Activation/Inactivation of Anticancer Drugs by CYP3A4: Influencing Factors for Personalized Cancer Therapy.

Cytochrome P450 3A4 (CYP3A4), one of the most important members of the cytochrome P450 subfamily, is a crucial catalyst in the metabolism of numerous drugs. As it catalyzes numerous processes for drug activation or inactivation, the pharmacological activities and clinical outcomes of anticancer drugs metabolized by CYP3A4 are highly dependent on the enzyme's activity and expression. Due to the complexity of tumor microenvironments and various influencing factors observed in human in vitro models and clinical studies, the pharmacokinetics of most anticancer drugs are influenced by the extent of induction or inhibition of CYP3A4-mediated metabolism, and these details are not fully recognized and highlighted. Therefore, this interindividual variability due to genetic and nongenetic factors, together with the narrow therapeutic index of most anticancer drugs, contributes to their unique set of exposures and responses, which have important implications for achieving the expected efficacy and minimizing adverse events of chemotherapy for cancer in individuals. To elucidate the mechanisms of CYP3A4-mediated activation/inactivation of anticancer drugs associated with personalized therapy, this review focuses on the underlying determinants that contribute to differences in CYP3A4 metabolic activity and provides a comprehensive and valuable overview of the significance of these factors, which differs from current considerations for dosing regimens in cancer therapy. We also discuss knowledge gaps, challenges, and opportunities to explore optimal dosing regimens for drug metabolic activation/inactivation in individual patients, with particular emphasis on pooling and analyzing clinical information that affects CYP3A4 activity. SIGNIFICANCE STATEMENT: This review focuses on anticancer drugs that are activated/deactivated by CYP3A4 and highlights outstanding factors affecting the interindividual variability of CYP3A4 activity in order to gain a detailed understanding of CYP3A4-mediated drug metabolism mechanisms. A systematic analysis of available information on the underlying genetic and nongenetic determinants leading to variation in CYP3A4 metabolic activity to predict therapeutic response to drug exposure, maximize efficacy, and avoid unpredictable adverse events has clinical implications for the identification and development of CYP3A4-targeted cancer therapeutics.

Activation of CYP3A by Accelerated Blood Clearance Phenomenon Potentiates the Hepatocellular Carcinoma-Targeting Therapeutic Effects of PEGylated Anticancer Prodrug Liposomes.

Reduced enzyme activity in hepatocellular carcinoma (HCC) and poor targeting limit the application of enzyme-activating prodrugs, which is also detrimental to the effective treatment of HCC. Here, we investigated whether accelerated blood clearance (ABC) phenomenon occurs in HCC models following repeated injections of PEGylated liposomes (PEG-L), thus inducing prodrug accumulation and activation in the liver and exerting highly effective and low-toxicity therapeutic effects on HCC. First, PEGylated liposomal cyclophosphamide was prepared by solvent injection and characterized. Importantly, preinjection of PEG-L induced the ABC phenomenon and activation of CYP3A in both HCC rats and HCC mice by studying the effects of repeated injections of PEG-L on pharmacokinetics and tissue distribution. Next, the efficacy and toxicity of repeated injections of PEG-L in HCC mice were examined, and our data indicate that repeated injections are administered in a manner that significantly enhances the antitumor effect compared with controls, with little or no toxicity to other organs. To further reveal the pharmacokinetic mechanism of PEG-L repeated administration for the treatment of HCC, the protein expression of hepatic CYP3A and the concentration of cyclophosphamide in the liver and spleen of HCC mice by inhibiting CYP3A were analyzed. These results revealed that inducing CYP3A to accelerate the rapid conversion of prodrugs that accumulate significantly in the liver is a key mechanism for the treatment of HCC with repeated injections of PEG-L. Collectively, this work taps into the application potential of the ABC phenomenon and provides new insights into the clinical application of PEGylated nanoformulations. SIGNIFICANCE STATEMENT: This study revealed that repeated injections of PEGylated liposomes could induce the accelerated blood clearance (ABC) phenomenon characterized by hepatic accumulation and CYP3A activation based on hepatocellular carcinoma (HCC) rats and HCC mice. Furthermore, it was verified that induction of the ABC phenomenon dependent on hepatic accumulation and CYP3A activation could enhance the antihepatocellular carcinoma effects of PEGylated anticancer prodrugs in HCC mice. This elucidated the relevant pharmacokinetic mechanisms and unearthed new clues for solving the clinical application of PEGylated nanoparticles.

