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The nanoparticle-induced endothelial leakiness effect can enhance the ability of nanoparticles (NPs) to cross the vascular barrier but also promote pathological processes. The rarity of NPs capable of endothelial penetration without adverse effects underscores a critical challenge. Addressing this, we designed a bivalve pH-responsive pathway that controlled self-shedding NPs. At its core lies a composite structure comprising indocyanine green-doped spiky SiO2 NPs within an inner-shell comprising the cationic polymer polyethylenimine (PEI), tethered to the core via hydrazone linkages, alongside the inclusion of the endothelial recovery factor angiopoietin-1 (Ang1) and an outermost biomimetic cell membrane shell. In drug delivery, our NPs can target and traverse the endothelial barrier. Then, the initiation of the first self-shedding process ensues upon exposure to an acidic milieu, eliciting the proton sponge effect facilitated by PEI, thereby inducing membrane rupture and enabling NP release, while at the same time, Ang1 is released to repair the disrupted endothelial barrier. Furthermore, the hydrazone bonds were broken in the more acidic environment closer to the tumor site to realize the second self-shedding process, which reproduced the spiky morphology for promoted endocytosis. Therefore, the designed self-shedding NPs can realize two steps of self-shedding to inhibit tumor metastasis and improve photothermal therapy. [ABSTRACT FROM AUTHOR]

High-strength and lightweight 7XXX Al alloys are widely applied in aerospace industries. Stress corrosion cracking (SCC) in these alloys has been extensively discussed, and electrochemical corrosion should be brought to the forefront when these materials are used in marine atmospheric environments. This work obtained the corrosion potentials (Ecorr) and corrosion rates of 40 as-cast 7XXX Al alloys by potentiodynamic polarization tests and immersion tests, respectively; then, chemical compositions and physical features were used to build a machine learning model to predict these parameters. RFR was used for the prediction model of Ecorr with the features Cu, Ti, Al, and Zn, and GPR for that of the corrosion rate with the features of specific heat, latent heat of fusion, and proportion of p electrons. The physical meaning and reasonability were discussed based on the analysis of corrosion morphology and precipitated composition. This work provides a reference for the design of corrosion-resistant 7XXX Al alloys and shows a method of conducting corrosion mechanism evaluation by using machine learning. [ABSTRACT FROM AUTHOR]

Cathodic protection is widely used to protect structural steel from corrosion in marine environments. However, an inappropriate cathodic potential may lead to hydrogen embrittlement (HE). Therefore, this study investigates the relationship between cathodic protection potential, structure and composition of calcareous deposits, and hydrogen embrittlement susceptibility of Q460 steel. The slow strain rate test results and fracture analysis reveal that Q460 steel had the smallest HE susceptibility when covered with the calcareous deposits formed under −1.1 VSCE. The deposits have a relatively thin calcium-rich inner layer and a condensed magnesium-rich outer layer, which can significantly inhibit hydrogen entry. A sustained deposition reaction during slow strain rate testing (SSRT) in artificial seawater can also decrease the HE susceptibility of Q460 steel. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB), the most common extracranial solid tumor in childhood, significantly contributes to cancer‐related mortality, presenting a dearth of efficacious treatment strategies. Previously, our studies have substantiated the potent cytotoxicity of arsenic trioxide (ATO) against NB cells, however, the specific underlying mechanism remains elusive. Here, we first identified ATO as a novel GPX4 inhibitor, which could trigger the ferroptosis in NB cells. In vitro, ATO significantly inhibited the proliferation and migration ability of NB cells SK‐N‐AS and SH‐SY5Y, and induced ferroptosis. Furthermore, the iron chelator deferoxamine reversed ATO‐mediated intracellular reactive oxygen species accumulation and hindered the generation of the lipid peroxidation product malondialdehyde. Conversely, ferric ammonium citrate notably intensified its cytotoxic effects, especially on retinoic acid (RA)‐resistant SK‐N‐AS cells. Subsequently, the quantitative real‐time polymerase chain reaction results showed ATO significantly inhibited the transcription of GPX4 in NB cells. Remarkably, immunoblotting analysis revealed that MG132 exhibited a notable effect on elevating GPX4 levels in NB cells. Nevertheless, pretreatment with MG132 failed to reverse the ATO‐mediated decrease in GPX4 levels. These findings suggested that ATO reduced the GPX4 expression level in NB cells by mediating GPX4 transcriptional repression rather than facilitating ubiquitinated degradation. In conclusion, our research has successfully indicated that ATO could induce ferroptosis and initiate lipid peroxidation by regulating the transcriptional repression of GPX4, and ATO holds promise as a potential anti‐tumor agent in NB, specifically for patients with RA‐resistant HR‐NB. [ABSTRACT FROM AUTHOR]

