Differential regulation of H3K9/H3K14 acetylation by small molecules drives neuron-fate-induction of glioma cell.

Differentiation therapy using small molecules is a promising strategy for improving the prognosis of glioblastoma (GBM). Histone acetylation plays an important role in cell fate determination. Nevertheless, whether histone acetylation in specific sites determines GBM cells fate remains to be explored. Through screening from a 349 small molecule-library, we identified that histone deacetylase inhibitor (HDACi) MS-275 synergized with 8-CPT-cAMP was able to transdifferentiate U87MG GBM cells into neuron-like cells, which were characterized by cell cycle arrest, rich neuron biomarkers, and typical neuron electrophysiology. Intriguingly, acetylation tags of histone 3 at lysine 9 (H3K9ac) were decreased in the promoter of multiple oncogenes and cell cycle genes, while ones of H3K9ac and histone 3 at lysine 14 (H3K14ac) were increased in the promoter of neuron-specific genes. We then compiled a list of genes controlled by H3K9ac and H3K14ac, and proved that it is a good predictive power for pathologic grading and survival prediction. Moreover, cAMP agonist combined with HDACi also induced glioma stem cells (GSCs) to differentiate into neuron-like cells through the regulation of H3K9ac/K14ac, indicating that combined induction has the potential for recurrence-preventive application. Furthermore, the combination of cAMP activator plus HDACi significantly repressed the tumor growth in a subcutaneous GSC-derived tumor model, and temozolomide cooperated with the differentiation-inducing combination to prolong the survival in an orthotopic GSC-derived tumor model. These findings highlight epigenetic reprogramming through H3K9ac and H3K14ac as a novel approach for driving neuron-fate-induction of GBM cells.

Dielectric Loss and Electrical Conductivity Behaviors of Epoxy Composites Containing Semiconducting ZnO Varistor Particles.

Polymer nanodielectrics render a great material platform for exhibiting the intrinsic nature of incorporated particles, particularly semiconducting types, and their interfaces with the polymer matrix. Incorporating the oxide fillers with higher loading percentages (>40 vol%) encounters particular challenges in terms of dispersion, homogeneous distribution, and porosity from the process. This work investigated the dielectric loss and electrical conduction behaviors of composites containing semiconducting ZnO varistor particles of various concentrations using the epoxy impregnation method. The ZnO varistor particles increased the dielectric permittivity, loss, and electrical conductivity of the epoxy composites into three different regimes (0−50 vol%, 50−70 vol%, 70−100 vol%), particularly under an electric bias field or at higher temperatures. For lower loading fractions below 50 vol%, the dielectric responses are dominated by the insulating epoxy matrix. When loading fractions are between 50 and 70 vol%, the dielectric and electric responses are mostly associated with the semiconducting interfaces of ZnO varistor particles and ZnO−epoxy. At above 70 vol%, the apparent increase in the dielectric loss and conductivity is primarily associated with the conducting ZnO core forming the interconnected channels of electric conduction. The foam-agent-assisted ZnO varistor particle framework appears to be a better way of fabricating composites of filler loading above 80 vol%. A physical model using an equivalent capacitor, diode, and resistor in the epoxy composites was proposed to explain the different property behaviors.

Systematic review and cost-effectiveness of pharmacokinetically guided sunitinib individualized treatment for patients with metastatic renal cell carcinoma.

Background: Sunitinib has a narrow therapeutic window, with considerable differences between patients. Dosing based on pharmacokinetics (PK) may help overcome some of those issues. This study aims to evaluate and compare the cost-effectiveness of PK-guided individualized treatment of sunitinib with its standard dose in patients with metastatic renal cell carcinoma (mRCC). Methods: A comprehensive literature search was performed, and relevant values were used to provide information for the decision analysis model. Utility data were derived from published studies, and costs were obtained from the perspective of payers in China and the United States. A Markov model was established to evaluate the associated costs and health outcomes for patients. The primary outputs of the model included lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analyses were conducted to evaluate the potential uncertainties of parameters. Results: Cost-effective analysis showed that the QALY of the PK-guided group increased by 0.83 compared with that in the standard dose group. From the perspective of both countries' health systems, the cost of PK-guided dose was lower than that of standard dose. Hence, PK-guided treatment was the dominant strategy. One-way and probability sensitivity analyses confirmed the reliability of these results. Conclusion: On the basis of currently available data, PK-guided sunitinib treatment may be a safe, effective, and economical intervention for patients with mRCC.