Identification of CBPA as a New Inhibitor of PD-1/PD-L1 Interaction.

Targeting of the PD-1/PD-L1 immunologic checkpoint is believed to have provided a real breakthrough in the field of cancer therapy in recent years. Due to the intrinsic limitations of antibodies, the discovery of small-molecule inhibitors blocking PD-1/PD-L1 interaction has gradually opened valuable new avenues in the past decades. In an effort to discover new PD-L1 small molecular inhibitors, we carried out a structure-based virtual screening strategy to rapidly identify the candidate compounds. Ultimately, CBPA was identified as a PD-L1 inhibitor with a KD value at the micromolar level. It exhibited effective PD-1/PD-L1 blocking activity and T-cell-reinvigoration potency in cell-based assays. CBPA could dose-dependently elevate secretion levels of IFN-γ and TNF-α in primary CD4+ T cells in vitro. Notably, CBPA exhibited significant in vivo antitumor efficacy in two different mouse tumor models (a MC38 colon adenocarcinoma model and a melanoma B16F10 tumor model) without the induction of observable liver or renal toxicity. Moreover, analyses of the CBPA-treated mice further showed remarkably increased levels of tumor-infiltrating CD4+ and CD8+ T cells and cytokine secretion in the tumor microenvironment. A molecular docking study suggested that CBPA embedded relatively well into the hydrophobic cleft formed by dimeric PD-L1, occluding the PD-1 interaction surface of PD-L1. This study suggests that CBPA could work as a hit compound for the further design of potent inhibitors targeting the PD-1/PD-L1 pathway in cancer immunotherapy.

[Preparation of vitexin albumin nanoparticles and its pharmacokinetic study].

This study aims to prepare vitexin albumin nanoparticles(VT-BSA-NPs) to alleviate the low bioavailability of vitexin(VT) in vivo due to its poor water solubility. VT micro powders were prepared by the antisolvent crystallization method, and the morphology, size, and physicochemical properties of VT micro powders were studied. The results showed that the VT micro powder had a particle size of(187.13±7.15) nm, an approximate spherical morphology, and a uniform size distribution. Compared with VT, the chemical structure of VT micro powders has not changed. VT-BSA-NPs were prepared from VT micro powders by desolvation-crosslinking curing method. The preparation process was screened by single factor test and orthogonal test, and the quality evaluation of the optimal prescription particle size, PDI, Zeta potential, EE, and morphology was performed. The results showed that the average particle size of VT-BSA-NPs was(124.33±0.47) nm; the PDI was 0.184±0.012; the Zeta potential was(-48.83±2.20) mV, and the encapsulation rate was 83.43%±0.39%, all of which met the formulation-related requirements. The morphological results showed that the VT-BSA-NPs were approximately spherical in appearance, regular in shape, and without adhesion on the surface. In vitro release results showed a significantly reduced release rate of VT-BSA-NPs compared with VT, indicating a good sustained release effect. LC-MS/MS was used to establish an analytical method for in vivo analysis of VT and study the plasma pharmacokinetics of VT-BSA-NPs in rats. The results showed that the specificity of the analytical method was good, and the extraction recovery was more than 90%. Compared with VT and VT micro powders, VT-BSA-NPs could significantly increase AUC, MRT, and t_(1/2), which was beneficial to improve the bioavailability of VT.

Effect of liver steatosis on liver stiffness measurement in chronic hepatitis B patients with normal serum alanine aminotransferase levels: A multicentre cohort study.

