A mixed blessing for liver transplantation patients - Rapamycin.

BACKGROUND: Liver transplantation (LT) is an effective treatment option for end-stage liver disease. Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, are widely used post LT. DATA SOURCES: In this review, we focused on the anti-cancer activities and metabolic side effects of rapamycin after LT. The literature available on PubMed for the period of January 1999-September 2022 was reviewed. The key words were rapamycin, sirolimus, liver transplantation, hepatocellular carcinoma, diabetes, and lipid metabolism disorder. RESULTS: Rapamycin has shown excellent effects and is safer than other immunosuppressive regimens. It has exhibited excellent anti-cancer activity and has the potential in preventing hepatocellular carcinoma (HCC) recurrence post LT. Rapamycin is closely related to two long-term complications after LT, diabetes and lipid metabolism disorders. CONCLUSIONS: Rapamycin prevents HCC recurrence post LT in some patients, but it also induces metabolic disorders. Reasonable use of rapamycin benefits the liver recipients.

Prognostic implication of early posttransplant hypercholesterolemia in liver transplantation for patients with hepatocellular carcinoma.

BACKGROUND: Hyperlipidemia is a common complication after liver transplantation (LT) and develops mostly in the early posttransplant period. Recently, some studies have reported a positive correlation between hyperlipidemia and favorable prognosis in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. This study aimed to evaluate the possibility of predicting prognosis in HCC patients receiving LT by early posttransplant dyslipidemia. METHODS: From January 2015 to December 2017, a total of 806 HCC patients from China Liver Transplant Registry database were retrospectively enrolled. The prognostic relevance of early posttransplant hypertriglyceridemia or hypercholesterolemia was examined using survival analysis, and subgroup analysis was implemented based on LT criteria. RESULTS: Early posttransplant hypercholesterolemia (EPHC) was independently inversely associated with the risk of recurrence [hazard ratio (HR) = 0.630; P = 0.022], but was not significantly correlated with the mortality. However, early posttransplant hypertriglyceridemia was not related to prognosis. Intriguingly, with further classification, we found that borderline EPHC (B-EPHC), instead of significant EPHC, was a predictor of lower risk for both recurrence (HR = 0.504; P = 0.006) and mortality (HR = 0.511; P = 0.023). Compared with non-EPHC patients, B-EPHC patients achieved significantly superior 1-year and 3-year tumor-free survival (89.6% and 83.7% vs. 83.8% and 72.7% respectively; P = 0.023), and 1-year and 3-year overall survival (95.8% and 84.8% vs. 94.6% and 77.6% respectively; P = 0.039). In the subgroup analysis, B-EPHC remained an independent predictor of better prognosis in patients beyond Milan criteria and those within Hangzhou criteria; whereas there was no significant relationship between B-EPHC and prognosis in patients within Milan criteria and those beyond Hangzhou criteria. More interestingly, patients beyond Milan criteria but within Hangzhou criteria were identified as the crucial subpopulation who benefited from B-EPHC (recurrence HR = 0.306, P = 0.011; mortality HR = 0.325, P = 0.031). CONCLUSIONS: B-EPHC could assist transplant teams in dynamically evaluating prognosis after LT for HCC as a postoperative non-oncological biomarker, especially in patients beyond Milan criteria but within Hangzhou criteria.

Key factors and potential drug combinations of nonalcoholic steatohepatitis: Bioinformatic analysis and experimental validation-based study.

BACKGROUND: Nonalcoholic fatty liver disease and its advanced stage, nonalcoholic steatohepatitis (NASH), are the major cause of hepatocellular carcinoma (HCC) and other end-stage liver disease. However, the potential mechanism and therapeutic strategies have not been clarified. This study aimed to identify potential roles of miRNA/mRNA axis in the pathogenesis and drug combinations in the treatment of NASH. METHODS: Microarray GSE59045 and GSE48452 were downloaded from the Gene Expression Omnibus and analyzed using R. Then we obtained differentially expressed genes (DE-genes). DAVID database was used for Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis. Protein-protein interaction (PPI) networks were used for the identification of hub genes. We found upstream regulators of hub genes using miRTarBase. The expression and correlation of key miRNA and its targets were detected by qPCR. Drug Pair Seeker was employed to predict drug combinations against NASH. The expression of miRNA and hub genes in HCC was identified in the Cancer Genome Atlas database and Human Protein Atlas database. RESULTS: Ninety-four DE-genes were accessed. GO and KEGG analysis showed that these predicted genes were linked to lipid metabolism. Eleven genes were identified as hub genes in PPI networks, and they were highly expressed in cells with vigorous lipid metabolism. hsa-miR-335-5p was the upstream regulator of 9 genes in the 11 hub genes, and it was identified as a key miRNA. The hub genes were highly expressed in NASH models, while hsa-miR-335-5p was lowly expressed. The correlation of miRNA-mRNA was established by qPCR. Functional verification indicated that hsa-miR-335-5p had inhibitory effect on the development of NASH. Finally, drug combinations were predicted and the expression of miRNA and hub genes in HCC was identified. CONCLUSIONS: In the study, potential miRNA-mRNA pathways related to NASH were identified. Targeting these pathways may be novel strategies against NASH.

