excellent reliability and sensitivity using rhodamine-6G (R6G) and rhodamine-B (RB) as target analytes, and the Raman sensitivity can reach 10-10 M. Meanwhile, the SERS substrate has excellent uniformity based on the Raman mapping result. The Raman enhancement factor of the SERS substrate was estimated to be 5.1 × 106. This kind of fabrication method for the SERS substrate may be used in some applications of Raman examination.

[Effect of matrine and cisplatin in combination on PDCD4 expression in SK-NEP-1 cells].

OBJECTIVE: Matrine, a major ingredient of sophora, has an anti-tumor activity, capable of suppressing the proliferation and metastasis and promoting apoptosis or differentiation of tumor cells. This study was designed to investigate the effects of matrine on survival and apoptosis of nephroblastoma cell line SK-NEP-1, reduction of drug-resistance of cisplatin and the mechanism(s) underlying these effects. METHODS: SK-NEP-1 cells were treated with matrine and cisplatin at various doses (0.5, 1.0 and 1.5 mg/mL), either each alone or in combination. The viability in treated SK-NEP-1 cells was assessed by MTT colorimetric assay, apoptosis by flow cytometry, and PDCD4 mRNA abundance by RT-PCR. RESULTS: As compared with the non-treatment control, matrine and cisplation, regardless of combination and dosage, significantly reduced the viability (P<0.01), induced apoptosis (P<0.01), and increased PDCD4 mRNA abundance (P<0.01), in SK-NEP-1 cells. The above effects of matrine and cisplation were dose-dependent when they were used alone, and were more pronounced when they were used in combination (P<0.05). CONCLUSIONS: Matrine can significantly induce apoptosis and inhibit growth of SK-NEP-1 cells in a dose-dependent manner, thus increasing the chemotherapeutic sensibility of cisplatin. The observed effects of matrine may be a result of increased PDCD4 expression.

Constructing a Uniform and Stable Mixed Conductive Layer to Stabilize the Solid-State Electrolyte/Li Interface by Cold Bonding at Mild Conditions.

Garnet-type Li6.4 La3 Zr1.4 Ta0.6 O12 (LLZ) electrolyte is a promising candidate for high-performance solid-state batteries, while its applications are hindered by interfacial problems. Although the utilization of functional coatings and molten lithium (Li) effectively solves the LLZ interfacial compatibility problem with Li metal, it poses problems such as high cost, high danger, and structural damage. Herein, a mixed conductive layer (MCL) is introduced at the LLZ/Li interface (RT-MCL) via an in situ cold bonding process at room temperature. Such a stable and compact RT-MCL can effectively suppress side reactions and protect the crystal structure of LLZ, and it also inhibits growth of Li dendrites and promotes uniform Li deposition. The critical current density (CCD) of the Li symmetric cell composed of RT-MCL-LLZ is increased to 1.8 mA cm-2 and provides stable cycling performance over 2000 h under 0.5 mA cm-2 . Additionally, this in situ cold bonding treatment can significantly reduce cost and eliminate potential safety issues caused by the high-temperature processing of Li metal. This work highlights tremendous potential of this cold bonding technique in the reasonable design and optimization of the LLZ/Li interface.

[Effects of matrine on the proliferation and apoptosis of human rhabdomyosarcoma RD cells].