Liver steatosis is becoming increasingly common in patients with chronic hepatitis B (CHB), and its effect on liver stiffness measurement (LSM), as assessed by transient elastography, remains controversial. Seven hundred and fifty-five patients with CHB and normal serum alanine aminotransferase levels, who underwent vibration-controlled transient elastography and liver biopsy, were included in the study. We examined whether the histological degree of liver steatosis affects the accuracy of transient elastography-assessed LSM in these patients. Among the 755 CHB patients included in the study, 286 (37.9%) had liver steatosis, of whom 156 had grade S1, 74 had grade S2, and 56 had grade S3 on histology. Presence of liver steatosis was independently associated with greater body mass index (BMI, adjusted-odds ratio [OR] = 5.786, 95% CI: 3.998-8.373, p = 0.018), and higher serum total cholesterol (adjusted-OR = 7.944, 95% CI: 4.731-13.339, p < 0.001) and triglyceride levels (adjusted-OR = 2.777, 95% CI: 2.050-3.761, p < 0.001). There was no significant association between liver steatosis and fibrosis stage (OR = 1.016, 95% CI: 0.905-1.140, p = 0.790). Age (B-coefficient = 0.020, 95% CI: 0.001-0.040, p = 0.044), BMI (B-coefficient = 0.060, 95% CI: 0.011-0.127, p = 0.019), serum gamma-glutamyl-transpeptidase (GGT, B-coefficient = 0.015, 95% CI: 0.001-0.029, p = 0.032), positivity for HBeAg (B-coefficient = -0.816, 95% CI: -1.568 to -0.064, p = 0.034), as well as liver fibrosis stage (B-coefficient = 2.796, 95% CI: 2.501-3.090, p < 0.001), and inflammation activity grade (B-coefficient = 0.648, 95% CI: 0.162-1.135, p = 0.009) were all independently associated with higher LSM, while no significant association was found between degree of liver steatosis and LSM. Among patients with the same histological fibrosis stage, LSM values did not show any significant difference among patients with absent, mild, moderate or severe steatosis. We conclude that liver steatosis has no significant effect on transient elastography-measured LSM in CHB patients with normal serum alanine aminotransferase levels.

Autophagy responsive intra-intercellular delivery nanoparticles for effective deep solid tumor penetration.

Deep tumor cells (cells in the center of solid tumors) play a crucial role in drug tolerance, metastasis, recurrence and microenvironment immune suppression. However, their deep location endows them with an untouched abdomen and makes them refractory to current treatments. Herein, we exploited the characteristic of higher autophagy in deep tumor cells than in superficial tumor cells and designed autophagy-responsive multifunctional nanoparticles (PGN) to enhance drug accumulation in deep tumor cells. PGNs were prepared by densely coating poly (lactic-co-glycolic acid) (PLGA) with cationic autophagy-responsive cell-penetrating peptide (GR9) and anionic 2,3-dimethylmaleic anhydride (DMA)-modified DSPE-PEG. The suitable nanoparticle size (122.4 nm) and charge-neutral surface (0.21 mV) of the NPs enabled long blood circulation. The hydrolysis of surface-anchored anionic DMA in the acidic microenvironment led to the exposure of the GR9 peptide and enhance tumor penetration. Once the PGN arrived in deep tumor cells with strong autophagy, GR9 was cut off by an autophagy shear enzyme, and the nanoparticles remained in the cells to undergo degradation. Furthermore, we prepared docetaxel (DTX) and chloroquine (CQ) loaded d-PGN. CQ inhibits autophagosome fusion with lysosomes, resulting in autophagosome accumulation, which further enhances the sensitivity of d-PGN to autophagy and their deep tumor retention. In vivo experiments showed that drug-loaded d-PGN achieved excellent antitumor efficacy with a peak inhibition rate of 82.1%. In conclusion, autophagy-responsive multifunctional nanoparticles provide a novel potential strategy for solid tumor treatment.

UV-C treatment inhibits browning, inactivates Pseudomonas tolaasii and reduces associated chemical and enzymatic changes of button mushrooms.