Multikinase Inhibitor CT-707 Targets Liver Cancer by Interrupting the Hypoxia-Activated IGF-1R-YAP Axis.

Given that Yes-associated protein (YAP) signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling. CT-707 arrested tumor growth in HepG2, Bel-7402, and HCC patient-derived xenografts. Mechanistically, the inhibitory activity of CT-707 on YAP signaling was due to the interruption of hypoxia-activated IGF1R. Overall, these findings not only identify CT-707 as a promising hypoxia-targeting agent against HCC, but they also unveil IGF1R as a new modulator specifically regulating hypoxia-activated YAP signaling.Significance: CT-707 may represent a novel clinical approach for patients with HCC suffering poor drug response due to intratumor hypoxia. Cancer Res; 78(14); 3995-4006. ©2018 AACR.

[Preparation and luminescent properties of light scattering fluorescent resin].

With the methods of compound-melting and high-temperature molding, PC/YAG:Ce fluorescent resin pieces were prepared. The transmittance of the prepared PC/YAG:Ce fluorescent resin in 500~800 nm reaches approximately 65% (0.71 mm thick, double sides polished). The fluorescent resin was characterized by XRD, SEM and PL. The X-ray diffraction (XRD) patterns demonstrated that the fluorescent resin was pure Y3Al5O12 phase. The scanning electron microscopy (SEM) images showed that YAG phosphor was distributed evenly in the fluorescent resin. The excitation spectra had a weak peak at 342 nm and a strong band at 448 nm. The broad emission peaks at about 532 nm can be attributed to 5d-->4f transition of Ce3+ ions. Decay curves for the fluorescence of PC/YAG:Ce fluorescent resin show that the lifetime of the fluorescent resin was 61.5 ns. The luminous efficacy of the white LED packaged by the fluorescent resin and blue LED chip was 81.12 lm · W(-1) at 100 mA. All results above of PC/YAG:Ce fluorescent resin indicate a promising fluorescent material for white LEDs.

[Preparation and optical properties of MgAl2O4/Ce:YAG transparent ceramics].

High-purity ultrafine MgAl2O4 powder was synthesized by metal-alkoxide method and calcining for 2-4 h. And then MgAl2O4/Ce:YAG transparent ceramics were fabricated by hot-pressed sintering and hot isostatic pressed sintering technique with YAG:Ce powder and MgAl2O4 powder. The transparent ceramics were characterized by XRD, SEM, EDS and fluorescence spectrometer, respectively. The results show that the crystal phase of the transparent ceramic was composed of MgAl2O4 and YAG,and the YAG phase dispersed well in the matrix of MgAl2O4. The excitation spectra had a weak band at 345 nm and a strong band at 475 nm. The broad emission peaks at about 533 nm were attributed to 5d-->4f transition of Ce3+ ions. Decay curves for the fluorescence of MgAl2O4/Ce:YAG transparent ceramic test show that the lifetime of the Ce:YAG glass ceramic was 59.74 ns. All results show that MgAl2O4/Ce:YAG transparent ceramic may be a promising fluorescent material for white LED applications.

Performance enhancement of blue light-emitting diodes without an electron-blocking layer by using special designed p-type doped InGaN barriers.

In this study, the characteristics of the nitride-based blue light-emitting diode (LED) without an electron-blocking layer (EBL) are analyzed numerically. The emission spectra, carrier concentrations in the quantum wells (QWs), energy band diagrams, electrostatic fields, and internal quantum efficiency (IQE) are investigated. The simulation results indicate that the LED without an EBL has a better hole-injection efficiency and smaller electrostatic fields in its active region over the conventional LED with an AlGaN EBL. The simulation results also show that the LED without an EBL has severe efficiency droop. However, when the special designed p-type doped InGaN QW barriers are used, the efficiency droop is markedly improved and the electroluminescence (EL) emission intensity is greatly enhanced which is due to the improvement of the hole uniformity in the active region and small electron leakage.

[The influential factors of MOCVD growth of InP in opals].

The key problem of fabricating the 3-D InP inverse opal photonic crystal is to increase the loading of InP in opals. In the present paper, low-pressure metal-organic chemical-vapour deposition (MOCVD) was used to infill the voids within synthetic opals with InP. The morphologies and optical properties of SiO2-InP photonic crystal were characterized by scanning electron microscopy and ultraviolet-visible spectrophotometry (UV-Vis). Several series of experiments were carried out in order to analyze the factors that influence the loading of InP in opals and determine the optimal InP growth conditions. The results of optical experiments are in good agreement with those derived from the theoretical considerations: By increasing the extent of InP infilling within the voids, the extent of refractive index contrast between the silica spheres and the void as well as the extent of natural optical properties change of the photonic crystal were increased. Cycle growth, low-pressure growth, and using the match substrate and the same configuration character between SiOi and InP are beneficial to increaseing the extent of InP infilling within the opal voids. The process has been optimized to achieve SiO2-InP photonic crystal with higher loading of InP. The study provides a scientific basis for manufacturing three-dimensional InP inverse opal photonic crystals.