The effect of Mo content of 1400 MPa-grade high-strength bolt steel on hydrogen diffusion behavior and the hydrogen evolution reaction were studied using a hydrogen permeation experiment, potentiodynamic polarization tests, thermal desorption spectroscopy, and the first-principle calculation. Two 1400 MPa-grade high-strength bolt steels with different Mo content were used. Based on the potentiodynamic polarization tests, both steels' electrochemical behavior was similar in the test range. The hydrogen permeation experiment showed that the process of hydrogen adsorption and absorption was significantly promoted, and hydrogen desorption and recombination were slightly promoted, with the Mo content increasing from 0.70 to 1.09 wt%. The thermal desorption spectroscopy showed the overall reaction of hydrogen permeation and evolution. The increasing Mo content facilitated hydrogen entry behavior and increased the hydrogen content. According to the first-principle calculation and the density functional theory, this phenomenon is induced by the stronger bonding ability of Mo-H than Fe-H. This work could guide the design of 1400 MPa-grade high-strength bolt steel. [ABSTRACT FROM AUTHOR]

Background: Alveolar rhabdomyosarcoma (ARMS) is a subtype of rhabdomyosarcoma characterized by its aggressive behavior and poor prognosis, highlighting the need for novel treatment options. Arsenic trioxide (ATO) has been shown to specifically inhibit tumor growth and the metastasis of ARMS in vitro by acting on the hedgehog pathway. Here we report on a pilot clinical study to evaluate the activity of an ATO-combined chemotherapy approach for the treatment of ARMS patients. Methods: We designed a therapeutic schedule of an ATO-combined chemotherapy, incorporating comprehensive management according to the Intergroup Rhabdomyosarcoma Study Group protocol. ATO was administered at 0.16 mg/kg per day over 8 h via an IV for 10 days combined with a chemotherapeutic regimen of vincristine, actinomycin, and cyclophosphamide (VAC regimen) on the third day, which was repeated every 21 days. A total of eight cycles of ATO-combined chemotherapy were applied throughout the entire scheme. Results: A total of three refractory/recurrent and one untreated ARMS patient, three male and one female, with a median age of 5.8 years (range, 5.1 to 12.5 years), were enrolled in the present study. All patients were sensitive to combined chemotherapy with ATO and achieved partial or complete remission during treatment. Except for reversible gastrointestinal reaction and myelosuppression, no other adverse events were observed during the process of treatment. Conclusions: The combined chemotherapy of ATO and the VAC regimen exhibited beneficial activities against ARMS in pediatrics and was well tolerated, but prospective large-scale clinical trials are warranted to determine the long-term efficacy, optimal courses, and late toxicity in this population. [ABSTRACT FROM AUTHOR]

Objective: The apoptotic and cytotoxic effects of arsenic trioxide (ATO) makes it a potentially suitable agent for the treatment of patients with neuroblastoma with poor prognosis; therefore, we try to evaluate the effectiveness and safety of ATO combined with reinduction/induction chemotherapy in children with recurrent/refractory or newly diagnosed stage 4 neuroblastoma. Methods: Retrospective analysis was performed on seven pediatric patients with recurrent /refractory or newly diagnosed stage 4 neuroblastoma treated with traditional reinduction/induction chemotherapy combined with ATO. Results: A total of 7 patients were treated synchronously with ATO and chemotherapy for up to nine courses; all patients received conventional chemotherapy plus a 0.16 mg/kg/day dose of intravenous ATO during reinduction/induction chemotherapy. Treatment was effective in five patients and ineffective in the other two patients. The overall response rate was 71.43% (5 of 7). The side effects of the ATO combination were minor, whereby only treatment in one patient was terminated at the sixth course due to a prolonged QT interval (0.51 s), which returned to normal after symptomatic treatment. Conclusions: ATO can be safely and effectively combined with chemotherapy drugs as a potential alternative means of treatment for high-risk stage 4 neuroblastoma, and we have observed that ATO can restore the sensitivity of chemotherapy in some patients who were resistant to previous chemotherapy. Further investigations and clinical data are required to confirm these observations. [ABSTRACT FROM AUTHOR]