BACKGROUND: Button mushrooms with completely white appearance are popular with consumers. However, button mushrooms are susceptible to infection with Pseudomonas tolaasii, which results in browning. This study evaluates the effects of ultraviolet-C (UV-C) treatment on the inactivation of P. tolaasii in vitro and in vivo and on the physiological and chemical changes of button mushrooms during storage for 21 days at 4 °C. RESULTS: UV-C doses of 0.5 to 9.0 kJ m-2 resulted in 3.91-6.26 log CFU mL-1 reduction of P. tolaasii populations in vitro, and UV-C treatment reduced P. tolaasii populations inoculated on mushroom cap surfaces and browning severity. Moreover, P. tolaasii increased polyphenol oxidase (PPO) activity, and decreased phenylalanine ammonia-lyase (PAL) activity, the accumulation of phenolics and contents of brown melanin precursors, including γ-l-glutaminyl-4-hydroxybenzene (GHB), γ-l-glutaminyl-3,4-dihydroxybenzene (GDHB), and tyrosine in button mushrooms. UV-C treatment was found to reduce the negative changes due to P. tolaasii infection. CONCLUSION: These results indicated that the application of UV-C treatment inhibited browning, inactivated P. tolaasii and reduced P. tolaasii - associated chemical and enzymatic changes of button mushrooms. © 2021 Society of Chemical Industry.

OSchol: an online consensus survival web server for cholangiocarcinoma prognosis analysis.

BACKGROUND: As the most common biliary ducts, cholangiocarcinoma (CHOL) is an aggressive malignancy with complex pathological context, high mortality and relapse rate. The current therapy of CHOL is mainly performed with surgery followed by chemoradiotherapy. Due to the high metastasis and relapse rate of CHOL, the prognosis of CHOL is still poor, and the molecular prognostic system is to be constructed. METHODS: In this study, we have established an online prognostic analysis web server named OSchol to evaluate the correlation between candidate genes and survival for CHOL. RESULTS: The prognostic values of previous published biomarkers in OSchol, including ITIH4, PTEN and DACH1, have been validated by OSchol. In addition, we have identified novel potential prognostic biomarker for CHOL using OSchol, that E2F1 has significant prognostic ability in OSchol (both TCGA and GSE107943 cohorts). CONCLUSION: Our study provides a platform for researchers and clinicians to screen, develop and validate their genes of interest to be potential prognostic biomarkers for CHOL and may also help guide the targeted therapies for CHOL.

OSuvm: An interactive online consensus survival tool for uveal melanoma prognosis analysis.

Uveal melanoma (UM) is a rare, aggressive, but the most frequent primary intraocular malignancy in adults, and up to 50% of patients develop a tendency of liver metastases. Great efforts have been made to develop biomarkers that facilitate diagnosis, prediction of the risk, and response to treatment of UM. However, a biologically informative and highly accurate gold standard system for prognostic evaluation of UM remains to be established. To facilitate assessment of the prognosis of UM patients, we established a user-friendly Online consensus Survival tool for uveal melanoma, named OSuvm, by which users can easily estimate the prognostic values of genes of interest by the Kaplan-Meier survival plot with hazard ratio and log-rank test. OSuvm comprises four independent cohorts including 229 patients with both gene expression profiles and relevant clinical follow-up information, and it has shown great performance in evaluating the prognostic roles of previously reported biomarkers. Using OSuvm enables researchers and clinicians to rapidly and conveniently explore the prognostic value of genes of interest and develop new potential molecular biomarkers for UM. OSuvm can be accessed at http://bioinfo.henu.edu.cn/UVM/UVMList.jsp.

Meta-analysis: Resistance Training Improves Cognition in Mild Cognitive Impairment.