Implementation of novel boolean logic gates for IMPLICATION and XOR functions using riboregulators.

To date, several different types of synthetic genetic switches, including riboregulators, riboswitches, and toehold switches, have been developed to construct AND, OR, NOT, NAND, NOR, and NOT IMPLICATION (NIMP) gates. The logic gate can integrate multiple input signals following a set of algorithms and generate a response only if strictly defined conditions are met. However, there are still some logic gates that have not been implemented but are necessary to build complex genetic circuits. Here, based on the toehold switches and three-way-junction (3WJ) repressors, we designed two novel biological Boolean logic gates of IMPLICATION (IMP) and XOR. Subsequently, the outputs of these two logic gates were characterized by fluorescence analysis, indicating that they can achieve the truth tables of logical gates. Furthermore, the fluorescence intensity under the logical TRUE condition was significantly higher than under the logical FALSE condition, suggesting the high dynamic range of the ON/OFF ratios. Because of the programmability of synthetic RNA switches, the constructed RNA logic gates could serve as elementary units to build a versatile and powerful platform for translational regulation and RNA-based biological computation.

Fixed-dose administration and pharmacokinetically guided adjustment of busulfan dose for patients undergoing hematopoietic stem cell transplantation: a meta-analysis and cost-effectiveness analysis.

This study aims to evaluate the efficacy, safety, and long-term cost-effectiveness of fixed-dose busulfan (Bu) administration and pharmacokinetically (PK) guided adjustment of Bu dose for patients who underwent hematopoietic stem cell transplantation. The efficacy and safety of both dosing strategies were compared using a systematic review and meta-analysis. A Markov model was used in estimating relevant cost and health outcomes from the perspective of the health system. The primary outcomes of interest were lifetime cost, quality adjusted life-years (QALYs) gained, and incremental cost-effectiveness ratio (ICER) in dollar per QALY gained. Results showed that progression-free survival and overall survival in the PK-guided group were higher than that in the fixed-dose group, and the PK-guided group was associated with low non-relapse mortality and relapse rate. In contrast to safety, the incidence of acute graft-versus-host disease (GVHD) was the same in the two groups (P > 0.05). Cost-effectiveness analysis showed that the QALY of the PK-guided group (12.8135 QALYs and $582,475.07) increased by 2.0609 relative to that in the fixed-dose group (10.7526 QALYs and $562,833.20), and the ICER was $9530.72/QALY. One-way and probability sensitivity analyses confirmed the reliability of the results. In conclusion, the PK-guided approach has higher efficacy and is safer.

Systematic review and cost-effectiveness of bosentan and sildenafil as therapeutic drugs for pediatric pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease in children, with significant mortality. Because of the limited research on pediatric PAH, first, systematic review of related drugs is conducted, and then economic evaluation of PAH drug treatment programs is conducted, which to provide a reference for the choice of more cost-effective treatment options. METHODS: The search includes electronic databases such as Pubmed, ScienceDirect, and Embase. Through inclusion and exclusion criteria, screen high-quality randomized controlled trials. We used TreeAge Pro 2011 software to construct the markov model, that to simulate the total medical cost and quality-adjusted life years (QALYs), and to calculate the incremental cost-effectiveness ratio. Sensitivity analysis of transfer probability, utility, and cost was carried out. RESULTS: Incorporate two studies that meet the criteria, one compared the therapeutic effects of bosentan and placebo on pediatric PAH, the other compared therapeutic effects of sildenafil and placebo on pediatric PAH, both articles were of good quality. Compared with the sildenafil group (3.38QALYs and $161,120.14), the QALY of the bosentan treatment group (3.33QALYs and $257,411.29) was reduced by 0.05, and the cost increased by $96,291.15. The estimated improvement to quality of life and reduced costs result in an estimate of economic dominance for sildenafil over bosentan. This dominant result persisted probabilistic analyses. CONCLUSIONS: Based on this model, a more cost-effective treatment drug for PAH in children is sildenafil.

Correction: Technology-Based Interventions in Oral Anticoagulation Management: Meta-Analysis of Randomized Controlled Trials.

[This corrects the article DOI: 10.2196/18386.].