In this study, the immune microenvironment in Langerhans cell histiocytosis (LCH) was characterized to determine if immune indices are predictive of severity. Serum samples from 54 treatment-naïve patients were analyzed quantitatively for inflammatory cytokines and immunoglobulins before and after the induction of chemotherapy. The initial serum sIL-2R, TNF-α, and IL-10 of untreated LCH patients with risk organ involvement (RO+) were significantly higher than those with single-system (SS) involvement. LCH patients with hematologic involvement exhibited a significantly higher sIL-2R, TNF-α, IL-10, and IL-1β expression, as compared to the group without involvement. sIL-2R, TNF-α, and IL-10 were increased in patients with liver or spleen involvement. Th cells have decreased in the liver+ and spleen+ group, and Ts cells were significantly decreased in non-response group after induction chemotherapy. The serum level of immune indices represents, to some extent, the severity of the disease. Pertinent laboratory inspections can be used to improve risk stratification and guide immunotherapy. [ABSTRACT FROM AUTHOR]

This nonrandomized, multicenter cohort, open-label clinical trial evaluated the efficacy and safety of combined chemotherapy with arsenic trioxide (ATO) in children with stage 4/M neuroblastoma (NB). We enrolled patients who were newly diagnosed with NB and assessed as stage 4/M and received either traditional chemotherapy or ATO combined with chemotherapy according to their own wishes. Twenty-two patients were enrolled in the trial group (ATO combined with chemotherapy), and 13 patients were enrolled in the control group (traditional chemotherapy). Objective response rate (ORR) at 4 weeks after completing induction chemotherapy was defined as the main outcome, and adverse events were monitored and graded in the meantime. Data cutoff date was December 31, 2019. Finally, we found that patients who received ATO combined with chemotherapy had a significantly higher response rate than those who were treated with traditional chemotherapy (ORR: 86.36% vs. 46.16%, p =0.020). Reversible cardiotoxicity was just observed in three patients who were treated with ATO, and no other differential adverse events were observed between the two groups. ATO combined with chemotherapy can significantly improve end-induction response in high-risk NB, and our novel regimen is well tolerated in pediatric patients. These results highlight the superiority of chemotherapy with ATO, which creates new opportunity for prolonging survival. In addition, this treatment protocol minimizes therapeutic costs compared with anti-GD2 therapy, MIBG, and proton therapy and can decrease the burden to families and society. However, we also need to evaluate more cases to consolidate our conclusion. [ABSTRACT FROM AUTHOR]

Background: Many formulas based on the patient's height, weight and/or age exist to determine central venous catheter (CVC) depth in children. However, this information is unavailable in some emergency conditions. Therefore, direct methods should be developed to guide catheter position in children.Methods: Eighty patients aged 1-10 y were enrolled from July 2015 to August 2016 and seventy-five were completed; fifty were male, and twenty-five were female. The exclusion criteria were inability to identify the sternal angle or failure to use the right internal jugular vein approach. The catheter was inserted using the right internal jugular vein approach, the distance from the skin puncture point to the midpoint of the sternal angle plane was measured, and the catheter tip was positioned to this distance minus 1 cm. Chest radiography were performed for those children after catheter insertion. The relative position between the catheter tip and carina was confirmed and the longitudinal distance from the catheter tip to the carina was calculated on radiographic images, and related complications were recorded.Results: All catheter tips were above the carina, and the average distance from the catheter tip to the carina was 9.8 mm. No patients experienced serious complications.Conclusion: The sternal angle is a useful and reliable anatomic landmark for guiding CVC position in children. Using this landmark, the catheter can be quickly and conveniently placed at a safety position in right internal jugular vein, especially in some emergency conditions. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is one of the most common extracranial, solid, pediatric malignancies. Despite improvements in conventional therapies, including surgery, chemotherapy and radiation therapy, the prognosis of stage IV NB remains poor, indicating that novel treatment strategies are required. Immunotherapies, such as anti-GD2 monoclonal antibodies, used alone or in combination with cytokines, and peripheral blood mononuclear cells or cord blood mononuclear cells (CBMNCs), have been indicated to cause NB cell death and to prolong patient survival in high-risk NB; however, they remain limited by severe cytotoxicity and side effects. In the present study, it was determined that anti-GD2 monoclonal antibody alone or CBMNC-isolated cytokine-induced killer (CIK)/natural killer (NK) cells alone significantly induced cell death of NB SK-N-SH cells, and the combination of anti-GD2 antibody and CIK/NK cells could significantly increase the cell death rate compared with either treatment alone. In addition, based on a method referred to our previous study, it was identified that a two-cytokine culture system, using interleukin IL-2 and IL-7, effectively stimulated the proliferation of CIK/NK cells. These results serve to suggest a novel treatment strategy for relapsed/refractory NB with high efficiency and few side effects. [ABSTRACT FROM AUTHOR]