This study investigated the benefits of resistance training on cognition in patients with mild cognitive impairment. We searched the PubMed, Embase and Cochrane Library databases, and seven randomized controlled trials were reviewed. We evaluated the risk of bias using the Cochrane Collaboration's bias assessment tool. Standard mean differences with 95% confidence intervals were calculated for statistical analysis. This meta-analysis assessed three variables: general cognitive function, executive function and working memory. The results indicate that general cognitive function improved significantly (standardized mean difference: 0.53, P=0.04), and further subgroup analyses on frequency and duration per session showed that the subgroups 'twice a week' (P=0.01) and 'duration per session >60 min' (P=0.0006) exhibited better performance than the subgroups 'three time a week' (P=0.47) and 'duration per session <60 min' (P=0.53). Additionally, a moderate effect size was found in executive function (standardized mean difference: 0.50, P=0.0003), and there was non-significant effect in working memory (P=0.14). In summary, resistance training may mitigate mild cognitive impairment by improving cognition. Larger-scale studies are recommended to demonstrate the relationship between resistance training and cognition in mild cognitive impairment.

Activation of Pregnane X Receptor-Cytochrome P450s Axis: A Possible Reason for the Enhanced Accelerated Blood Clearance Phenomenon of PEGylated Liposomes In Vivo.

Recently, we reported that repeated injection of PEGylated liposomes (PEG-L) at certain intervals to the same rat lead to the disappearance of their long-circulation properties, referred to as the "accelerated blood clearance (ABC) phenomenon". Evidence from our recent studies suggested that cytochrome P450s (P450s) contribute to induction of the ABC phenomenon, a possibility that had been previously ignored. However, few details are known about the mechanism for induction of P450s. The present study was undertaken to investigate the roles in the ABC phenomenon of pregnane X receptor (PXR) and constitutive androstane receptor (CAR), the major upstream transcriptional regulators of the P450 genes, including CYP3A1, CYP2C6, and CYP1A2. The results demonstrated that expression of rat PXR and CAR was significantly increased in the ABC phenomenon and was accompanied by elevated CYP3A1, CYP2C6, and CYP1A2 levels. Further findings revealed that PXR but not CAR protein was substantially upregulated in the hepatocyte nucleus, together with marked nuclear colocalization of the PXR-retinoid X receptor alpha (RXRα) transcriptionally active heterodimer, indicating that nuclear translocation of PXR was induced in the ABC phenomenon, whereas nuclear translocation of CAR was not observed. Notably, pretreatment with the specific PXR inducer dexamethasone significantly induced accelerated systemic clearance of the subsequent injection of PEG-L, associating with increased nuclear colocalization of PXR-RXRα These results revealed that the induction of P450s in the ABC phenomenon may be attributable largely to the activation of PXR induced by sequential injections of PEG-L, thus confirming the crucial involvement of the PXR-P450s axis in promoting the ABC phenomenon. SIGNIFICANCE STATEMENT: The results of this study revealed that the induction of P450s in the ABC phenomenon may be largely attributable to the activation of PXR induced by sequential injections of PEG-L, thus confirming the crucial involvement of the PXR-P450s axis in promoting the ABC phenomenon. The data may help to extend our insights into 1) the role of P450s, which are regulated by the liver-enriched nuclear receptor PXR, in the ABC phenomenon, and 2) the therapeutic potential of targeting the PXR-P450 axis for reducing the magnitude of the ABC phenomenon in clinical practice.

Induction of Cytochrome P450 Involved in the Accelerated Blood Clearance Phenomenon Induced by PEGylated Liposomes In Vivo.