OBJECTIVE: To investigate the effects of matrine on the proliferation and apoptosis of human rhabdomyosarcoma RD cells in vitro, and to explore the mechanism of matrine inducing apoptosis of RD cells. METHODS: MTT assay was used to measure the proliferation inhibition rates of RD cells that were treated with matrine (final concentrations= 0.5, 1.0, 1.5, and 2.0 mg/mL). Flow cytometry was used to evaluate the apoptosis of RD cells treated with the four concentrations of matrine. RT-PCR was used to measure the mRNA expression of cyclin D1 and survivin in RD cells treated with 0.5, 1.0, and 1.5 mg/mL of matrine. RESULTS: The RD cells treated with various concentrations of matrine showed significantly higher proliferation inhibition rates and apoptotic rates than those that were not treated with matrine (P<0.01), and with increased matrine concentration, the proliferation inhibition rate of RD cells increased gradually, thus exhibiting a dose dependence. The mRNA expression of cyclin D1 and survivin was seen in all RD cells, but was significantly lower in RD cells treated with matrine than in those that were not treated with matrine (P<0.01). There were significant differences in cyclin D1 mRNA level among the RD cells treated with 0.5, 1.0, and 1.5 mg/mL of matrine (P<0.05), while there was significant difference in survivin mRNA level between the RD cells treated with 0.5 and 1.5 mg/mL of matrine (P<0.05). CONCLUSIONS: Matrine can significantly inhibit proliferation and induce apoptosis of RD cells, which may be related to downregulating the mRNA expression of cyclin D1 and survivin.

Plasmon-enhanced nonlinear nanofocusing of gold nanoprisms driven via an ultrafast azimuthal vector beam.

We present the plasmon-enhanced nonlinear nanofocusing of a gold (Au) nanoprism array substrate (ANAS) driven via an ultrafast azimuthal vector beam (AVB). Theoretical calculations show that the electric-field intensity of the ANAS vertically excited via the femtosecond AVB is higher than that of LPB excitation. In this experiment, the second-order surface nonlinear optical response of the ANAS is adopted to examine the nonlinear plasmonic nanofocusing of the ANAS, and it was observed that the second harmonic (SH) intensity of the ANAS excited via the femtosecond AVB is ∼3.8 times higher than that of LPB excitation, revealing that the ANAS under AVB excitation has a better nonlinear plasmonic nanofocusing characteristic than that under LPB excitation. Furthermore, the GaSe nanosheets are transferred on the ANAS to examine the nonlinear plasmonic nanofocusing of the ANAS. The SH intensity of the GaSe nanosheets deposited on the ANAS via the femtosecond AVB excitation has been enhanced ∼4.7 times than that of LPB excitation, indicating that the ANAS via AVB excitation has better nonlinear plasmonic nanofocusing than that of LPB excitation. This method may be used as a nonlinear nanofocusing light source to increase the light-matter nonlinear interaction.

Effect of matrine combined with cisplatin on the expression of XIAP in human rhabdomyosarcoma RD cells.

The combined effects of matrine (Mat) and cisplatin on the survival and apoptosis of rhabdomyosarcoma (RMS) RD cells, as well as the possible mechanism of the synergistic effect of Mat and cisplatin were investigated in the present study. RMS RD cells were divided and treated as follows: control group, 5 mg/l cisplatin group, Mat groups (0.5, 1.0 and 1.5 g/l), and Mat (0.5, 1.0 and 1.5 g/l) combined with 5 mg/l cisplatin groups. An MTT assay and flow cytometry were applied to detect the survival and apoptotic rates, respectively, while RT-PCR was applied to detect the expression levels of X-linked inhibitor of apoptosis protein (XIAP) mRNA in the RD cells of each group. The survival rates of RD cells in each experimental group were lower than in the control group, and the apoptotic rates were higher than those in the control group (P<0.05). An increase in drug concentrations led to the cell proliferation inhibitory and apoptotic rates of the single Mat groups increasing as a function of dose (pairwise comparison among the groups, P<0.05), while the proliferation inhibitory and apoptotic rates of Mat combined with the cisplatin groups under different concentration were significantly higher than those of the single Mat and single cisplatin groups under the same concentration (P<0.01). The expression levels of XIAP mRNA in the RD cells of each experimental group were lower than those in the control group (P<0.05). Additionally, the expression levels of XIAP mRNA in the group treated with Mat and cisplatin were significantly lower than those of the single cisplatin and single Mat groups (P<0.01). In conclusion, Mat and cisplatin are capable of inhibiting the proliferation of RD cells and inducing apoptosis by suppressing the XIAP mRNA expression levels.