The excellent thermoelectric efficiencies of half-Heusler compounds mainly originate from their distinctive crystal structure, high-thermal stability, and outstanding electrical transport performance. In this work, we investigate the elastic constants, electronic structure, and thermoelectric properties of MPtSn (M = Ti, Zr, and Hf) compounds using semi-classical Boltzmann transport theory and deformation potential model. The predicted maximum ZT value of n -type TiPtSn reaches up to 2.19 at the optimal electron carrier concentration of 5.98 × 1020 cm−3 at 1000 K. This ZT value is much higher than the previously experimental reported value. The electronic structure and phonon dispersion of the p -type HfPtSn compound suggest that doping at the Pt position can decrease the lattice thermal conductivities and modify the carrier concentrations. It is expected that these investigations could provide valuable guidance for exploring high-performance thermoelectric materials. [Display omitted] • The thermoelectric properties are investigated by utilizing first-principles calculations. • Doping at the Pt position of MPtSn (M = Ti, Zr, and Hf) can significantly change the carrier concentrations. • n -type TiPtSn is forecasted to exhibit the high ZT value of 2.19 at 1000 K when n = 5.98 × 1020 cm−3. [ABSTRACT FROM AUTHOR]

Half-Heusler compound is a promising thermoelectric material due to its excellent conversion performance. In this study, we investigate the electronic structure, and thermoelectric properties of XCoGe (X = V, Nb, and Ta) compounds based on density functional theory. Combining the semi-classical Boltzmann transport equation and the deformation potential theory, the thermoelectric properties such as Seebeck coefficient, relaxation time, electrical conductivity, power factor, electronic thermal conductivity, and lattice thermal conductivity are analyzed. The NbCoGe compound possesses a large dimensionless figure of merit, which is related to the large electrical conductivity, small effective mass, and large relaxation time. The ZT values of n- and p-type NbCoGe compounds reach 1.6 and 1.3 at T = 1200 K, respectively. These findings will provide valuable guidance for exploring half-Heusler compounds with high thermoelectric performance. [ABSTRACT FROM AUTHOR]

Tungsten carbide (WC) has received widespread attention as a new type of nonprecious metal catalyst for hydrogen evolution reaction (HER). However, it is still a challenge to improve the surface HER catalytic activity. In this work, the effects of different nonmetallic dopants on the catalytic activity and stabilities of WC (0001) surface for HER were studied by first principles methods. The effects of different types of non-metal (NM = B; N; O; P and S) and doping concentrations (ni = 25–100%) on HER catalytic activity and stability were investigated by calculating the Gibbs free energy of hydrogen adsorption (∆GH) and substitution energy. It was found that the catalytic performance can be improved by doping O and P non-metallic elements. Especially, the ∆GH with P doped is −0.04eV better than Pt (−0.085 eV), which is a potential ideal catalyst for HER. Furthermore, the electronic structure analysis was used to explore the origin of the regulation of doping on stability and catalytic activity. The results show that nonmetallic doping is an effective strategy to control the catalytic activity, which provides theoretical support for the future research of HER catalysts. [ABSTRACT FROM AUTHOR]