Polyethylene glycol (PEG) is recognized as an attractive excipient to modify liposomes due to its extended-circulation properties. Nevertheless, intravenous injection of polyethylene glycol-coated liposomes (PEG-L) usually triggers a rapid systemic clearance of the subsequent dose from blood circulation, which is referred to as an accelerated blood clearance (ABC) phenomenon. Therefore, since the induction of cytochrome P450 (P450) activity may lead to enhanced drug clearance, it motivated us to investigate the possibility of P450 involvement in the ABC phenomenon. In this study, polyethylene glycol-coated liposomal docetaxel was prepared and used to evaluate the magnitude of the ABC phenomenon in rats induced by repeated injection of PEG-modified liposomes. Notably, the ABC phenomenon was observed when the time interval between two doses was from 1 to 7 days, and its magnitude reached the maximum level at 3 days before gradually decreasing the time. Meanwhile, increased activity of CYP3A1, CYP2C6, and CYP1A2 was detected when PEG-L was repeatedly injected in male rats at a 3-day interval. Consistently, the expression levels of hepatic CYP3A1, CYP2C6, and CYP1A2 were also significantly increased in the repeated injection groups and their levels were highest in the 3-day interval group. P450 selective inhibitors confirmed the inhibition of hepatic CYP3A1 was accompanied by an attenuated magnitude of the ABC phenomenon, which strongly suggests that P450s may be induced by repeated injection of PEG-L, thus favoring metabolic clearance of the second dose. Collectively, herein, for the first time we demonstrate that the contribution of P450s should not be ignored in the ABC phenomenon.

A modified DAW-22 compound F-B1 inhibits Bcr/Abl and induces apoptosis in chronic myelogenous leukemia cells.

The Bcr/Abl kinase is an oncogenic fusion protein that plays a central role in the pathogenesis of chronic myeloid leukemia (CML). Some small-molecule kinase inhibitors such as imatinib were developed in the treatment of CML; however, resistant to imatinib is an emerging problem of CML therapy. Hence, additional approaches or compounds targeting leukemogenic cells are required. F-B1 is a new compound obtained by modifying DAW-22, a natural sesquiterpenoid coumarin, which was isolated from traditional Chinese medicine Ferula ferulaeoides (Steud.) Korov. F-B1 was found to inhibit the growth of myelogenous leukemia cell lines, that is, K562 cells bearing wild-type Bcr/Abl and imatinib-resistant K562G cells. F-B1 potently down-regulated the mRNA and protein levels of Bcr/Abl, followed by suppression of the downstream molecules such as Akt, externally regulated kinases, and nuclear factor κB. In addition, F-B1 also induced cell apoptosis by impairing the balance between proapoptotic protein Bax and antiapoptotic proteins Bcl-2 and Bcl-XL and increased the activity of mitochondrial-dependent apoptosis in nude mouse xenografts. Experimental validation results together demonstrated that F-B1 can inhibit Bcr/Abl fusion proteins in K562 and K562G cells, implying that F-B1 might be a promising drug to treat CML, especially the imatinib-resistant CML.

A chimeric protein PTEN-L-p53 enters U251 cells to repress proliferation and invasion.

PTEN, a well-known tumor suppressor, dephosphorylates PIP3 and inhibits AKT activity. A translational variant of PTEN has been identified and termed PTEN-Long (PTEN-L). The additional 173 amino acids (PTEN-L leader) at the N-terminal constitute a potential signal peptide. Differing from canonical PTEN, PTEN-L is secreted into the extracellular fluid and re-enters recipient cells, playing the similar roles as PTEN in vivo and in vitro. This character confers the PTEN-L a therapeutic ability via directly protein delivering instead of traditional DNA and RNA vector options. In the present study, we employed PTEN-L leader to assemble a fusion protein, PTEN-L-p53, inosculated with the transcriptional regulator TP53, which is another powerful tumor suppressor. We overexpressed PTEN-L-p53 in HEK293T cells and detected it in both the cytoplasm and nucleus. Subsequently, we found that PTEN-L-p53 was secreted outside of the cells and detected in the culture media by immunoblotting. Furthermore, we demonstrated that PTEN-L-p53 freely entered the cells and suppressed the viability of U251cells (p53R273H, a cell line with p53 R273H-mutation). PTEN-L-p53 is composed of endogenous protein/peptide bearing low immunogenicity, and only the junction region between PTEN-L leader and p53 can act as a new immune epitope. Accordingly, this fusion protein can potentially be used as a therapeutic option for TP53-abnormality cancers.