[Reversal effect of nuclear factor-κB protease inhibitor PDTC on multidrug resistance of K562/AO2 cells and its mechanism].

This study was purposed to investigate the relationship between activation of nuclear factor-κB (NF-κB) and multidrug resistance in K562/AO2 cells and its mechanism. Human erythroleukemic cell line K562 and its adriamycin-resistant counterpart K562/AO2 cells were used in the study. After inhibiting the activation of NF-κB with noncytotoxic concentration of antioxidant pyrrolidine dithiocarbamate (PDTC) in vitro, the multiple of drug resistance of K562/AO2 cells was assessed by MTT assay. RT-PCR and flow cytometry method were used to detect the relative expression of mdr-1 mRNA and P-gp, respectively. The results showed that (1) multidrug resistance of K562/AO2 cells to ADM was 59 times higher than that of K562 cells. When being pretreated with 0.2 µmol/L PDTC which is noncytotoxic to cells, the IC50 of ADM in K562/AO2 cells was sharply decreased with relative reverse efficiency of 93.03%, which was more higher than that of classic modifying agents Verapamil (Ver); (2) NF-κB activity of K562/AO2 cells was significantly higher than that of K562 cells (p < 0.01). When being treated with PDTC, the activation of NF-κB was sharply decreased in K562/AO2 cells; with 0.2 µmol/L PDTC for 24 hours it decreased to the lowest, nearly to the K562 cell level (p > 0.05); (3) the relative expression of both mdr-1 mRNA and P-gp in K562/AO2 cells was more higher; the expressions of mdr-1 mRNA and P-gp both were inhibited in K562/AO2 cell group treated with PDTC for 48 hours. It is concluded that the PDTC used as an inhibitor of NF-κB activity can partially reverse the multidrug resistance of K562/AO2 cells, which mechanism can be associated with the down-regulation of mdr-1 mRNA and P-gp.

[Effect of proteasome inhibitor MG-132 on L1210 cell apoptosis and its mechanism].

This study was aimed to investigate the effect of proteasome inhibitor MG-132 on apoptosis of L1210 cells and its mechanism. L1210 cells were treated with MG-132 of different concentrations (0, 2.5, 5, 10, 10 micromol/L). Cell viability was tested by MTT assay, apoptosis rate was detected by using flow cytometry, activity of caspase 3 was detected by colorimetry, the expression of NF-kappaB nuclear protein was detected by Western blot. The results showed that the growth inhibition of L1210 cells treated for a same time (24 hours) was enhanced along with increasing of MG-132 concentrations (0, 2.5, 5, 10, 20 micromol/L); the inhibitory rate, apoptosis rate and activity of caspase 3 increased also along with raising of MG-132 concentrations; while the expression of NF-kappaB nuclear protein decreased along with raising of GM-132 concentrations. It is concluded that MG-132 can induce the apoptosis of L1210. The mechanism of apoptosis may be related to the down-regulation of the expression of NF-kappaB and the activation of caspase 3.

[Effect of proteasome inhibitors MG-132 at different doses on cultured K562 cell apoptosis].

This study was aimed to investigate the effect of proteasome inhibitor MG-132 at different doses on cultured K562 cell apoptosis. MTT assay was used to observe the activity of K562 cell proliferation inhibition rate after treating for 48 hours at different doses (0, 2, 4, 8, 16, 32 micromol/L). Immunocytochemistry was used to detect the NF-kappaB activity and glucocorticoid receptor (GR) expression. Flow cytometry was used to determine the K562 cell apoptosis. The results indicated that proliferation inhibition rate of K562 cells after treated for 48 hours showed dose-dependent, the inhibitory rates of cell proliferation in test groups were significant higher than that in control group, and the effect in 32 micromol/L test group was the most obvious (45.24 +/- 4.12)% (p < 0.05). The NF-kappaB activity and GR expression after treating for 48 hours showed dose-dependent. Compared with control group, the NF-kappaB activities in test groups were lower (p < 0.05), and the NF-kappaB activity in 32 micromol/L test group was the lowest (63.60 +/- 2.95); the GR expression in test groups was higher (p < 0.05), and the GR expression in 16 micromol/L test group was the highest (75.62 +/- 2.70). The K562 cell apoptosis rate after treating for 48 hours also showed dose-dependent. Compared with control group, the K562 cell apoptosis rates in test groups were higher (p < 0.05), the K562 cell apoptosis rate in 32 micromol/L test group was the highest (21.37 +/- 2.02)%. It is concluded that the MG-132 may induce K562 cell apoptosis and proliferation inhibition through up-regulation of NF-kappaB activity and down-regulation of GR expression both in dose-dependent manner.