• Effect of carbon on hydrogen adsorption and absorption on Fe-C alloys was studied. • Carbon doping surfaces are more unstable for hydrogen to adsorb on, hydrogen surface coverage was reduced. • Carbon doping reduces the thermodynamic energy difference and diffusion barriers, making hydrogen penetration into the bulk more facile. Electrochemical experiments and first-principle calculations were conducted in this study to investigate the impact of carbon doping on the adsorption and absorption on Fe-C alloy surfaces. The generalized Iyer-Pickering-Zawenzaden model was adopted to determine the kinetics related to hydrogen adsorption/absorption. Discharge rate constant k 1 was found increased with the presence of carbon, suggesting the promotion of the H 2 O ionization process and more hydrogen atoms were generated on the surface. Meanwhile, the recombination rate constant k 2 decreased on carbon doping surface, indicating recombination process of hydrogen atoms were inhibited. Results also showed the hydrogen surface coverage dropped with increasing carbon content. Additionally, EIS results indicate that the distance between the adsorbed hydrogen atoms and the sample surfaces is reduced by carbon doping. All experimental results are in accordance with the first-principle calculation results which demonstrate that the presence of carbon elevated the binding energy for hydrogen adsorption while lowering the energy barrier for diffusion. Thus, carbon solutes reduce the stability for hydrogen atoms to adsorb on the surface and facilitate their diffusion into the bulk. Image, graphical abstract [ABSTRACT FROM AUTHOR]

The global outbreak of the COVID-19 pandemic has indisputably wreaked havoc on societies worldwide, compelling the scientific community to seek urgently needed therapeutic agents with low-cost and low-side effect profiles. Numerous approaches have been investigated in the quest to prevent or treat COVID-19, but many of them exhibit unwelcome side effects, such as dysfunctional viral immune responses and inflammation. Herein, we present the preparation of solid natural human pulmonary alveolar epithelial cell (ATII) membrane-coated PLGA NPs (PLGA NPs@ATII-M), which demonstrate remarkable affinity and competitiveness to neutralize the SARS-CoV-2 S1 protein-coated NPs (SCMMA NPs-S1), which are employed as a surrogate for coronavirus particles. In addition, we first considered the antifouling properties of these types of NPs, and we found that this membrane-coated NP formulation boasts excellent antifouling capabilities, which serve to protect their neutralization properties out of shielding by protein coronas in blood circulation. Moreover, this formulation is easily prepared and stored with a low-cost profile and exhibits good specificity, high targeting efficiency, and potentially side effect avoiding, thus making it a highly promising candidate for COVID-19 treatment.

Ewing's sarcoma (ES) is a rare and highly aggressive malignant tumor arising from bone and soft tissue. Suffering from intractable or recurrent diseases, the patients' therapy options are very limited. It is extremely urgent to identify novel potential therapeutic targets for ES and put them into use in clinical settings. In the present study, high-throughput screening of a small molecular pharmacy library was performed. The killing effect of the Aurora kinase A (AURKA) inhibitor TCS7010 in ES cells was identified, and AURKA was selected as the research object for further study. Disparate suppressants were adopted to study the cell death manner of TCS7010. TCS7010 and RNA silencing were used to evaluate the functions of AURKA in the apoptosis and ferroptosis of ES cells. Co-immunoprecipitation assay was used to investigate the correlation of AURKA and nucleophosmin1 (NPM1) in ES. Nude-mice transplanted tumor model was used for investigating the role of AURKA in ES in vivo. Investigations into the protein activities of AURKA were conducted using ES cell lines and xenograft models. AURKA was found to be prominently upregulated in ES. The AURKA expression level was remarkably connected to ES patients' shorter overall survival (OS) and event-free survival (EFS). Furthermore, AURKA inhibition markedly induced the apoptosis and ferroptosis of ES cells and attenuated tumorigenesis in vivo. On the part of potential mechanisms, it was found that AURKA inhibition triggered the apoptosis and ferroptosis of ES cells through the NPM1/Yes1 associated transcriptional regulator (YAP1) axis, which provides new insights into the tumorigenesis of ES. AURKA may be a prospective target for clinical intervention in ES patients., (© 2024. The Author(s).)