Effect of palm oil consumption on plasma lipid concentrations related to cardiovascular disease: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: The precise association between palm oil consumption and lipid-related cardiovascular disease risk remains unclear. A systematic review was thus performed to assess whether palm oil consumption has a negative effect on plasma lipid-related cardiovascular disease marker levels. METHODS AND STUDY DESIGN: In June 2018, the electronic bibliographic databases PubMed, EMBASE (Ovid), the Cochrane Library (Ovid) and the Chinese National Knowledge Infrastructure were searched and a total of 11 eligible dietary intervention articles involving 961 volunteers were selected. Both random and fixed effect models were used to calculate pooled weighted mean differences (WMD). RESULTS: A total of 11 articles involving 547 participants met the inclusion criteria. The pooled analysis revealed that palm oil increased the concentration of high-density lipoprotein cholesterol (WMD: 0.15 mmol/L; p<0.00001). Palm oil consumption had no significant effects on blood total cholesterol (WMD: -0.01 mmol/L; p=0.82) and LDL-c (WMD: -0.05mmol/L; p=0.10) and triglyceride concentrations (WMD: 0.00 mmol/L; p=0.96), relative to the effects of unsaturated fatty acid consumption. Subgroup analyses revealed that palm oil has a beneficial effect on High-density lipoprotein cholesterol levels when more than 30% of total dietary energy was constituted by fat. CONCLUSIONS: This review revealed that palm oil does not induce increases in cardiovascular disease risk risk-related biomarkers relative to unsaturated fatty acids. Furthermore, larger-scale samples of human dietary intervention trials are required to increase the accuracy of meta-analyses.

Metasurface with multi-sized structure for multi-band coherent perfect absorption.

We demonstrate that multi-band coherent perfect absorption can be achieved at infrared frequencies by a metasurface in which four-sized columnar metal patches are separated by a dielectric layer in a unit cell. The absorption bandwidth is enhanced by three times compared with single-band absorption while high absorbance is maintained. The coherent perfect absorption is polarization-independent and can be independently modulated at each resonant frequency by tuning the phase difference of two coherent incident beams. Moreover, the resonant frequency is sensitive to the radius of the columnar patch, and thus a wide coherent perfect absorption frequency range can be obtained by adjusting the radius. Through optimizing the structural parameters, nearly perfect absorption at oblique incidence for both TE and TM polarizations are achieved. The optimized metasurface can be used as a beamsplitter at oblique incidence.

Dual-band tunable perfect metamaterial absorber based on graphene.

In this paper, a dual-band perfect metamaterial absorber based on graphene is proposed in the terahertz region. The metamaterial absorber consists of two sizes of graphene disks and a gold film separated by a dielectric spacer in a unit cell. The numerical results demonstrate that the dual-band perfect absorption can be achieved by the superposition of the specific absorption peaks induced by different disks. The resonance frequency can be tuned via controlling the graphene conductivity and the sizes of the disks. The metamaterial absorber can achieve selectively frequency tunability and it can tune each resonance independently. And the dual-band absorption will not be changed when the small disks move along the diagonal within the range of our research. In addition, owing to the symmetry of the structure, the absorber is insensitive to polarization and can keep a high absorptivity with a wide angle. The flexible and simple design makes it possible for our proposed single-layer graphene absorber to be applied in many metamaterial fields, such as sensing, detecting, and cloaking objects.

Programmed drug delivery system based on optimized "size decrease and hydrophilicity/hydrophobicity transformation" for enhanced hepatocellular carcinoma therapy of doxorubicin.

Requirements on drug delivery systems to surmount a complex series of pathophysiological barriers bear "cascading contradictions", especially size and hydrophilicity/hydrophobicity contradiction. Herein, a programmed drug delivery system (GNPs-Dox-Lac) based on optimized "size decrease and hydrophilicity/hydrophobicity transformation" was developed by combination the gelatin nanoparticle (GNPs) and prodrug Doxorubicin-Lactose (Dox-Lac). The results showed that GNPs-Dox-Lac (133.3 nm) were kinetically stable in blood circulation and inclined to accumulate at the tumor site. Then the degradation of the GNPs triggered by tumor extracellular matrix metalloproteinase-2 (MMP2) led to the release of prodrug Dox-Lac (Mw 898 Da) to facilitate the tumor tissue penetration and cellular uptake. Last, pH-responsive disassociation of Dox-Lac in tumor cells resulted in the free Dox (Mw 543 Da) release to induce toxicity. As expected, GNPs-Dox-Lac achieved superior tumor inhibition rate of 90.8% with low toxicity in vivo, suggesting its potential for enhanced hepatocellular carcinoma (HCC) therapy of doxorubicin in future.