[Effect of N-tosyl-L-phenylalnylchloromethyl ketone and dexamethasone on expression of nuclear transcription factor-kappaB in childhood acute lymphoblastic leukemia and its significance].

In order to investigate the effect of N-tosyl-L-phenylalnylchloromethyl ketone (TPCK) and dexamethasone (Dex) on expression of nuclear transcription factor-kappaB (NF-kappaB) in childhood acute lymphoblastic leukemia (ALL) and its significance, so as to provide the experimental basis for corresponding clinical treatment of ALL, in which NF-kappaB is taken as a target. The biotin-streptavidin method was used to detect the expression of NF-kappaB P65 protein and the effects of TPCK and Dex at clinically relevant dosage on activity of NF-kappaB P65 protein in 20 childhood ALL patients. The results indicated that the expression of NF-kappaB P65 protein was strongly diminished and reached to negative level at 2 hours by treatment with 40 micromol/L TPCK, the positive expression of NF-kappaB P65 protein was (2.5 +/- 1.6)%. TPCK had a time-dependent inhibitory effect on ALL cells cultured in vitro. The expression of NF-kappaB P65 protein in ALL cells was strongly inhibited by clinically relevant concentration of dexamethasone 5.0 microg/ml for 24 hours in vitro. The positive expression was (25.0 +/- 3.0)%, there was significant difference, as compared with untreated ALL cells (T=55, P<0.01). It is concluded that TPCK and Dex can inhibit NF-kappaB activity. Inhibition of NF-kappaB activity may be one of the effect mechanism of dexamethasone on ALL cells. Inhibition of NF-kappaB conduction pathway may have a significant value in childhood ALL treatment.

[Expression of nuclear transcription factor kappaB in childhood acute lymphoblastic leukemia and its significance].

To investigate the expression of nuclear transcription factor kappaB (NF-kappaB) in childhood acute lymphoblastic leukemia (ALL) and its significance, the biotin-streptavidin method and microscopy were used to detect NF-kappaB P65 protein in cells from 32 childhood ALL patients and 40 children without hematologic malignancies as control. The results showed that the positive expression rate of NF-kappaB P65 protein in cells from 32 childhood ALL patients was 87.50%, obviously higher than that in control group (12.50%) (chi(2) = 40.56, p < 0.01). In 28 childhood ALL patients with positive expression, the ratio of weakly positive (+) cases to all positive cases was 10.71% (3/28); the ratio of generally positive (++) case was 42.86% (12/28), and the ratio of strongly positive (+++) cases was 46.43% (13/28). While in the control group the of NF-kappaB P65 protein showed low expression with 100% (5/5). There was significant difference in the level of NF-kappaB P65 protein between ALL patients and control group. While the level of NF-kappaB P65 protein had no significent difference in morphology, immunophenotype (T-lineage ALL and B-lineage ALL) and the courses in the de novo and the relaspsed cases. It is concluded that NF-kappaB P65 protein expresses in cells of childhood ALL, the inhibition of NF-kappaB transduction pathway may have significant value in childhood ALL treatment. This study provides experimental basis concerning clinical treatment for ALL, when NF-kappaB is taken as a target.