Background: Treatment for parameningeal rhabdomyosarcoma (PM-RMS) has been a challenge since local control is difficult. The goal of this study was to analyse the impact of different local treatment approaches on childhood PM-RMS patients and help dispel the doubt that whether secondary radical surgery (SRS) should be encouraged in the management of PM-RMS., Methods: A total of 17 children with PM-RMS who received unified systemic chemotherapy and individualized local therapy such as radiotherapy (RT) and/or SRS were included in this retrospective study. The overall survival (OS) and event free survival (EFS) were compared between groups adopting different local strategies., Results: The 3-year OS and EFS of our PM-RMS patients was 75.5% and 56.5% respectively. The OS and EFS of patients who received SRS were both significantly lower than that of the non-SRS group (3-year OS: 50.0% vs 90.0%, P = .031; 3-year EFS: 33.3% vs 60.6%, P = .020). The OS and EFS of the patients who received RT was higher than that of the patients of the non-RT group (3-year OS: 85.6% vs 0%, P = .001; 3-year EFS: 64.0% vs 0%, P = .011)., Conclusion: This study illustrates that SRS was associated with poor prognosis of PM-RMS and should not be routinely performed. Optimized RT strategies along with more intensive chemotherapy may be alternative options to improve the survival of patients with PM-RMS. Multi-center, large sample and prospective studies are needed to further validate these findings., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Neuroblastoma (NB), the most common extracranial solid tumor in childhood, significantly contributes to cancer-related mortality, presenting a dearth of efficacious treatment strategies. Previously, our studies have substantiated the potent cytotoxicity of arsenic trioxide (ATO) against NB cells, however, the specific underlying mechanism remains elusive. Here, we first identified ATO as a novel GPX4 inhibitor, which could trigger the ferroptosis in NB cells. In vitro, ATO significantly inhibited the proliferation and migration ability of NB cells SK-N-AS and SH-SY5Y, and induced ferroptosis. Furthermore, the iron chelator deferoxamine reversed ATO-mediated intracellular reactive oxygen species accumulation and hindered the generation of the lipid peroxidation product malondialdehyde. Conversely, ferric ammonium citrate notably intensified its cytotoxic effects, especially on retinoic acid (RA)-resistant SK-N-AS cells. Subsequently, the quantitative real-time polymerase chain reaction results showed ATO significantly inhibited the transcription of GPX4 in NB cells. Remarkably, immunoblotting analysis revealed that MG132 exhibited a notable effect on elevating GPX4 levels in NB cells. Nevertheless, pretreatment with MG132 failed to reverse the ATO-mediated decrease in GPX4 levels. These findings suggested that ATO reduced the GPX4 expression level in NB cells by mediating GPX4 transcriptional repression rather than facilitating ubiquitinated degradation. In conclusion, our research has successfully indicated that ATO could induce ferroptosis and initiate lipid peroxidation by regulating the transcriptional repression of GPX4, and ATO holds promise as a potential anti-tumor agent in NB, specifically for patients with RA-resistant HR-NB., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Neuroblastoma (NB) remains associated with a low overall survival rate over the long term. Abnormal activation of the Hedgehog (HH) signaling pathway can activate the transcription of various downstream target genes that promote NB. Both arsenic trioxide (ATO) and itraconazole (ITRA) can inhibit tumor growth., Objective: To determine whether ATO combined with ITRA can be used to treat NB with HH pathway activation, we examined the effects of ATO and ITRA monotherapy or combined inhibition of the HH pathway in NB., Methods: Analysis of CCK8 and flow cytometry showed cell inhibition and cell cycle, respectively. Real-time PCR analysis was conducted to assess the mRNA expression of HH pathway., Results: We revealed that as concentrations of ATO and ITRA increased, the killing effects of both agents on SK-N-BE(2) cells became more apparent. During G2/M, the cell cycle was largely arrested by ATO alone and combined with ITRA, and in the G0/G1 phase by ITRA alone. In the HH pathway, ATO inhibited the transcription of the SHH, PTCH1, SMO and GLI2 genes, however, ITRA did not. Instead of showing synergistic effects in a combined mode, ITRA decreased ATO inhibitory effects., Conclusion: We showed that ATO is an important inhibitor of HH pathway but ITRA can weaken the inhibitory effect of ATO. This study provides an experimental evidence for the clinical use of ATO and ITRA in the treatment of NB with HH pathway activation in cytology., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Neuroblastoma (NB) is one of the most common extracranial tumors with limited therapeutic options. Retinoic acid (RA) has been identified to play anticancer role against NB cells by inducing the differentiation and apoptosis of immature neuroblasts. However, silencing HoxC9 promoter by EZH2-induced H3K27me3 hypermethylation can lead to RA resistance. Previous studies have suggested that arsenic trioxide (ATO), an inhibitor of DNA methylation, could downregulate the expression of EZH2 in breast cancer cells., Objectives: In our study, we attempted to obtain some insight into the mechanisms of differentiation of RA-resistant NB cells by detecting the expressions of HoxC9 and EZH2 in NB cells treated with ATO, so as to provide a basis for the subsequent treatment of RA-resistant NB by ATO., Material and Methods: Two NB cell lines, SK-N-AS (retinoic acid-resistant neuroblastoma cells) and SK-N-SH (retinoic acid-sensitive neuroblastoma cells), were used in our experiments. Cell proliferation and apoptosis were respectively determined with Cell Counting Kit-8 (CCK-8) assay kit and Annexin V staining. The inverted phase contrast microscope was used to observe cell growth and measure the total length of nerve synapses. We employed label-free quantitative proteomic analysis to profile ATO-dependent changes in the proteome of NB cells. Western blot was used to detect the expressions of HoxC9, HoxD8 and EZH2., Results: Arsenic trioxide inhibited the cell proliferation and increased apoptosis and total length of synapses in two NB cell lines. The expressions of HoxC9 and HoxD8 were upregulated, while the expression of EZH2 was downregulated in the SK-N-AS cell line. No significant changes in the 3 proteins mentioned above were observed in the SK-N-SH cell line after ATO treatment., Conclusions: Arsenic trioxide may reactivate the expression of HoxC9 by downregulating EZH2, which leads to restoring RA sensitivity and promoting the differentiation and apoptosis of RA-resistant NB cells.