Expression of PTEN-long mediated by CRISPR/Cas9 can repress U87 cell proliferation.

PTEN is a tumour suppressor that is frequently mutated in a variety of cancers. Hence, PTEN has significant potential as a therapeutic molecule. PTEN-long is an alternative translation variant, with an additional 173 amino acids added to the N-terminal of the canonical PTEN when CUG of the mRNA is utilized as the start codon. PTEN-long is secreted into serum and can re-enter cells throughout the body. One of the major barriers for gene therapy is to efficiently and specifically deliver DNA or RNA material to target cells. As an alternative approach, if a therapeutic protein can be directly delivered to target cell of interest, it should theoretically function well within the cells, particularly for genes that are deficiently expressed in vivo. Most therapeutic proteins are incapable of efficiently permeating the cell membrane. In this study, we have employed CRISPR/Cas9 gene editing tool combined with single-stranded template to edit CTG of PTEN-long to ATG in the genome. Two guide RNAs close to CTG site were found to have similar efficiency in driving PTEN-long expression. Furthermore, we detected PTEN-long expression in transfected whole-cell lysate and in concentrated culture media in Western blot. Interestingly, the culture media of PTEN-long expression can reduce Akt phosphorylation level and repress U87 cell proliferation compared to wild-type U87 or control media. Taken together, PTEN-long driven by CRISPR/Cas9 imports and exports cells and represses nearby cell proliferation, indicating the PTEN-long generated by CRISPR/Cas9 has potential to be an alternative strategy for PTEN gene therapy.

Cytokines Interleukin 4 (IL-4) and Interleukin 10 (IL-10) Gene Polymorphisms as Potential Host Susceptibility Factors in Virus-Induced Encephalitis.

BACKGROUND This study aimed to analyze and explore the relationship between the cytokines IL-4 and IL-10 in relation to gene polymorphism and their respective effects on the susceptibility to virus-induced encephalitis. MATERIAL AND METHODS From January 2012 to June 2013, 112 patients with virus-induced encephalitis (the case group and 109 healthy individuals (the control group) were recruited for the purposes of this study. The functional variations that IL-4 and IL-10 genes exhibit were detected through the use of a function analysis and selection tool for single-nucleotide polymorphisms (FASTSNP). The genotypes of IL-4 were rs2227283 and IL-4 rs2227288, and the genotypes of IL-10 were rs1800871 and IL-10 rs1800872. These genotypes were respectively assessed using direct sequencing. RESULTS IL-4 rs2227283 and IL-10 rs1800871 have no correlation in with risk of virus-induced encephalitis (both P>0.05) GA and AA genotypes were related to IL-4 rs2227288 and GT, while TT and GT + TT genotypes were related to IL-10 rs1800872. These were highlighted as being risk factors in virus-induced encephalitis (all P<0.05). However, the duration of fever, white blood cell (WBC) count, C-reactive protein (CRP), neutrophils, and lymphocytes and monocytes of virus-induced encephalitis patients with IL-4 rs2227288 and IL-10 rs1800872 all displayed significant differences (all P<0.05). Frequencies of GAGT and CAGT haplotypes were evaluated and deemed to be of statistical significance and subsequently were highlighted as being risk factors in virus-induced encephalitis (all P<0.05). CONCLUSIONS IL-4 rs2227288 and IL-10 rs1800872 may contribute to an increased risk for virus-induced encephalitis. Through use of direct sequencing, we showed that genotypes of IL-4 rs2227288 and IL-10 rs1800872 may have particular host susceptibility to virus-induced encephalitis.