Technology-Based Interventions in Oral Anticoagulation Management: Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: An increasing number of patients have received prophylactic or therapeutic oral anticoagulants (OACs) for thromboembolic complications of diseases. The use of OACs is associated with both clinical benefits and risks. Considering the challenges imposed by this class of drugs, as well as the enormous progress made in portable device technology, it is possible that technology-based interventions may improve clinical benefits for patients and optimize anticoagulation management. OBJECTIVE: This study was designed to comprehensively evaluate the role of technology-based interventions in the management of OACs. METHODS: We searched 6 databases-PubMed, EMBASE, Cochrane, Cumulative Index to Nursing and Allied Health Literature, Scopus, and PsycINFO-to retrieve relevant studies published as of November 1, 2019, to evaluate the effect of technology-based interventions on oral anticoagulation management. RevMan (version 5.3; Cochrane) software was used to evaluate and analyze clinical outcomes. The methodological quality of studies was assessed by the Cochrane risk of bias tool. RESULTS: A total of 15 randomized controlled trials (RCTs) were selected for analysis. They reported data for 2218 patients (1110 patients in the intervention groups and 1108 patients in the control groups). A meta-analysis was performed on the effectiveness and safety data reported in the RCTs. Technology-based interventions significantly improved the effectiveness of oral anticoagulation management (mean difference [MD]=6.07; 95% CI 0.84-11.30; I2=72%; P=.02). The safety of oral anticoagulation management was also improved, but the results were not statistically significant. Bleeding events were reduced (major bleeding events MD=1.02; 95% CI 0.78-1.32; I2=0%; P=.90; minor bleeding events MD=1.06, 95% CI 0.77-1.44; I2=41%; P=.73) and thromboembolism events were reduced (MD=0.71; 95% CI 0.49-1.01; I2=0%; P=.06). In general, patients were more satisfied with technology-based interventions, which could also improve their knowledge of anticoagulation management, improve their quality of life, and reduce mortality and hospitalization events. CONCLUSIONS: Using technology to manage OACs can improve the effectiveness and safety of oral anticoagulation management, result in higher patient satisfaction, and allow greater understanding of anticoagulation.

Economic Evaluations of Immune Checkpoint Inhibitors for Patients with Non-Small Cell Lung Cancer: A Systematic Review.

OBJECTIVE: This review aimed to assess the quality of available evidence on the economic evaluations of immune checkpoint inhibitors in patients with non-small cell lung cancer (NSCLC) and provide evidence to improve the efficiency of healthcare resources. MATERIALS AND METHODS: Literature search was performed using some electronic databases (PubMed, Embase and Cochrane Central Register of Controlled Trials). Final search was performed in December 2019. Study characteristics and results were recorded and compared. The quality of the studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklists. We did not elaborate the restrictions on the target population. We included patients with squamous or non-squamous NSCLC and metastatic or advanced cancer. RESULTS: Of 98 papers considered, 21 were chosen for this review. Most of them are cost-effectiveness analysis. Comparative regimens consisted of either immune checkpoint inhibitor monotherapy, immune checkpoint inhibitor plus chemotherapy, or chemotherapy alone. Fourteen, four, and three studies were about pembrolizumab, nivolumab, and atezolizumab, respectively. The methods mostly used in these studies were modeling and sensitivity analysis. All studies used quality-adjusted life year (QALY) and life years (LY) as outcomes. Most studies were conducted in high-income countries. Based on the willingness to pay threshold, atezolizumab, and pembrolizumab were found to be cost-effective in one and 10 studies, respectively. None of the studies concluded that nivolumab was cost-effective. For quality assessment, all studies fulfilled more than 50% of the CHEERS checklist. CONCLUSION: The included studies indicated that pembrolizumab regimens are cost-effective as first-line treatment for patients with NSCLC in developed countries. Nivolumab and atezolizumab are likely to be cost-effective as second-line treatment but not as first-line treatment.

Perfect optical absorbers in a wide range of incidence by photonic heterostructures containing layered hyperbolic metamaterials.

We theoretically and experimentally investigate the wide-angle perfect absorptance in a photonic heterostructure composed of a metal film and a truncated photonic crystal (PC) with layered hyperbolic metamaterials (HMMs) in the near ultraviolet and visible regions. The wide-angle perfect optical absorption depends on the dispersionless Tamm plasmon polarition (TPP) under TM polarization, which originates from reflection phase compensation condition between the metal and the truncated PC with HMMs. Our experimental results show nearly perfect absorptance over 0.91 in an angle range of 0-45 degree, which facilitates the design of perfect optical absorbers working in a wide angle range.