This nonrandomized, multicenter cohort, open-label clinical trial evaluated the efficacy and safety of combined chemotherapy with arsenic trioxide (ATO) in children with stage 4/M neuroblastoma (NB). We enrolled patients who were newly diagnosed with NB and assessed as stage 4/M and received either traditional chemotherapy or ATO combined with chemotherapy according to their own wishes. Twenty-two patients were enrolled in the trial group (ATO combined with chemotherapy), and 13 patients were enrolled in the control group (traditional chemotherapy). Objective response rate (ORR) at 4 weeks after completing induction chemotherapy was defined as the main outcome, and adverse events were monitored and graded in the meantime. Data cutoff date was December 31, 2019. Finally, we found that patients who received ATO combined with chemotherapy had a significantly higher response rate than those who were treated with traditional chemotherapy (ORR: 86.36% vs. 46.16%, p =0.020). Reversible cardiotoxicity was just observed in three patients who were treated with ATO, and no other differential adverse events were observed between the two groups. ATO combined with chemotherapy can significantly improve end-induction response in high-risk NB, and our novel regimen is well tolerated in pediatric patients. These results highlight the superiority of chemotherapy with ATO, which creates new opportunity for prolonging survival. In addition, this treatment protocol minimizes therapeutic costs compared with anti-GD2 therapy, MIBG, and proton therapy and can decrease the burden to families and society. However, we also need to evaluate more cases to consolidate our conclusion.

This study investigated arsenic trioxide (As2O3), cisplatin (DDP) and etoposide (Vp16) on the anticancer effects and P-glycoprotein (P-gp) expression in neuroblastoma (NB) SK-N-SH cells. The potential influence of As2O3, DDP and Vp16 currently included in NB routine treatment protocols on cytotoxicity in SK-N-SH cells was measured by flow cytometry and drug half-maximal inhibitory concentration (IC50) was established. Moreover, chemotherapeutic agent-mediated changes of cellular expression levels of resistant-related P-gp, was monitored using western blotting. The data showed that As2O3, DDP and Vp16 significantly inhibited the growth and survival of the SK-N-SH cells at different concentration. Notably, the levels of apoptosis were upregulated in SK-N-SH cells with an acceleration of the exposure time and the concentration of As2O3, DDP and Vp16. As2O3, DDP and Vp16 were observed with their IC50 values on SK-N-SH cells being 3 µM, 8 and 100 µg/ml, respectively. Flow cytometry analysis showed that As2O3 at low concentrations in SK-N-SH cells led to enhanced accumulation of cell populations in G2/M phase with increasing the exposure time, and increased levels of apoptosis. In contrast, we observed that SK-N-SH cell populations arrested in S phase by DDP and Vp16. In vitro examination revealed that following pretreatment of SK-N-SH cells with As2O3, the expression of P-gp was not increased. The expression of P-gp downregulation were noted following the group treated by As2O3 at 2 and 3 µM. Exposed to As2O3 at 3 µM for 72 h, SK-N-SH cells exhibited lower expression of P-gp than 2 µM As2O3 for 72 h. In contrast, the expression of P-gp was upregulated by DDP and VP16. In summary, SK-N-SH cells were responsive to chemotherapeutic agent-induced apoptosis in a dose-dependent and time-dependent manner. In particular, ours findings showed that low dose of As2O3 markedly reduced the P-gp expression and increased apoptotic cell death in human NB cell line.